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Abstract

Background: Seasonal influenza is responsible for a large disease and economic burden. Despite the expanding recommendation of influenza vaccination, influenza has continued to be a major public health concern in the United States (U.S.). To evaluate influenza prevention strategies it is important that policy makers have current estimates of the economic burden of influenza. Objective: To provide an updated estimate of the average annual economic burden of seasonal influenza in the U.S. population in the presence of vaccination efforts. Methods: We evaluated estimates of age-specific influenza-attributable outcomes (ill-non medically attended, office-based outpatient visit, emergency department visits, hospitalizations and death) and associated productivity loss. Health outcome rates were applied to the 2015 U.S. population and multiplied by the relevant estimated unit costs for each outcome. We evaluated both direct healthcare costs and indirect costs (absenteeism from paid employment) reporting results from both a healthcare system and societal perspective. Results were presented in five age groups (<5 years, 5-17 years, 18-49 years, 50-64 years and ≥65 years of age). Results: The estimated average annual total economic burden of influenza to the healthcare system and society was $11.2 billion ($6.3-$25.3 billion). Direct medical costs were estimated to be $3.2 billion ($1.5-$11.7 billion) and indirect costs $8.0 billion ($4.8-$13.6 billion). These total costs were based on the estimated average numbers of (1) ill-non medically attended patients (21.6 million), (2) office-based outpatient visits (3.7 million), (3) emergency department visit (0.65 million) (4) hospitalizations (247.0 thousand), (5) deaths (36.3 thousand) and (6) days of productivity lost (20.1 million). Conclusions: This study provides an updated estimate of the total economic burden of influenza in the U.S. Although we found a lower total cost than previously estimated, our results confirm that influenza is responsible for a substantial economic burden in the U.S.

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... The Centers for Disease Control and Prevention (CDC) estimates that influenza accounted for 4.3-21 million medical visits, 140,000-810,000 hospitalizations, and 12,000-61,000 deaths annually in the US during the 2010-11 through 2019-20 influenza seasons [1]. In turn, the estimated total economic burden of influenza is substantial at $11.2 billion (ranging from $6.3-$25.3 billion) [2] and as high as $87.1 billion (95% confidence interval [CI], $47.2-$149.5) [3]. ...
... [3]. Direct medical costs have been estimated at $3.2 billion annually, of which 70% ($2.3 billion) is due to hospitalizations [2], despite hospitalization in only 1-2% of medically-attended influenza cases [1]. ...
... Although influenza is generally self-limiting with mild symptoms in healthy individuals [4], certain vulnerable populations are at elevated risk for serious influenza-related medical complications. For example, while the elderly population ≥ 65 years of age has the lowest median incidence of influenza (3.9%) compared to children 0-17 years (9.3%) or adults 18-64 years (8.8%) [5], they account for 50-70% of influenza-related hospitalizations, 70-85% of deaths [6], and 42.7% of direct medical costs [2]. Chronic medical conditions, including pulmonary, cardiovascular, renal, hepatic, and metabolic disorders, have also been identified as predictors of influenza-related complications [7][8][9][10][11][12]. ...
Preprint
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Background Seasonal influenza poses a substantial clinical and economic burden in the United States and vulnerable populations, including the elderly and those with comorbidities, are at elevated risk for influenza-related medical complications. Methods We conducted a retrospective cohort study using the IQVIA PharMetrics® Plus claims database in two stages. In Stage 1, we identified patients with evidence of medically-attended influenza during influenza seasons from October 1, 2014 to May 31, 2018 (latest available data for Stage 1) and used a multivariable logistic regression model to identify patient characteristics that predicted 30-day influenza-related hospitalization. Findings from Stage 1 informed high-risk subgroups of interest for Stage 2, where we selected cohorts of influenza patients during influenza seasons from October 1, 2014 to March 1, 2019 and used 1:1 propensity score matching to patient without influenza with similar high-risk characteristics to compare influenza-attributable rates of all-cause hospital and emergency department visits during follow-up (30-day and in index influenza season). Results In Stage 1, more than 1.6 million influenza cases were identified, of which 18,509 (1.2%) had a hospitalization. Elderly age was associated with 9 times the odds of hospitalization (≥65 years vs. 5-17 years; OR=9.4, 95% CI 8.8-10.1) and select comorbidities were associated with 2-3 times the odds of hospitalization. In Stage 2, elderly influenza patients with comorbidities had 3 to 7 times higher 30-day hospitalization rates compared to matched patients without influenza, including patients with congestive heart failure (41.0% vs.7.9%), chronic obstructive pulmonary disease (34.6% vs. 6.1%), coronary artery disease (22.8% vs. 3.8%), and late-stage chronic kidney disease (44.1% vs. 13.1%; all p<0.05). Conclusions The risk of influenza-related complications is elevated in the elderly, especially those with certain underlying comorbidities, leading to excess healthcare resource utilization. Continued efforts, beyond currently available vaccines, are needed to reduce influenza burden in high-risk populations.
... Small children, the elderly, pregnant women and people with medical conditions are especially at risk to develop severe complications 6,9 . In addition to the disease burden of influenza, the economic burden to the healthcare system and society due to direct medical costs as well as indirect costs caused by absenteeism and lost productivity is substantial 7,10 . ...
... Influenza virus is the causative agent of the flu in humans and annually leads to around 3 to 5 million cases of severe illness and around 290 000 to 650 000 death worldwide 6 . This disease burden is accompanied by a substantial economic burden resulting from direct medical costs as well as indirect costs caused by absenteeism and a loss of productivity 7,10 . Several vaccines and several classes of antiviral drugs are available to combat influenza. ...
Thesis
Ein vielversprechender Ansatz zur Verhinderung von Infektionen mit Influenzavirus ist die kompetitive Inhibition der Virusanhaftung an die Wirtszellen durch Behinderung der Bindung des viralen Hemagglutinin (HA) an sialylierte Glykanrezeptoren. Allerdings erschwert die hohe Variabilität des HA die Entwicklung von universellen Sialinsäure (SA)-basierten Virostatika. In dieser Arbeit wurde der antivirale Effekt von mit SA funktionalisierten Polyglycerolen (PGs) auf Influenza A Viren (IAV) evaluiert. SA-basierte PGs waren nur bei der Inhibition einer geringen Anzahl an IAV Stämmen effektiv. Um die molekulare Basis für diese Beschränkung zu ergründen, wurden mittels Serienpassagen IAV Mutanten selektiert, die gegen sialyliertes PG resistent waren. Es entwickelten sich drei unabhängige resistente Virusvarianten, die einen einfachen bzw. doppelten Aminosäuren-Austausch in der HA RBS aufwiesen. Durch Hemagglutinations-Elution, Einzel-Virus Kraft-Untersuchungen und Glykanarray Analysen konnte eine verringerte Rezeptorbindungsstabilität sowie ein verändertes Rezeptorbindeprofil für diese Virusvarianten gezeigt werden. Interessanterweise wurden drei unterschiedliche Fälle von Virusbindung und Inhibition beobachtet: 1) Virales HA wurde vom PG gebunden und die Virusreplikation inhibiert, 2) virales HA wurde vom PG gebunden ohne Inhibition der Virusreplikation und 3) Virales HA wurde nicht vom PG gebunden und es gab keine Inhibition. Diese Ergebnisse suggerieren, dass es eine Mindestanforderung an die Affinität oder Avidität für eine effektive kompetitive Inhibition von HA gibt. Durch modifizierte PGs, die Sialyllaktose statt SA und einen Amidlinker enthielten, konnte das Potential von PGs als breite IAV Inhibitoren demonstriert werden. Zusammenfassend bieten die Ergebnisse dieser Arbeit wertvolle Einblicke in die Entwicklung von Resistenzen in IAV gegen Inhibitoren des HA-Attachment und in das strategische Design von sialylierten mutlivalenten Inhibitoren gegen IAV.
... Each year, seasonal influenza results in 290,000 to 650,000 deaths globally, 9 million to 36 million cases in the United States alone, and results in significant economic burdens [1][2][3]. Despite widespread vaccination and increased surveillance efforts in recent years, influenza continues to show prominent seasonality in temperate regions and causes a year-round burden in tropical regions [4,5]. ...
Preprint
Seasonal influenza kills hundreds of thousands every year, with multiple constantly-changing strains in circulation at any given time. A high mutation rate enables the influenza virus to evade recognition by the human immune system, including immunity acquired through past infection and vaccination. Here, we capture the genetic similarity of influenza strains and their evolutionary dynamics with genotype networks. We show that the genotype networks of influenza A (H3N2) hemagglutinin are characterized by heavy-tailed distributions of module sizes and connectivity, suggesting critical-like behavior. We argue that: (i) genotype networks are driven by mutation and host immunity to explore a subspace of networks predictable in structure, and (ii) genotype networks provide an underlying structure necessary to capture the rich dynamics of multistrain epidemic models. In particular, inclusion of strain-transcending immunity in epidemic models is dependent upon the structure of an underlying genotype network. This interplay suggests a self-organized criticality where the epidemic dynamics of influenza locates critical-like regions of its genotype network. We conclude that this interplay between disease dynamics and network structure might be key for future network analysis of pathogen evolution and realistic multistrain epidemic models.
... Influenza A viruses (IAVs) are the causative agent for seasonal epidemics in the human population and account for a substantial morbidity and mortality that results in a considerable economic burden [1,2]. The ability of IAVs to rapidly cross interspecies barriers and circulate in a variety of avian and mammalian species of wildlife and livestock creates a breeding ground for zoonotic strains with pandemic potential. ...
Article
Full-text available
Zoonotic infections of humans with influenza A viruses (IAVs) from animal reservoirs can result in severe disease in individuals and, in rare cases, lead to pandemic outbreaks; this is exemplified by numerous cases of human infection with avian IAVs (AIVs) and the 2009 swine influenza pandemic. In fact, zoonotic transmissions are strongly facilitated by manmade reservoirs that were created through the intensification and industrialization of livestock farming. This can be witnessed by the repeated introduction of IAVs from natural reservoirs of aquatic wild bird metapopulations into swine and poultry, and the accompanied emergence of partially- or fully-adapted human pathogenic viruses. On the other side, human adapted IAV have been (and still are) introduced into livestock by reverse zoonotic transmission. This link to manmade reservoirs was also observed before the 20th century, when horses seemed to have been an important reservoir for IAVs but lost relevance when the populations declined due to increasing industrialization. Therefore, to reduce zoonotic events, it is important to control the spread of IAV within these animal reservoirs, for example with efficient vaccination strategies, but also to critically surveil the different manmade reservoirs to evaluate the emergence of new IAV strains with pandemic potential.
... The objective of our study is to experimentally evaluate the impact of social norms messages about vaccination coverage rates on individuals' seasonal influenza vaccination intentions. Seasonal influenza poses a severe public health and economic burden to society, with 3-5 million new cases and 290,000-650,000 deaths annually worldwide (World Health Organization, 2018), costing an estimated $11.2 billion each year in the United States (Putri et al., 2018). Although vaccines have been shown to be a low-cost yet highly effective method of reducing disease burden (Quinn et al., 2017), vaccination rates remain suboptimal (Jorgensen et al., 2018). ...
Article
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‘Nudge’-based social norms messages conveying high population influenza vaccination coverage levels can encourage vaccination due to bandwagoning effects but also discourage vaccination due to free-riding effects on low risk of infection, making their impact on vaccination uptake ambiguous. We develop a theoretical framework to capture heterogeneity around vaccination behaviors, and empirically measure the causal effects of different messages about vaccination coverage rates on four self-reported and behavioral vaccination intention measures. In an online experiment, N = 1365 UK adults are randomly assigned to one of seven treatment groups with different messages about their social environment's coverage rate (varied between 10% and 95%), or a control group with no message. We find that treated groups have significantly greater vaccination intention than the control. Treatment effects increase with the coverage rate up to a 75% level, consistent with a bandwagoning effect. For coverage rates above 75%, the treatment effects, albeit still positive, stop increasing and remain flat (or even decline). Our results suggest that, at higher coverage rates, free-riding behavior may partially crowd out bandwagoning effects of coverage rate messages. We also find significant heterogeneity of these effects depending on the individual perceptions of risks of infection and of the coverage rates.
... Influenza viruses cause ;5 million cases of severe illness and 290,000 to 650,000 deaths worldwide per year (39). In the U.S., there are ;36,000 deaths and more than 200,000 hospitalizations annually (40) with an average annual economic cost greater than $11 billion (41). Infection with influenza virus does not preclude coinfection with a second pathogen. ...
Article
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seasonal influenza viruses are co-circulating in the human population. However, only a few cases of viral co-infection with these two viruses have been documented in humans with some people having severe disease and others mild disease. In order to examine this phenomenon, ferrets were co-infected with SARS-CoV-2 and human seasonal influenza A viruses (IAVs) (H1N1 or H3N2) and were compared to animals that received each virus alone. Ferrets were either immunologically naïve to both viruses or vaccinated with the 2019-2020 split-inactivated influenza virus vaccine. Co-infected naive ferrets lost significantly more body weight than ferrets infected with each virus alone and induced more severe inflammation in both the nose and lungs than ferrets single-infected with each virus. Co-infected naïve animals had predominantly higher IAV titers than SARS-CoV-2 titers, and IAVs efficiently transmitted to the co-housed ferrets by direct contact. Comparatively, SARS-CoV-2 failed to transmit to the ferrets that co-housed with co-infected ferrets by direct contact. Moreover, vaccination significantly reduced IAVs virus titers and shortened the viral shedding, but did not completely block influenza virus direct contact transmission. Notably, vaccination significantly ameliorated the influenza associated disease by protecting vaccinated animals from severe morbidity after IAV single infection or IAV and SARS-CoV-2 co-infection, suggesting that seasonal influenza virus vaccination is pivotal to prevent severe disease induced by IAVs and SARS-CoV-2 co-infection during the COVID-19 pandemic. Importance Influenza A viruses cause severe morbidity and mortality during each influenza virus season. The emergence of SARS-CoV-2 infection in the human population offers the opportunity to potential co-infections of both viruses. The development of useful animal models to asses pathogenesis, transmission, and viral evolution of these viruses as the co-infect a host is of critical importance for the development of vaccines and therapeutics. The ability to prevent the most severe effects of viral co-infections can be studied using effect co-infection ferret models described in this report.
... Influenza A Virus (IAV) and Influenza B Virus (IBV) are responsible for seasonal epidemics and can cause severe respiratory illness including primary viral pneumonia [8][9][10] and secondary bacterial pneumonia [11,12], especially in the elderly and immune compromised [13]. Together, these viruses are globally responsible for between 290,000 and 650,000 deaths annually [14] with the economic burden in the US estimated to exceed $14 billion yearly as of 2018 (healthcare + lost productivity estimates combined) [15]. ...
Article
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Cigarette smoking has been shown to increase the risk of respiratory infection, resulting in the exacerbation of infectious disease outcomes. Influenza viruses are a major respiratory viral pathogen, which are responsible for yearly epidemics that result in between 20,000 and 50,000 deaths in the US alone. However, there are limited general summaries on the impact of cigarette smoking on influenza pathogenic outcomes. Here, we will provide a systematic summarization of the current understanding of the interplay of smoking and influenza viral infection with a focus on examining how cigarette smoking affects innate and adaptive immune responses, inflammation levels, tissues that contribute to systemic chronic inflammation, and how this affects influenza A virus (IAV) disease outcomes. This summarization will: (1) help to clarify the conflict in the reports on viral pathogenicity; (2) fill knowledge gaps regarding critical anti-viral defenses such as antibody responses to IAV; and (3) provide an updated understanding of the underlying mechanism behind how cigarette smoking influences IAV pathogenicity.
... Tests such as Harmony will be necessary to help identify individuals with not only SARS-CoV-2 but also other respiratory pathogens such as influenza and Rous sarcoma virus, as the symptoms of these are similar. Before the current SARS-CoV-2 pandemic, the yearly influenza infections caused nearly 30 million cases in the United States alone, with 400,000 hospital admission and 35,000 deaths (33,34). In particular, when more typical patterns of respiratory infections occur, there will be a need for tests that can perform multiplex testing for individuals presenting respiratory symptoms. ...
Article
RNA amplification tests sensitively detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but their complexity and cost are prohibitive for expanding coronavirus disease 2019 (COVID-19) testing. We developed “Harmony COVID-19,” a point-of-care test using inexpensive consumables, ready-to-use reagents, and a simple device. Our ready-to-use, multiplexed reverse transcription, loop-mediated isothermal amplification (RT-LAMP) can detect down to 0.38 SARS-CoV-2 RNA copies/μl and can report in 17 min for high–viral load samples (5000 copies/μl). Harmony detected 97 or 83% of contrived samples with ≥0.5 viral particles/μl in nasal matrix or saliva, respectively. Evaluation in clinical nasal specimens (n = 101) showed 100% detection of RNA extracted from specimens with ≥0.5 SARS-CoV-2 RNA copies/μl, with 100% specificity in specimens positive for other respiratory pathogens. Extraction-free analysis (n = 29) had 95% success in specimens with ≥1 RNA copies/μl. Usability testing performed first time by health care workers showed 95% accuracy.
... Se estimó que, en 2018, los costos médicos directos se estimaron en $ 3.2 mil millones ($ 1.5-$ 11.7 mil millones) y los costos indirectos en $ 8.0 mil millones ($ 4.8-$ 13.6 mil millones) 44 . ...
Article
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La influenza es una enfermedad costosa para la población. Es causa de morbimortalidad estacional, epidemias y pandemias o sindemias. Debido a la variabilidad del virus, se implementan sistemas de vigilancia para actualizar las cepas e incluirlas en la vacuna antiinfluenza anual. Actualmente se recomienda esta vacuna en algunos grupos de alto riesgo. Sin embargo, la vacunación universal es aún controvertida. Objetivo: Evaluar la evidencia y describir la posición de un panel de expertos sobre la pertinencia de la vacunación universal contra el virus de influenza. Material y métodos: Se realizaron cinco preguntas clínicas, con las que se realizó una búsqueda sistemática de la literatura en fuentes electrónicas y un panel Delphi. Se analizó la evidencia y se emitieron recomendaciones por los expertos. Resultados: El grupo de expertos recomienda vacunar a la población desde los seis meses de edad e incluir a personas que viven con alergia a la proteína del huevo, con comorbilidades (diabetes, obesidad, cáncer), trabajadores de la salud y embarazadas. Conclusiones: La vacunación, iniciando con los grupos vulnerables, es una estrategia necesaria, ética y costo-efectiva. Sin embargo, extender la cobertura para lograr la vacunación universal podría disminuir la transmisión de la enfermedad y sus consecuencias en la población. PALABRAS CLAVE: Influenza. Vacunación. Grupos de riesgo. Embarazo. Profesionales de la salud
... Analysis of the results also points to children and adults under 65 suffer the most from the decrease in vaccine effectiveness due to egg adaptations. This population is also the most likely to cause an indirect cost burden, which is a key part of the total influenza burden [37,38]. If confirmed, under 65s may be the population that would benefit the most from the use of non-egg-based influenza vaccines. ...
Article
Full-text available
Background: Influenza vaccines are the main tool to prevent morbidity and mortality of the disease; however, egg adaptations associated with the choice of the manufacturing process may reduce their effectiveness. This study aimed to estimate the impact of egg adaptations and antigenic drift on the effectiveness of trivalent (TIV) and quadrivalent (QIV) influenza vaccines. Methods: Nine experts in influenza virology were recruited into a Delphi-style exercise. In the first round, the experts were asked to answer questions on the impact of antigenic drift and egg adaptations on vaccine match (VM) and influenza vaccine effectiveness (IVE). In the second round, the experts were presented with the data from a systematic literature review on the same subject and aggregated experts' responses to round one questions. The experts were asked to review and confirm or amend their responses before the final summary statistics were calculated. Results: The experts estimated that, across Europe, the egg adaptations reduce, on average, VM to circulating viruses by 7-21% and reduce IVE by 4-16%. According to the experts, antigenic drift results in a similar impact on VM (8-24%) and IVE (5-20%). The highest reduction in IVE was estimated for the influenza virus A(H3N2) subtype for the under 65 age group. When asked about the frequency of the phenomena, the experts indicated that, on average, between the 2014 and 19 seasons, egg adaptation and antigenic drift were significant enough to impact IVE that occurred in two and three out of five seasons, respectively. They also agreed that this pattern is likely to reoccur in future seasons. Conclusions: Expert estimates suggest there is a potential for 9% on average (weighted average of "All strains" over three age groups adjusted by population size) and up to a 16% increase in IVE (against A(H3N2), the <65 age group) if egg adaptations that arise when employing the traditional egg-based manufacturing process are avoided.
... In the season of 2017-2018, it is estimated that flu caused approximately 51,000 deaths and 710,000 hospitalizations, making it the most life-threatening infectious disease [1]. The estimated average yearly economic burden of influenza is $11.2 billion, including $3.2 billion in direct costs and $8.0 billion in indirect costs annually [2]. The origin of IBV was first discovered in 1940, and later circulating strains diverged into two lineages, were named in 1983 as the Yamagata and Victoria lineages [3]. ...
Article
Full-text available
The identification and elucidation of host pathways for viral infection are critical for understanding the viral infection processes and novel therapeutics development. Here, for the first time, we discover that the human SUMOylation pathway is essential for the IBV viral life cycle. First, IBV viruses were completely inhibited by a novel SUMOylation specific inhibitor, STE025, discovered from our FRET-based high-throughput screening, and the inhibition was very potent, with IC50~ 0.1 µM in an IBV-induced cell death rescue assay; Second, we determined that the IBV M1 protein was SUMOylated, which was mediated by the SUMOylation E2 conjugation enzyme and the E3 ligase enzyme at very high affinities, of 0.20 µM and 0.22 µM, respectively; Third, the mutation of the IBV M1 SUMOylation site, K21R, completely abolished the viral particle generation, strongly suggesting the requirement of SUMOylation for the IBV life cycle. These results suggest that the blockage of the host human SUMOylation pathway is very effective for IBV inhibition. We therefore propose that the host SUMOylation pathway is a critical host factor for the IBV virus life cycle. The identification and inhibition of critical host factor(s) provide a novel strategy for future anti-viral therapeutics development, such as IBV and other viruses.
... Les conséquences de la maladie s'accompagnent d'un impact économique important. Pour exemple, en 2015, l'épidémie de grippe aurait induit un coût total estimé à 11,2 milliards de dollars aux États-Unis[144]. Dans les régions tempérées, les épidémies saisonnières sont synchronisées sur les mois d'hiver et en conséquence inversées entre les deux hémisphères. ...
Thesis
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Les virus influenza A (IAV) sont les agents étiologiques de la peste aviaire et de la grippe chez certains mammifères, dont l’Homme. Ils constituent une importante problématique de santé vétérinaire et humaine. La protéine PB1-F2 est un facteur de virulence des IAV dont les fonctions varient selon l’hôte ainsi que la souche virale considérés. La compréhension des mécanismes d’action de cette protéine est incomplète mais son aptitude à moduler la réponse immunitaire de l’hôte suggère une contribution de PB1-F2 dans l’adaptation d’une souche virale à son hôte. L’objectif de ce travail de thèse a été de caractériser les propriétés de PB1-F2 chez l’hôte aviaire et mammifère. En modèles cellulaires, nous n’avons pas observé de modulation de la réponse de l’hôte par la protéine PB1-F2 d’un virus aviaire H7N1 tandis que la protéine PB1-F2 d’un virus H3N2 humain présente une action pro inflammatoire. A l’inverse, en modèle murin, la PB1- F2 du virus H7N1 contribue de façon majeure à la pathogénicité en exacerbant la réponse inflammatoire. De façon surprenante, un virus chimérique de fond génétique H3N2 exprimant la protéine PB1-F2 aviaire H7N1 induit une inflammation réduite chez la souris par rapport au virus H3N2 sauvage. Ainsi, les fonctions de PB1-F2 ne sont pas strictement transposables et dépendent fortement du contexte viral dans lequel elle est exprimée. Enfin, les interactomes différentiels des protéines PB1-F2 ont été définis en cellules aviaires et humaines par biotinylation de proximité (BioID2). Nous avons identifié des voies biologiques régulées par les protéines PB1-F2 étudiées et différencié les voies spécifiques des voies communes. Nos travaux apportent des éléments de caractérisation des fonctions de PB1-F2 chez l’hôte aviaire et mammifère mais également dans un contexte de franchissement de la barrière d’espèce ou de virus réassortant exprimant une PB1-F2 d’origine aviaire
... With regard to the life sciences, Dual-Use of Research of Concern (DURC) denotes research that is intended for benefit, but which might easily be misapplied to cause harm (WHO: https://www.who.int/publications/i/item/who-consultative-meeting-on-a-global-guidanceframework-to-harness-the-responsible-use-of-life-sciences (28 October 2021, date last accessed). ...
Article
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Research in infection biology aims to understand the complex nature of host-pathogen interactions. While this knowledge facilitates strategies for preventing and treating diseases, it can also be intentionally misused to cause harm. Such dual-use risk is potentially high for highly pathogenic microbes such as Risk Group-3 (RG3) bacteria and RG4 viruses, which could be used in bioterrorism attacks. However, other pathogens such as influenza virus (IV) and enterohaemorrhagic Escherichia coli (EHEC), usually classified as RG2 pathogens, also demonstrate high dual-use risk. As the currently-approved therapeutics against these pathogens are not satisfactorily effective, previous outbreaks of these pathogens caused enormous public fear, media attention, and economic burden. In this interdisciplinary review, we summarize the current perspectives of dual-use research on IV and EHEC, and further highlight the dual-use risk associated with evolutionary experiments with these infectious pathogens. We support the need to carry-out experiments pertaining to pathogen evolution, including to gain predictive insights on their evolutionary trajectories, which cannot be otherwise achieved with stand-alone theoretical models and epidemiological data. However, we also advocate for increased awareness and assessment strategies to better quantify the risks-versus-benefits associated with such evolutionary experiments. In addition to building public trust in dual-use research, we propose that these approaches can be extended to other pathogens currently classified as low risk, but bearing high dual-use potential, given the particular pressing nature of their rapid evolutionary potential.
... 1,2 Influenza infection is related to substantial economic burden owing to healthcare expenses, absence from work or education, and frequent complications, including bacterial pneumonia. 2, 3 Typically, vaccination can prevent influenza but could be ineffective in the case of an antigenic drift or shift, resulting in public health completely unprotected against circulating viruses. 4,5 Antiviral agents are usually prescribed to treat newly surfaced or variant viruses owing to their ability to target stable viral parts. ...
Article
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Baloxavir marboxil, a novel influenza therapeutic agent, is a prodrug rapidly metabolized into its active form, baloxavir acid, which inhibits cap‐dependent endonuclease. This study evaluated the pharmacokinetics (PKs) and safety of baloxavir acid in healthy Korean subjects and compared them with published data in Japanese subjects. This open‐label and single‐ascending dose study was conducted in 30 Korean male subjects, with a single oral dose of baloxavir marboxil (20, 40, or 80 mg) administered to eight subjects each; additionally, 80 mg was administered to six subjects (body weight >80 kg). Noncompartmental and population PK analyses were performed, and results were compared with those of Japanese subjects. Appropriateness of the body weight‐based dosing regimen was evaluated by simulation. PK profiles of baloxavir acid revealed multicompartment behavior with a long half‐life (80.8–98.3 h), demonstrating a dose‐proportional increase. Baloxavir acid reached peak plasma concentration from 3.5 to 4.0 h postdosing. Body weight was identified as a significant covariate of apparent oral clearance and apparent volume of distribution, which was similar to that observed in Japanese subjects. Body weight‐adjusted analysis revealed that exposure to baloxavir acid did not significantly differ between Korean and Japanese subjects. Simulated exposures to baloxavir acid demonstrated that the body weight‐based dosing regimen for baloxavir marboxil was appropriate. Based on a PK study, clinical data including dosing regimen developed in Japan were adequately extrapolated to Korea, supporting the approval of baloxavir marboxil in Korean as a new treatment option for influenza.
... In addition to health impact, seasonal influenza also has a significant economic impact. Older adults contribute to the majority of influenza-related economic burden in the US [35]. Economic data are an essential part for effective decision-making by policy makers. ...
Article
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The burden of influenza is disproportionally higher among older adults. We evaluated the relative vaccine effectiveness (rVE) of adjuvanted trivalent (aIIV3) compared to high-dose trivalent influenza vaccine (HD-IIV3e) against influenza and cardio-respiratory disease (CRD)-related hospitalizations/ER visits among adults ≥65 years during the 2019–2020 influenza season. Economic outcomes were also compared. A retrospective cohort analysis was conducted using prescription, professional fee claims, and hospital data. Inverse probability of treatment weighting (IPTW) was used to adjust for confounding. IPTW-adjusted Poisson regression was used to evaluate the adjusted rVE of aIIV3 versus HD-IIV3e. All-cause and influenza-related healthcare resource utilization (HCRU) and costs were examined post-IPTW. Recycled predictions from generalized linear models were used to estimate adjusted costs. Adjusted analysis showed that aIIV3 (n = 798,987) was similarly effective compared to HD-IIV3e (n = 1,655,979) in preventing influenza-related hospitalizations/ER visits (rVE 3.1%; 95% CI: −2.8%; 8.6%), hospitalizations due to any cause (−0.7%; 95% CI: −1.6%; 0.3%), and any CRD-related hospitalization/ER visit (0.9%; 95% CI: 0.01%; 1.7%). Adjusted HCRU and annualized costs were also statistically insignificant between the two cohorts. The adjusted clinical and economic outcomes evaluated in this study were comparable between aIIV3 and HD-IIV3e during the 2019–2020 influenza season.
... T h e ne w e ngl a nd jou r na l o f m e dicine I nfluenza is a common cause of respiratory tract infections in children worldwide and places substantial burdens on health care resources. [1][2][3][4] Although influenza vaccines prevent influenza disease in randomized trials, [5][6][7] vaccine effectiveness is frequently suboptimal. [8][9][10] Egg-adaptive mutations in the globular head of the hemagglutinin protein in egg-based vaccine viruses may contribute to observed low vaccine effectiveness. ...
Article
BACKGROUND Cell-culture–derived influenza vaccines may enable a closer antigenic match to circulating strains of influenza virus by avoiding egg-adapted mutations. METHODS We evaluated the efficacy of a cell-culture–derived quadrivalent inactivated influenza vaccine (IIV4c) using a Madin–Darby canine kidney cell line in children and adolescents 2 to less than 18 years of age. During three influenza seasons, participants from eight countries were enrolled in an observer-blinded, randomized clinical trial comparing IIV4c with a noninfluenza vaccine (meningococcal ACWY). All the participants received a dose of a trial vaccine. Children 2 to less than 9 years of age without previous influenza vaccination who were assigned to the IIV4c group received a second dose on day 29; their counterparts who were assigned to the comparator group received placebo. Participants were followed for at least 180 days for efficacy and safety. The presence of influenza virus in naso-pharyngeal swabs from participants with influenza-like illness was confirmed by reverse-transcriptase–polymerase-chain-reaction assay and viral culture. A Cox proportional-hazards model was used to evaluate the efficacy of IIV4c as measured by the first occurrence of laboratory-confirmed type A or B influenza (primary end point). RESULTS Between 2017 and 2019, a total of 4514 participants were randomly assigned to receive IIV4c or the meningococcal ACWY vaccine. Laboratory-confirmed influenza occurred in 175 of 2257 participants (7.8%) in the IIV4c group and in 364 of 2252 participants (16.2%) in the comparator group, and the efficacy of IIV4c was 54.6% (95% confidence interval [CI], 45.7 to 62.1). Efficacy was 80.7% (95% CI, 69.2 to 87.9) against influenza A/H1N1, 42.1% (95% CI, 20.3 to 57.9) against influenza A/H3N2, and 47.6% (95% CI, 31.4 to 60.0) against influenza B. IIV4c showed consistent vaccine efficacy in subgroups according to age, sex, race, and previous influenza vaccination. The incidences of adverse events were similar in the IIV4c group and the comparator group. CONCLUSIONS IIV4c provided protection against influenza in healthy children and adolescents across seasons, regardless of previous influenza vaccination
... Adults 65 years and older (hereinafter referred to as seniors) are at greater risk for complications following influenza infection compared with younger adults, due in part to immunosenescence and increased comorbid conditions, leading to decreased vaccine efficacy and increased severity of influenza related complications [1][2][3]. In the U.S., the annual cost of hospitalizations associated with influenza are estimated to be $1.3 billion for this age group [4]. Given this substantial cost, a health economic analysis of the various influenza vaccination strategies aiming to increase protection for this age group is pertinent. ...
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Two influenza vaccines are licensed in the U.S. exclusively for the 65 years and older population: a trivalent inactivated high-dose influenza vaccine (HD-IIV3) and a trivalent inactivated adjuvanted influenza vaccine (aIIV3). In a recent publication, we estimated a relative vaccine effectiveness (rVE) of HD-IIV3 vs. aIIV3 of 12% (95% CI: 3.3-20%) for influenza-related hospitalizations using a retrospective study design, but did not report the number of prevented hospitalizations nor the associated avoided cost. In this paper we report estimations for both. Methods: Leveraging the rVE of a cohort study over two influenza seasons (2016/17 and 2017/18), we collected cost data for healthcare provided to the same study population. Vaccine costs were obtained from the Medicare pricing schedule. Our economic assessment compared cost of vaccination and hospital care for patients experiencing acute respiratory or cardiovascular illness. Results: We analyzed 1.9 million HD-IIV3 and 223,793 aIIV3 recipients. Average vaccine list prices were $46.23 for HD-IIV3 and $48.26 for aIIV3. The hospitalization rates for respiratory disease in HD-IIV3 and aIIV3 recipients were 187 (95% CI: 185-189) and 212 (195-231) per 10,000 persons-years, respectively. Attributing the average cost per hospitalization of $12,652 ($12,214-$13,090) to the difference in hospitalization rates, we estimate net savings of HD-IIV3 to be $34 ($10-$62) per recipient. Conclusion: Pooled over two predominantly A/H3N2 respiratory seasons, vaccination with HD-IIV3 was associated with lower hospitalization rates and associated costs compared to aIIV3 in senior members of a large national managed health care company in the U.S. Reduced hospitalizations affect healthcare utilization overall, and therefore other costly health outcomes.
... In 2018, direct medical costs in the US were estimated to be USD $ 3.2 billion ($ 1.5-$ 11.7 billion), and indirect costs, $ 8.0 billion ($ 4.8-$ 13.6 billion) 44 . ...
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Objective: Influenza is a costly disease for the population. It is a cause of seasonal morbidity and mortality, epidemics and pandemics or syndemics. Given the variability of the virus, surveillance systems are implemented in order to update the strains and include them in the annual influenza vaccine. This vaccine is currently recommended in some high-risk groups. However, universal vaccination remains controversial. To evaluate the evidence and describe the position of a panel of experts on the relevance of universal vaccination against influenza virus. Material and methods: Five clinical questions were asked, whereby a systematic search of the literature in electronic sources and a Delphi panel were carried out. The evidence was analyzed, and recommendations were issued by the experts. Results: The group of experts recommends vaccinating the population starting at six months of age and include people who live with egg protein allergy, with comorbidities (diabetes, obesity, cancer), health workers and pregnant women. Conclusions: Vaccination, starting with vulnerable groups, is a necessary, ethical and cost-effective strategy. However, expanding the coverage to achieve universal vaccination could reduce the transmission of the disease and its consequences in the population.
... A recent study in the United States estimated that the average annual total economic burden of influenza was as high as $11.2 billion. 6 In the present study, the epidemiological and economic burden of hospitalization and in-hospital mortality directly due to influenza (i.e., influenza related) as calculated from the French healthcare databases 7,10 was supplemented by the burden calculated from excess hospitalization and mortality indirectly due to influenza (influenza associated) and related costs. ...
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Background In France, each year, influenza viruses are responsible for seasonal epidemics leading to 2–6 million cases. Influenza can cause severe disease that may lead to hospitalization or death. As severe disease may be due to the virus itself or to disease complications, estimating the burden of severe influenza is complex. The present study aimed at estimating the epidemiological and economic burden of severe influenza in France during eight consecutive influenza seasons (2010–2018). Methods Influenza-related hospitalization and mortality data and patient characteristics were taken from the French hospital information database, PMSI. An ecological approach using cyclic regression models integrating the incidence of influenza syndrome from the Sentinelles network supplemented the PMSI data analysis in estimating excess hospitalization and mortality (CépiDc—2010–2015) and medical costs. Results Each season, the average number of influenza-related hospitalizations was 18,979 (range: 8627–44,024), with an average length of stay of 8 days. The average number of respiratory hospitalizations indirectly related with influenza (i.e., influenza associated) was 31,490 (95% confidence interval [CI]: 24,542–39,012), with an average cost of €141 million (range: 54–217); 70% of these hospitalizations and 77% of their costs concerned individuals ≥65 years of age (65+). More than 90% of excess mortality was in 65+ subjects. Conclusions The combination of two complementary approaches allowed estimation of both influenza-related and associated hospitalizations and deaths and their burden in France, showing the substantial impact of complications. The present study highlighted the major public health burden of influenza and its severe complications, especially in 65+ subjects.
... Seasonal influenza contributes to widespread individual and societal costs. Infection causes school and work absenteeism, medical visitation, hospitalization, and death, with direct and indirect costs between $6.3 and $25.3 billion annually in the United States [1]. Although school-aged children have the highest rates of medically-attended influenza (MAI) [2], they have relatively low rates of hospitalization and death [3]. ...
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Background Schools are primary venues of influenza amplification with secondary spread to communities. We assessed K-12 student absenteeism monitoring as a means for early detection of influenza activity in the community. Materials and methods Between September 2014 and March 2020, we conducted a prospective observational study of all-cause (a-TOT), illness-associated (a-I), and influenza-like illness–associated (a-ILI) absenteeism within the Oregon School District (OSD), Dane County, Wisconsin. Absenteeism was reported through the electronic student information system. Students were visited at home where pharyngeal specimens were collected for influenza RT-PCR testing. Surveillance of medically-attended laboratory-confirmed influenza (MAI) occurred in five primary care clinics in and adjoining the OSD. Poisson general additive log linear regression models of daily counts of absenteeism and MAI were compared using correlation analysis. Findings Influenza was detected in 723 of 2,378 visited students, and in 1,327 of 4,903 MAI patients. Over six influenza seasons, a-ILI was significantly correlated with MAI in the community (r = 0.57; 95% CI: 0.53–0.63) with a one-day lead time and a-I was significantly correlated with MAI in the community (r = 0.49; 0.44–0.54) with a 10-day lead time, while a-TOT performed poorly (r = 0.27; 0.21–0.33), following MAI by six days. Discussion Surveillance using cause-specific absenteeism was feasible and performed well over a study period marked by diverse presentations of seasonal influenza. Monitoring a-I and a-ILI can provide early warning of seasonal influenza in time for community mitigation efforts.
... The number of deaths due to influenza is approximately 290,000-650,000 annually [3]. These factors constitute a global health, medical, and economic burden [4][5][6]. ...
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Flu is a serious health, medical, and economic problem, but no therapy is yet available that has satisfactory results and reduces the occurrence of these problems. Nearly 20 years after the registration of the previous therapy, baloxavir marboxil, a drug with a new mechanism of action, recently appeared on the market. This is a promising step in the fight against the influenza virus. This article presents the possibilities of using all available antiviral drugs specific for influenza A and B. We compare all currently recommended anti-influenza medications, considering their mechanisms of action, administration, indications, target groups, effectiveness, and safety profiles. We demonstrate that baloxavir marboxil presents a similar safety and efficacy profile to those of drugs already used in the treatment of influenza. Further research on combination therapy is highly recommended and may have promising results.
... Seasonal influenza has historically posed a large burden on the health care system (1,2). The 2017-2018 influenza season was especially severe. ...
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Objective: Patients with rheumatoid arthritis (RA) are vulnerable to severe complications of influenza. We assessed whether health care resource use (HRU) and costs differed between patients with RA and influenza who received antiviral medication compared with matched patients with RA and influenza not receiving antiviral therapy. Methods: This was a retrospective US health insurance claims analysis over three influenza seasons (each October to April) in 2016-2019. Adults with RA and a subsequent diagnosis of influenza were included. Treated patients (receiving antiviral influenza treatment within 2 days of diagnosis) and untreated patients were propensity score matched using baseline covariates. HRU and costs were assessed for inpatient, emergency department (ED), and outpatient visits and compared between cohorts using χ2 tests and t tests. Results: After matching, 2638 treated and 1319 untreated patients were included. For treated versus untreated patients, the mean number of all-cause outpatient visits was 0.96 versus 1.21 during 14 days of follow-up (P < 0.001) and 1.94 versus 2.24 over 28 days (P = 0.001), respectively. Over 28 days, the mean number of all-cause ED visits was lower among treated (0.23) than untreated (0.30) patients (P = 0.042). The mean number of respiratory-related outpatient visits was significantly lower for treated versus untreated patients, and mean costs for these visits were $17.89 versus $35.27 over 14 days (P < 0.001) and $28.92 versus $48.77 over 28 days (P < 0.001) for treated versus untreated patients, respectively. Conclusion: Our findings demonstrate that prompt antiviral treatment after influenza diagnosis may reduce HRU and costs in patients with RA.
... Influenza continues to affect millions of individuals of all age groups, with enormous public health and socioeconomic burdens. 1,2 Influenza is considered a self-limiting disease, and most adults present with uncomplicated influenza, a mildto-moderate, self-limited illness with symptoms including high fever, chills, myalgias, and malaise. 3 Still, it can cause serious complications (3-5 million people each year) like pneumonia, myositis, myocarditis, and central nervous system diseases. ...
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Background: The aim of this study was to analyse changes in influenza detection rates of the influenza seasons 2017/2018, 2018/2019, 2019/2020, and 2020/2021 and the changes in personal awareness of protection during the COVID-19 pandemic. Methods: This retrospective study included patients tested for influenza virus A and B from November 2017 to March 2021 at the Affiliated People's Hospital of Ningbo University (Ningbo, China). Influenza virus A and B tested by direct RT-PCR. A small group of 100 regular participants in influenza virus detection were surveyed on the use of protective measures in four different influenza seasons. Results: There were 14,902, 14,762, 25,070, and 1107 tests of influenza virus A and B in the four influenza periods, for total positive rates of 32.45%, 35.77%, 29.40%, and 0.54%, respectively. In the two periods of four influenza seasons, from November to January, the total number of influenza samples was 8530, 4980, 22,925, 868; from February to March, the number of tests was 6372, 9782, 2145, 239. Total number of tests and positive rate decreased significantly from February/March onwards of the 2019/2020 season, coinciding with the beginning of COVID-19. The proportion of people taking protective measures also increased during the 2019/20 and 2020/21 flu seasons. Conclusion: The influenza virus has a high incidence in this area. The diagnosis rate of influenza decreased after the start of the COVID-19 pandemic. The COVID-19 pandemic had an important impact on the detection rates for influenza virus.
... Although many consider influenza a mild, self-limiting viral illness, it represents a serious public health problem because of the accompanying pneumonia and high mortality among the at-risk population [1]. Furthermore, it can cause a considerable socioeconomic impact through reduced workplace productivity and absenteeism during the infection epidemic [2]. ...
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The high disease burden of influenza in elderly and chronically ill adults may be due to the suboptimal effectiveness and mismatch of the conventional trivalent influenza vaccine (TIV). This study evaluated the cost-effectiveness of quadrivalent (QIV), adjuvanted trivalent (ATIV), and high-dose quadrivalent (HD-QIV) vaccines versus TIV used under the current Korean National Immunization Program (NIP) in older adults aged ≥65 years. We also evaluated the cost-effectiveness of programs for at-risk adults aged 19–64 and adults aged 50–64. A one-year static population model was used to compare the costs and outcomes of alternative vaccination programs in each targeted group. Influenza-related parameters were derived from the National Health Insurance System claims database; other inputs were extracted from the published literature. Incremental cost-effectiveness ratios (ICERs) were assessed from a societal perspective. In the base case analysis (older adults aged ≥65 years), HD-QIV was superior, with the lowest cost and highest utility. Compared with TIV, ATIV was cost-effective (ICER $34,314/quality-adjusted life-year [QALY]), and QIV was not cost-effective (ICER $46,486/QALY). The cost-effectiveness of HD-QIV was robust for all parameters except for vaccine cost. The introduction of the influenza NIP was cost-effective or even cost-saving for the remaining targeted gr3oups, regardless of TIV or QIV.
... Each year, numerous respiratory viruses co-circulate in the population, causing substantial public health burden 1 and economic loss. 2,3 Previous studies have suggested that respiratory viruses may interfere with and change the risk, timing, or natural history of infection of one another. 4 For instance, in 2009, seasonal epidemic of respiratory syncytial virus (RSV) in Israel was temporarily delayed due to the A(H1N1) pandemic. ...
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Background: Non-pharmaceutical interventions (NPIs) and voluntary behavioral changes during the COVID-19 pandemic have influenced the circulation of non-SARS-CoV-2 respiratory infections. We aimed to examine interactions among common non-SARS-CoV-2 respiratory virus and further estimate the impact of the COVID-19 pandemic on these viruses. Methods: We analyzed incidence data for seven groups of respiratory viruses in New York City (NYC) during October 2015 to May 2021 (i.e., before and during the COVID-19 pandemic). We first used elastic net regression to identify potential virus interactions and further examined the robustness of the found interactions by comparing the performance of Seasonal Auto Regressive Integrated Moving Average (SARIMA) models with and without the interactions. We then used the models to compute counterfactual estimates of cumulative incidence and estimate the reduction during the COVID-19 pandemic period from March 2020 to May 2021, for each virus. Results: We identified potential interactions for three endemic human coronaviruses (CoV-NL63, CoV-HKU, and CoV-OC43), parainfluenza (PIV)-1, rhinovirus, and respiratory syncytial virus (RSV). We found significant reductions (by ~70-90%) in cumulative incidence of CoV-OC43, CoV-229E, human metapneumovirus, PIV-2, PIV-4, RSV, and influenza virus during the COVID-19 pandemic. In contrast, the circulation of adenovirus and rhinovirus was less affected. Conclusions: Circulation of several respiratory viruses has been low during the COVID-19 pandemic, which may lead to increased population susceptibility. It is thus important to enhance monitoring of these viruses and promptly enact measures to mitigate their health impacts (e.g., influenza vaccination campaign and hospital infection prevention) as societies resume normal activities.
... In the European Union, of the estimated 1.38 million DALYs for all infectious diseases for the period between 2009 and 2013, influenza had the highest burden, representing 30% of this total (Cassini et al., 2018). In 2017, the WHO estimated that seasonal flu causes up to 650,000 deaths each year (Lee et al., 2018) and estimates from 2015 compute average losses caused by influenza in the United States to be $11.2 billion ($6.3-$25.3 billion) (Putri et al., 2018). In addition, if our hypotheses are correct, increased MHC variability may directly contribute to increasing poultry disease resistance, and therefore generate direct economic gains to breeders and farmers. ...
Article
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Every year commercial poultry operations produce and crowd billions of birds, a source of inexpensive animal protein. Commercial poultry is intensely bred for desirable production traits, and currently presents very low variability at the Major Histocompatibility Complex. This situation dampens the advantages conferred by the MHC’s high genetic variability, and crowding generates immunosuppressive stress. We address the proteins of influenza A viruses directly and indirectly involved in host specificities. We discuss how mutants with increased virulence and/or altered host specificity may arise if few class I alleles are the sole selective pressure on avian viruses circulating in immunocompromised poultry. This hypothesis is testable with peptidomics of MHC ligands. Breeding strategies for commercial poultry can easily and inexpensively include high variability of MHC as a trait of interest, to help avoid the billions of dollars in disease burden caused by influenza and decrease the risk of selecting highly virulent strains.
... The economic burden of seasonal influenza in the United States is about US $6.3 to US $25.3 billion [20]. Assuming the economic cost scales linearly with the number of infections, a scenario in which at least 95% of infections are reduced (which includes both the mask mandate and masks suggested scenarios) saves US $6 to US $24 billion per season at negligible cost. ...
Article
Background Face mask mandates have been instrumental in the reduction of transmission of airborne COVID-19. Thus, the question arises whether comparatively mild measures should be kept in place after the pandemic to reduce other airborne diseases such as influenza. Objective In this study, we aim to simulate the quantitative impact of face masks on the rate of influenza illnesses in the United States. Methods Using the Centers for Disease Control and Prevention data from 2010 to 2019, we used a series of differential equations to simulate past influenza seasons, assuming that people wore face masks. This was achieved by introducing a variable to account for the efficacy and prevalence of masks and then analyzing its impact on influenza transmission rate in a susceptible-exposed-infected-recovered model fit to the actual past seasons. We then compared influenza rates in this hypothetical scenario with the actual rates over the seasons. Results Our results show that several combinations of mask efficacy and prevalence can substantially reduce the burden of seasonal influenza. Across all the years modeled, a mask prevalence of 0.2 (20%) and assumed moderate inward and outward mask efficacy of 0.45 (45%) reduced influenza infections by >90%. Conclusions A minority of individuals wearing masks substantially reduced the number of influenza infections across seasons. Considering the efficacy rates of masks and the relatively insignificant monetary cost, we highlight that it may be a viable alternative or complement to influenza vaccinations.
... The reduction in IRMEs for the pediatric population and adults younger than 65 years of age observed in this study could do much to reduce the overall burden of influenza. Influenza infections in children and adults <65 years of age account for an estimated annual average economic burden of $1.84 billion in direct medical expenditures and $6.94 billion in indirect costs due to missed school by sick children and missed work by sick adults and the parents and guardians who care for children with influenza [54,55]. The results discussed in this review are part of a broader set of studies that have evaluated the relative vaccine effectiveness and cost effectiveness of IIV4c compared to IIV4e [27,[56][57][58][59]. ...
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The adaptation of influenza seed viruses in egg culture can result in a variable antigenic vaccine match each season. The cell-based quadrivalent inactivated influenza vaccine (IIV4c) contains viruses grown in mammalian cell lines rather than eggs. IIV4c is not subject to egg-adaptive changes and therefore may offer improved protection relative to egg-based vaccines, depending on the degree of match with circulating influenza viruses. We summarize the relative vaccine effectiveness (rVE) of IIV4c versus egg-based quadrivalent influenza vaccines (IIV4e) to prevent influenza-related medical encounters (IRMEs) from three retrospective observational cohort studies conducted during the 2017–2018, 2018–2019, and 2019–2020 US influenza seasons using the same underlying electronic medical record dataset for all three seasons—with the addition of linked medical claims for the latter two seasons. We identified IRMEs using diagnostic codes specific to influenza disease (ICD J09*-J11*) from the records of over 10 million people. We estimated rVE using propensity score methods adjusting for age, sex, race, ethnicity, geographic location, week of vaccination, and health status. Subgroup analyses included specific age groups. IIV4c consistently had higher relative effectiveness than IIV4e across all seasons assessed, which were characterized by different dominant circulating strains and variable antigenic drift or egg adaptation.
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Tumor progression locus 2 (Tpl2) is a serine-threonine kinase known to promote inflammation in response to various pathogen-associated molecular patterns (PAMPs), inflammatory cytokines and G-protein-coupled receptors and consequently aids in host resistance to pathogens. We have recently shown that Tpl2-/- mice succumb to infection with a low-pathogenicity strain of influenza (x31, H3N2) by an unknown mechanism. In this study, we sought to characterize the cytokine and immune cell profile of influenza-infected Tpl2-/- mice to gain insight into its host protective effects. Although Tpl2-/- mice display modestly impaired viral control, no virus was observed in the lungs of Tpl2-/- mice on the day of peak morbidity and mortality suggesting that morbidity is not due to virus cytopathic effects but rather to an overactive antiviral immune response. Indeed, increased levels of interferon-β (IFN-β), the IFN-inducible monocyte chemoattractant protein-1 (MCP-1, CCL2), Macrophage inflammatory protein 1 alpha (MIP-1α; CCL3), MIP-1β (CCL4), RANTES (CCL5), IP-10 (CXCL10) and Interferon-γ (IFN-γ) was observed in the lungs of influenza-infected Tpl2-/- mice at 7 days post infection (dpi). Elevated cytokine and chemokines were accompanied by increased infiltration of the lungs with inflammatory monocytes and neutrophils. Additionally, we noted that increased IFN-β correlated with increased CCL2, CXCL1 and nitric oxide synthase (NOS2) expression in the lungs, which has been associated with severe influenza infections. Bone marrow chimeras with Tpl2 ablation localized to radioresistant cells confirmed that Tpl2 functions, at least in part, within radioresistant cells to limit pro-inflammatory response to viral infection. Collectively, this study suggests that Tpl2 tempers inflammation during influenza infection by constraining the production of interferons and chemokines which are known to promote the recruitment of detrimental inflammatory monocytes and neutrophils.
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Background: Influenza viruses pose significant disease burdens through seasonal outbreaks and unpredictable pandemics. Existing surveillance programs rely heavily on reporting of medically attended influenza (MAI). Continuously monitoring cause-specific school absenteeism may identify local acceleration of seasonal influenza activity. The Oregon Child Absenteeism Due to Respiratory Disease Study (ORCHARDS; Oregon, WI) implements daily school-based monitoring of influenza-like illness-specific student absenteeism (a-ILI) in kindergarten through Grade 12 schools and assesses this approach for early detection of accelerated influenza and other respiratory pathogen transmission in schools and surrounding communities. Methods: Starting in September 2014, ORCHARDS combines automated reporting of daily absenteeism within six schools and home visits to school children with acute respiratory infection (ARI). Demographic, epidemiological, and symptom data are collected along with respiratory specimens. Specimens are tested for influenza and other respiratory viruses. Household members can opt into a supplementary household transmission study. Community comparisons are possible using a pre-existing and highly effective influenza surveillance program, based on MAI at five family medicine clinics in the same geographical area. Results: Over the first 5 years, a-ILI occurred on 6634 (0.20%) of 3,260,461 student school days. Viral pathogens were detected in 64.5% of 1728 children with ARI who received a home visit. Influenza was the most commonly detected virus, noted in 23.3% of ill students. Conclusion: ORCHARDS uses a community-based design to detect influenza trends over multiple seasons and to evaluate the utility of absenteeism for early detection of accelerated influenza and other respiratory pathogen transmission in schools and surrounding communities.
Article
Objective: Examine characteristics and time trends of respiratory tract infection (RTI) consultations in Norwegian primary care and compare consultations in daytime general practice and out-of-hours (OOH) services. Design: Registry-based study using reimbursement claims data. Setting: All in-person primary care consultations during 2006-2015. Patients: All patients visiting primary care during the study period. Main outcome measures: The main outcome variable was RTI consultations. Differences regarding service type (general practice or OOH services) and changes over time were investigated. We report associations with patient age and sex, season, point-of-care C-reactive protein (CRP) test use, and sickness certificate issuing. Results: RTI consultations (n = 16 304 777) represented 11.6% of all consultations (N = 140 199 637) in primary care over the ten-year period. The annual number of RTI consultations per 1000 inhabitants decreased from 335 to 314, while the number of consultations for any reason increased. Of RTI consultations, 83.2% occurred in general practice. OOH services had a higher proportion of RTI consultations (21.4%) compared with general practice (10.6%). Young children (0-4 years) represented 18.9% of all patients in RTI consultations. CRP testing was used in 56.2% of RTI consultations, and use increased over time. Sickness certificates were issued in 31.9% of RTI consultations with patients of working age (20-67 years). Conclusion: Most RTI consultations occurred in general practice, although the proportion was higher in OOH services. Laboratory testing and/or issuing of sickness certificates were part of most consultations. This could be an important reason for seeking health care. Key PointsPatients with a respiratory tract infection (RTI) are mostly managed in primary care, where they represent much of the workload.Most consultations for RTIs took place in daytime general practice, but out-of-hours services had a higher proportion of RTI consultations.RTIs were the dominating reason for encounter among young children both in out-of-hours services and daytime general practice.CRP tests were used in over half of RTI consultations, and their use expanded over time.
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Seasonal influenza outbreaks represent a large burden for the health care system as well as the economy. While the role of the microbiome has been elucidated in the context of various diseases, the impact of respiratory viral infections on the human microbiome is largely unknown. In this study, swine was used as an animal model to characterize the temporal dynamics of the respiratory and gastrointestinal microbiome in response to an influenza A virus (IAV) infection. A multi-omics approach was applied on fecal samples to identify alterations in microbiome composition and function during IAV infection. We observed significantly altered microbial richness and diversity in the gastrointestinal microbiome after IAV infection. In particular, increased abundances of Prevotellaceae were detected, while Clostridiaceae and Lachnospiraceae decreased. Moreover, our metaproteomics data indicated that the functional composition of the microbiome was heavily affected by the influenza infection. For instance, we identified decreased amounts of flagellin, correlating with reduced abundances of Lachnospiraceae and Clostridiaceae, possibly indicating involvement of a direct immune response toward flagellated Clostridia during IAV infection. Furthermore, enzymes involved in short-chain fatty acid (SCFA) synthesis were identified in higher abundances, while metabolome analyses revealed rather stable concentrations of SCFAs. In addition, 16S rRNA gene sequencing was used to characterize effects on the composition and natural development of the upper respiratory tract microbiome. Our results showed that IAV infection resulted in significant changes in the abundance of Moraxellaceae and Pasteurellaceae in the upper respiratory tract. Surprisingly, temporal development of the respiratory microbiome structure was not affected. IMPORTANCE Here, we used swine as a biomedical model to elucidate the impact of influenza A H1N1 infection on structure and function of the respiratory and gastrointestinal tract microbiome by employing a multi-omics analytical approach. To our knowledge, this is the first study to investigate the temporal development of the porcine microbiome and to provide insights into the functional capacity of the gastrointestinal microbiome during influenza A virus infection.
Article
Despite wide availability, only 50.2% of the United States (US) adult population and 50.3% of adult Arkansans were vaccinated for influenza during the 2020-2021 influenza season. The proportion of the population vaccinated for influenza varies by age, sex, race/ethnicity, education, rural/urban residence, and income. However, measures of healthcare access have not been adequately investigated as predictors of influenza vaccination. Using a large, statewide random sample, this study examined 5-year influenza vaccination among Arkansans by sociodemographic characteristics (age, sex, race/ethnicity, education, rural/urban residence), general vaccine hesitancy, and healthcare access (having a primary care provider, having health insurance, forgoing health care due to cost, and frequency of doctor checkups). Older age, being female, being Hispanic, having a bachelor's degree or higher, having a primary care provider, visiting a doctor for a checkup in the past two years, and lack of hesitancy towards vaccines were significant predictors of receiving influenza vaccination.
Article
Objective The beneficial effect of influenza vaccination (IV) in patients with diabetes was not completely understood. Methods Using the research data of health insurance, we performed a cohort study of patients aged ≥ 20 years who were admitted to inpatient care due to diabetes in 2008-2013 in Taiwan. We performed the propensity score matching and the outcomes of complications and mortality following the diabetes admission was compared between patients with and without IV. Results Among 61002 patients with diabetes admission, IV reduced 30-day in-hospital mortality (odds ratio [OR] 0.75, 95% confidence interval [CI] 0.66-0.84), particularly among patients with prior diabetes hospitalization, inadequate control for diabetes, and diabetes-related comorbidities, such as eye involvement, ketoacidosis, renal manifestations, and coma. Compared with non-IV control group, patients with IV also had decreased risks of pneumonia (OR 0.92, 95% CI 0.87-0.97), septicemia (OR 0.83, 95% CI 0.79-0.88), urinary tract infection (OR 0.94, 95% CI 0.90-0.97), and intensive care (OR 0.29, 95% CI 0.27-0.31). Conclusion In patients with diabetes admission, IV was associated with reduced risks of complications and mortality. Our study implicated the urgent need to promote influenza vaccination for this susceptible population with diabetes.
Article
Viral diseases have contributed significantly to worldwide morbidity and mortality throughout history. Despite the existence of therapeutic treatments for many viral infections, antiviral resistance and the threat posed by novel viruses highlight the need for an increased number of effective therapeutics. In addition to small molecule drugs and biologics, antimicrobial peptides (AMPs) represent an emerging class of potential antiviral therapeutics. While AMPs have traditionally been regarded in the context of their antibacterial activities, many AMPs are now known to be antiviral. These antiviral peptides (AVPs) have been shown to target and perturb viral membrane envelopes and inhibit various stages of the viral life cycle, from preattachment inhibition through viral release from infected host cells. Rational design of AMPs has also proven effective in identifying highly active and specific peptides and can aid in the discovery of lead peptides with high therapeutic selectivity. In this review, we highlight AVPs with strong antiviral activity largely curated from a publicly available AMP database. We then compile the sequences present in our AVP database to generate structural predictions of generic AVP motifs. Finally, we cover the rational design approaches available for AVPs taking into account approaches currently used for the rational design of AMPs.
Article
Background and Objective: Not everyone gets sick after an exposure to influenza A viruses (IAV). Although KLRD1 has been identified as a potential biomarker for influenza susceptibility, it remains unclear whether forecasting symptomatic flu infection based on pre-exposure host gene expression might be possible. Method: To examine this hypothesis, we developed DeepFlu using the state-of-the-art deep learning approach on the human gene expression data infected with IAV subtype H1N1 or H3N2 viruses to forecast who would catch the flu prior to an exposure to IAV. Results: The results indicated that such forecast is possible and, in other words, gene expression could reflect the strength of host immunity. In the leave-one-person-out cross-validation, DeepFlu based on deep neural network outperformed the models using convolutional neural network, random forest, or support vector machine, achieving 70.0% accuracy, 0.787 AUROC, and 0.758 AUPR for H1N1 and 73.8% accuracy, 0.847 AUROC, and 0.901 AUPR for H3N2. In the external validation, DeepFlu also reached 71.4% accuracy, 0.700 AUROC, and 0.723 AUPR for H1N1 and 73.5% accuracy, 0.732 AUROC, and 0.749 AUPR for H3N2, surpassing the KLRD1 biomarker. In addition, DeepFlu which was trained only by pre-exposure data worked the best than by other time spans and mixed training data of H1N1 and H3N2 did not necessarily enhance prediction. DeepFlu is available at https://github.com/ntou-compbio/DeepFlu. Conclusions: DeepFlu is a prognostic tool that can moderately recognize individuals susceptible to the flu and may help prevent the spread of IAV.
Article
The most effective means of preventing seasonal influenza is through strain‐specific vaccination. In this study, we investigated the efficacy, effectiveness and safety of cell‐based trivalent and quadrivalent influenza vaccines. A systematic literature search was conducted in electronic databases and grey literature sources up to 7 February 2020. Randomised controlled trials (RCTs) and non‐randomised studies of interventions (NRSIs) were eligible for inclusion. Two reviewers independently screened, extracted data and assessed the risk of bias of included studies. Certainty of evidence for key outcomes was assessed using the GRADE methodology. The search returned 28,846 records, of which 868 full‐text articles were assessed for relevance. Of these, 19 studies met the inclusion criteria. No relative efficacy data were identified for the direct comparison of cell‐based vaccines compared with traditional vaccines (egg‐based). Efficacy data were available comparing cell‐based trivalent influenza vaccines with placebo in adults (aged 18–49 years). Overall vaccine efficacy was 70% against any influenza subtype (95% CI 61%–77%, two RCTS), 82% against influenza A(H1N1) (95% CI 71%–89%, 2 RCTs), 72% against influenza A(H3N2) (95% CI 39%–87%, 2 RCTs) and 52% against influenza B (95% CI 30%–68%, 2 RCTs). Limited and heterogeneous data were presented for effectiveness when compared with no vaccination. One NRSI compared cell‐based trivalent and quadrivalent vaccination with traditional trivalent and quadrivalent vaccination, finding a small but significant difference in favour of cell‐based vaccines for influenza‐related hospitalisation, hospital encounters and physician office visits. The safety profile of cell‐based trivalent vaccines was comparable to traditional trivalent influenza vaccines. Compared with placebo, cell‐based trivalent influenza vaccines have demonstrated greater efficacy in adults aged 18–49 years. Overall cell‐based vaccines are well‐tolerated in adults, however, evidence regarding the effectiveness of these vaccines compared with traditional seasonal influenza vaccines is limited.
Article
Background: Rapid diagnostic tests (RDTs) for influenza used by individuals at home could potentially expand access to testing and reduce the impact of influenza on health systems. Improving access to testing could lead to earlier diagnosis following symptom onset, allowing more rapid interventions for those who test positive, including behavioral changes to minimize spread. However, the accuracy of RDTs for influenza has not been determined in self-testing populations. Objective: This study aims to assess the accuracy of an influenza RDT conducted at home by lay users with acute respiratory illness compared with that of a self-collected sample by the same individual mailed to a laboratory for reference testing. Methods: We conducted a comparative accuracy study of an at-home influenza RDT (Ellume) in a convenience sample of individuals experiencing acute respiratory illness symptoms. Participants were enrolled in February and March 2020 from the Greater Seattle region in Washington, United States. Participants were mailed the influenza RDT and reference sample collection materials, which they completed and returned for quantitative reverse-transcription polymerase chain reaction influenza testing in a central laboratory. We explored the impact of age, influenza type, duration, and severity of symptoms on RDT accuracy and on cycle threshold for influenza virus and ribonuclease P, a marker of human DNA. Results: A total of 605 participants completed all study steps and were included in our analysis, of whom 87 (14.4%) tested positive for influenza by quantitative reverse-transcription polymerase chain reaction (70/87, 80% for influenza A and 17/87, 20% for influenza B). The overall sensitivity and specificity of the RDT compared with the reference test were 61% (95% CI 50%-71%) and 95% (95% CI 93%-97%), respectively. Among individuals with symptom onset ≤72 hours, sensitivity was 63% (95% CI 48%-76%) and specificity was 94% (95% CI 91%-97%), whereas, for those with duration >72 hours, sensitivity and specificity were 58% (95% CI 41%-74%) and 96% (95% CI 93%-98%), respectively. Viral load on reference swabs was negatively correlated with symptom onset, and quantities of the endogenous marker gene ribonuclease P did not differ among reference standard positive and negative groups, age groups, or influenza subtypes. The RDT did not have higher sensitivity or specificity among those who reported more severe illnesses. Conclusions: The sensitivity and specificity of the self-test were comparable with those of influenza RDTs used in clinical settings. False-negative self-test results were more common when the test was used after 72 hours of symptom onset but were not related to inadequate swab collection or severity of illness. Therefore, the deployment of home tests may provide a valuable tool to support the management of influenza and other respiratory infections.
Article
Background: Influenza and respiratory syncytial virus (RSV) are associated with substantial morbidity and mortality in the United States. We assessed risk factors for severe disease and medical resource utilization (MRU) among US adults hospitalized with influenza or RSV in the Hospitalized Acute Respiratory Tract Infection (HARTI) study. Methods: HARTI was a prospective global (40 centers, 12 countries) epidemiological study of adults hospitalized with acute respiratory tract infections conducted across the 2017-2019 epidemic seasons. Patients with confirmed influenza or RSV were followed up to 3 months post-discharge. Baseline characteristics, prevalence of core risk factors (CRFs) for severe disease (age ≥65 years, chronic heart or renal disease, chronic obstructive pulmonary disease, or asthma), and MRU were summarized descriptively. Results: The US cohort included 280 influenza-positive and 120 RSV-positive patients. RSV patients were older (mean: 63.1 vs. 59.7 years) and a higher proportion had CRFs (87.5% vs. 81.4%). Among those with CRFs (influenza, n = 153; RSV, n = 99), RSV patients required longer hospitalizations (median length of stay: 4.5 days) and a greater proportion (79.8%) required oxygen supplementation during hospitalization compared with influenza patients (4.0 days and 59.5%, respectively). At 3 months post-discharge, a greater proportion of RSV patients with CRFs reported use of antibiotics, antitussives, bronchodilators, and inhaled and systemic steroids versus those with influenza and CRFs. Many patients with CRFs reported hospital readmission at 3 months post-discharge (RSV: 13.4%; influenza: 11.9%). Conclusions: MRU during and post-hospitalization due to RSV in adults is similar to or greater than that of influenza. Enhanced RSV surveillance and preventive and therapeutic interventions are needed.
Article
Although caused by different pathogens, COVID-19 and influenza share many clinical features, as well as the potential for inflammatory, cardiovascular, and other long-term complications. During the 2020-2021 influenza season, COVID-19 mitigation efforts and a robust influenza vaccination campaign led to an unprecedented reduction in influenza cases. The lack of exposure to influenza, along with antigenic changes, may have reduced population immunity to influenza and set the stage for a high severity influenza season in 2021-2022. For the second consecutive season, the UK Department of Health and Social Care has expanded influenza vaccine eligibility to mitigate the impact of both COVID-19 and influenza. Continuation of clear policy decisions, as well as ongoing coordination between manufacturers, distributors, health authorities, and healthcare providers, is key to reducing the burden of influenza and COVID-19 and preventing large numbers of severe cases that can overwhelm the healthcare system.
Article
Seasonal influenza is a major public health problem. Nosocomial influenza is particularly concerning as it may affect patients at high risk for complications. Unvaccinated health care workers (HCWs) are an important source of nosocomial influenza and therefore a priority target group for vaccination. Despite the fact that some European countries have high coverage rates such as UK (76.8% in season 2020/21), others continue to have low coverage rates for influenza vaccines. This study aims to estimate vaccination coverage in HCWs in Cyprus, an island country located in the Eastern Mediterranean region and describe their attitudes towards influenza vaccination. Methods This is a questionnaire based, nation-wide study assessing flu vaccination coverage in 2019–2020 and attitudes related to vaccination acceptance, of 962 HCWs in both public and private health care facilities. Multivariable logistic regression was used to investigate factors associated with flu vaccination status. Results Flu vaccination coverage was estimated as 31.8%. The top two reasons for getting vaccinated were to protect their family (81.4%) and themselves (77.4%). The top two reasons for not getting immunised, besides “no particular reason” (25.7%), included disbelief for vaccine effectiveness (21.5%) and safety (29.3%). The regression model showed that doctors compared to nurses had 10 times the odds of being vaccinated. Other factors positively associated with flu vaccination were encouragement by the supervisor, having sufficient knowledge on flu and flu vaccination and easy access to vaccination. A percentage of 54.8% of participants stated that COVID-19 pandemic strongly or somewhat influenced their decision to get vaccinated. Conclusion Flu vaccination coverage in HCWs in Cyprus is rather low, similar to some other European countries. Barriers and facilitators in this study can be considered in strategies to increase flu vaccination uptake. Such questionnaire-based surveys should be repeated in order to evaluate effectiveness of targeted vaccination campaigns.
Chapter
Vaccination is the first choice to protect against influenza. However, the vaccine must be adjusted annually, and effectiveness is consistently only 50% or less. Since the vaccination rate is on average below 50%, only roughly 25% of the population is protected by vaccination. Therefore, antiviral drugs are important for therapeutic intervention. Moreover, in the case of a pandemic, especially in the early stages, when no vaccine is yet available, we are completely dependent on antiviral drugs. In this chapter, the currently available drugs for the therapy of influenza or those that are in clinical development will be presented.
Article
The high prevalence of pediatric upper respiratory conditions combined with poor availability of specialized care for the proper diagnosis of these diseases continues to be a significant cause of morbidity and mortality worldwide. Despite advances in computer-assisted diagnosis, there are no automated triage tools that can effectively provide a first step guide for the parents or cognitive assistance for the care providers to improve the efficacy and accuracy of diagnosis in these children. We propose a new approach to designing expert systems using an integration of logical criteria and variable evoking strength to improve these tools’ diagnostic accuracy. We conducted a retrospective chart review of the electronic health records of children evaluated for several upper respiratory conditions at a large university-based health system in the United States. The diagnoses recorded in the charts were compared to the output from the tool. The accuracy rate of the tool was based on the assumption that human physicians are the gold standard of diagnosis. A total of 138 cases, ranging in age between 6 months to 18 years, were reviewed. Forty-three percent of the participants self-identified as female. The average accuracy of the tool in matching the physician diagnosis of the eight types of upper respiratory conditions that were included in this study was 75% for the first diagnosis and 84% for matching one of the top two differential diagnoses. Integration of logical diagnostic criteria and variable evoking strength into the design of expert systems can significantly improve the diagnostic accuracy of these tools.
Article
Introduction Influenza vaccination is a recommended tool in preventing influenza-related illnesses, medical visits, and hospitalizations. With many patients remaining unvaccinated each year, the Emergency Department (ED) represents a unique opportunity to provide vaccinations to patient not yet vaccinated. However, busy urban safety-net EDs maybe challenged to safely execute such a vaccination program. The aim of this quality improvement project was to assess influenza vaccination feasibility in the ED and improve influenza vaccination rates in our community. Methods The quality improvement work-group, comprised of ED physicians, nurses, and pharmacists, designed and implemented an influenza vaccination protocol that aligned with the ED workflow. The outcome measure was the total number of patients vaccinated per month and per influenza season. Process measures included the type of influenza vaccine administered and type of care area within ED. Balancing measures were also included. Results Following the initiative, a total of 337 patients received influenza vaccinations in the ED between September 1, 2018 and December 31, 2020 compared to none during the previous influenza season. With each influenza season, the number of vaccinated patients increased from 61 to 134 and 142, respectively. The average age of the patients was 48.23 ± 15.29, 52.89 ± 15.91, and 44.92 ± 18.97 years old. Most patients received the vaccination while roomed in the high acuity section of the adult ED. No adverse effects or automated dispensing cabinet stockouts were observed. Conclusion Our structured program indicates that influenza vaccine administration to eligible patients is feasible in a busy urban safety-net ED. Piloting new and further developing existing ED-based influenza vaccination programs have the potential to significantly benefit public health.
Article
Influenza A kills hundreds of thousands of people globally every year and has potential to generate more severe pandemics. Influenza A’s RNA genome and transcriptome provide many potential therapeutic targets. Here, nuclear magnetic resonance (NMR) experiments suggest that one such target could be a hairpin loop of eight nucleotides in a pseudoknot that sequesters a 3' splice site in canonical pairs until a conformational change releases it into a dynamic 2X2 nucleotide internal loop. NMR experiments reveal that the hairpin loop is dynamic and able to bind oligonucleotides as short as pentamers. A 3D NMR structure of the complex contains four and likely five base pairs between pentamer and loop. Moreover, a hairpin sequence was discovered that mimics the equilibrium of the influenza hairpin between its structure in the pseudoknot and upon release of the splice site. Oligonucleotide binding shifts the equilibrium completely to the hairpin secondary structure required for pseudoknot folding. The results suggest this hairpin can be used to screen for compounds that stabilize the pseudoknot and potentially reduce splicing.
Article
Influenza vaccines can mitigate illness severity, including reduced risk of ICU admission and death, in people with breakthrough infection. Less is known about vaccine attenuation of mild/moderate influenza illness. We compared subjective severity scores in vaccinated and unvaccinated persons with medically attended illness and laboratory-confirmed influenza. Participants were prospectively recruited when presenting for care at five US sites over nine seasons. Participants aged ≥ 16 years completed the EQ-5D-5L visual analog scale (VAS) at enrollment. After controlling for potential confounders in a multivariable model, including age and general health status, VAS scores were significantly higher among 2,830 vaccinated participants compared with 3,459 unvaccinated participants, indicating vaccinated participants felt better at the time of presentation for care. No differences in VAS scores were observed by the type of vaccine received among persons aged ≥ 65 years. Our findings suggest vaccine-associated attenuation of milder influenza illness is possible.
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At-home testing with rapid diagnostic tests (RDTs) for respiratory viruses could facilitate early diagnosis, guide patient care, and prevent transmission. Such RDTs are best used near the onset of illness when viral load is highest and clinical action will be most impactful, which may be achieved by at-home testing. We evaluated the diagnostic accuracy of the QuickVue Influenza A + B RDT in an at-home setting. A convenience sample of 5,229 individuals who were engaged with an on-line health research platform were prospectively recruited throughout the United States. "flu@home" test kits containing a QuickVue RDT and reference sample collection and shipping materials were pre-positioned with participants at the beginning of the study. Participants responded to daily symptom surveys. If they reported experiencing cough along with aches, fever, chills, and/or sweats, they used their flu@home kit following instructions on a mobile app and indicated what lines they saw on the RDT. Of the 976 participants who met criteria to use their self-collection kit and completed study procedures, 202 (20.7%) were positive for influenza by qPCR. The RDT had a sensitivity of 28% (95% CI: 21-36) and specificity of 99% (98–99) for influenza A, and 32% (95% CI: 20-46) and 99% (95% CI: 98-99), for influenza B. Our results support the concept of app-supported, pre-positioned at-home RDT kits using symptom-based triggers, although it cannot be recommended with the RDT used in this study. Further research is needed to determine ways to improve the accuracy and utility of home-based testing for influenza.
Article
While the economic burden of influenza infection is well described among adults aged 65 and older, less is known about younger adults. A systematic literature review was conducted to describe the economic burden of seasonal influenza in adults aged 18 to 64 years, to identify the main determinants of direct and indirect costs, and to highlight any gaps in the existing published evidence. MEDLINE and Embase were searched from 2007 to February 7, 2020, for studies reporting primary influenza‐related cost data (direct or indirect) or absenteeism data. Of the 2613 publications screened, 51 studies were included in this review. Half of them were conducted in the United States, and 71% of them described patients with influenza‐like illness rather than laboratory‐confirmed disease. Only 12 studies reported cost data specifically for at‐risk populations. Extracted data highlighted that within the 18‐ to 64‐year‐old group, up to 88% of the economic burden of influenza was attributable to indirect costs, and up to 75% of overall direct costs were attributable to hospitalizations. Furthermore, within the 18‐ to 64‐year‐old group, influenza‐related costs increased with age and underlying medical conditions. The reported cost of influenza‐related hospitalizations was found to be up to 2.5 times higher among at‐risk populations compared with not‐at‐risk populations. This review documents the considerable economic impact of influenza among adults aged 18 to 64. In this age group, most of the influenza costs are indirect, which are generally not recognized by decision makers. Future studies should focus on at‐risk subgroups, lab‐confirmed cases, and European countries.
Article
Aims: This retrospective analysis of Optum Clinformatics® Data Mart database evaluated US patient characteristics, healthcare resource utilization (HCRU), costs, and treatment patterns among unvaccinated adults with outpatient-diagnosed COVID-19 to quantify US economic burden. Materials and methods: Index event was the earliest outpatient diagnosis of confirmed COVID-19 from May 1‒December 10, 2020. Patients had 12 months' continuous enrollment before and were followed for ≥60 days after index date until insurance disenrollment or study end. Results: 236,589 patients had outpatient-diagnosed COVID-19 (7,692 with and 228,897 without subsequent COVID-19-related inpatient admission >48 hours post-diagnosis). Median age was 51 years (≥65 years, 30.0%); 72.4% had ≥1 risk factor. Patients with versus without subsequent inpatient admission were more often male, older, Black/Hispanic, and had comorbidities/risk factors. With a median follow-up of 162 days, patients had a median of 1 COVID-19-related outpatient visit (with inpatient admission, 5 outpatient visits). Those with inpatient admission had a median of 1 COVID-19-related inpatient visit (median length of stay [LOS], 6 days), 33.3% were admitted to intensive care (median LOS, 8 days), 8.4%, 7.1%, and 13.3% received invasive mechanical ventilation, noninvasive mechanical ventilation, and supplemental oxygen, respectively; 13.5% experienced readmission. Inpatient mortality was 6.0% (0.3% for nonhospitalized patients). Antithrombotic therapy, antibiotics, corticosteroids, and remdesivir use increased among patients with inpatient admission versus without. Median total COVID-19-related non-zero medical costs were $208 for patients without inpatient admission (with inpatient admission, $39,187). Limitations: Results reflect the circulating SARS-CoV-2 and treatment landscape during the study period. Requirements for continuous enrollment could have biased the population. Cost measurements may have included allowed (typically higher) and charge amounts. Conclusions: Given the numbers of the US population who are still not fully vaccinated and the evolving epidemiology of the pandemic, this study provides relevant insights on real-world treatment patterns, HCRU, and cost burden of outpatient-diagnosed COVID-19.
Article
Influenza A viruses (IAVs) have a main natural reservoir in wild birds. IAVs are highly contagious, continually evolve, and have a wide host range that includes various mammalian species including horses, pigs, and humans. Furthering our understanding of host-pathogen interactions and cross-species transmissions is therefore essential. This review focuses on what is known regarding equine influenza virus (EIV) virology, pathogenesis, immune responses, clinical aspects, epidemiology (including factors contributing to local, national, and international transmission), surveillance, and preventive measures such as vaccines. We compare EIV and human influenza viruses and discuss parallels that can be drawn between them. We highlight differences in evolutionary rates between EIV and human IAVs, their impact on antigenic drift, and vaccine strain updates. We also describe the approaches used for the control of equine influenza (EI), which originated from those used in the human field, including surveillance networks and virological analysis methods. Finally, as vaccination in both species remains the cornerstone of disease mitigation, vaccine technologies and vaccination strategies against influenza in horses and humans are compared and discussed.
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Seasonal influenza epidemics have a substantial public health and economic burden in the United States (US). On average, over 200,000 people are hospitalized and an estimated 23,000 people die from respiratory and circulatory complications associated with seasonal influenza virus infections each year. Annual direct medical costs and indirect productivity costs across the US have been found to average respectively at $10.4 billion and $16.3 billion. The objective of this study was to estimate the economic impact of severe influenza-induced illness on the US Veterans Affairs population. The five-year study period included 2010 through 2014. Influenza-attributed outcomes were estimated with a statistical regression model using observed emergency department (ED) visits, hospitalizations, and deaths from the Veterans Health Administration of the Department of Veterans Affairs (VA) electronic medical records and respiratory viral surveillance data from the Centers for Disease Control and Prevention (CDC). Da
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Background: Although many studies have modelled the national burdens of hospitalizations and deaths due to influenza, few studies have considered the outpatient burden. To fill this gap for the United States (US), we applied traditional statistical modelling approaches to time series derived from large medical claims databases held in the private sector. Methods: We accessed ICD-9-coded office visit data extracted from Truven Health Analytics' MarketScan Commercial database covering about one third of the US population <65 years during 2001-2009, and Medicare Supplemental data covering about one fifth of US seniors 65+ during 2006-2009. We extracted weekly time series of visits due to respiratory diagnoses, otitis media (OM), and urinary tract infections (UTI), a "negative control". We used multiple linear regression modelling to estimate age-specific influenza-related excess in office visits. Results: In the <65 year age group, in the 8 pre-pandemic seasons studied and for the broadest defined respiratory outcome, the model attributed an average of ~14.5 M (Standard deviation [SD] across seasons 3.9 million) office visits to influenza (rate of 5,581/100,000 population). Of these, ~80 % of visits occurred in the 5-17 and 18-49 age group. In school children aged 5-17 year olds and adult 18-64 year age groups the majority of visits were due to influenza B, while A/H3N2 explained most visits in children <5 year olds. The model further attributed ~2.2 M OM visits (SD across seasons 790,000) annually to influenza, of which 86 % of these occurred in children <18 years; this indicates that 6.4 % of all infants <2 years and 4.9 % of all toddlers aged 2-4 years in the US have an influenza-attributable outpatient visit with an OM diagnosis. In seniors 65 years and older, our model attributed ~0.7 M (SD across seasons 351,000) respiratory visits to influenza (rate of 1,887/100,000 population). The model identified no significant excess UTI (negative control) visits in most seasons. Conclusions: This is to our knowledge a first study of the outpatient burden of influenza in the US in a large database. The model estimated that 10 % of all children <18 years and 4 % of the entire population <65 years seek outpatient care for respiratory illness attributable to influenza annually. Trial registration: ClinicalTrial.gov, NCT02019732 .
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This report updates the 2015-16 recommendations ofthe Advisoiy Committee on Immunization Practices (ACIP) regarding the use of seasonal influenza vaccines (Grohskopf LA, Sokolow LZ, Olsen SJ, Bresee JS, Broder KR, Karron RA. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices, United States, 2015-16 influenza season. MMWR Morb Mortal Wkly Rep 2015;64:818-25). Routine annual influenza vaccination is recommended for all persons aged months who do not have contraindications. For the 2016-17 influenza season, inactivated influenza vaccines (IIVs) will be available in both trivalent (IIV3) and quadrivalent (IIV4) formulations. Recombinant influenza vaccine (RIV) will be available in a trivalent formulation (RIV3). In light of concerns regarding low effectiveness against influenza A(H1N1)pdm09 in the United States during the 2013-14 and 2015-16 seasons, for the 2016-17 season, ACIP makes the interim recommendation that live attenuated influenza vaccine (LAIV4) should not be used. Vaccine virus strains included in the 2016-17 U.S. trivalent influenza vaccines will be an A/California/7/2009 (H1N1) like virus, an A/Hong Kong/4801/2014 (H3N2) like virus, and a B/Brisbane/60/2008 like virus (Victoria lineage). Quadrivalent vaccines will include an additional influenza B virus strain, a B/Phuket/3073/2013 like virus (Yamagata lineage). Recommendations for use of different vaccine types and specific populations are discussed. A licensed, age -appropriate vaccine should be used. No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one licensed, recommended product is otherwise appropriate. This information is intended for vaccination providers, immunization program personnel, and public health personnel. Information in this report reflects discussions during public meetings ofACIP held on October 21, 2015; February 24, 2016; andJune 22, 2016 These recommendations apply to all licensed influenza vaccines used within Food and DrugAdministration licensed indications, including those licensed after the publication of this report. Updates and other information are available at CDC's influenza website (http://www.cdc.govfflit). Vaccination and health care providers should check CDC's influenza website periodically for additional information.
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Background: Designed to overcome influenza B mismatch, new quadrivalent influenza vaccines (QIVs) contain one additional B strain compared with trivalent influenza vaccines (TIVs). Objective: To examine the expected public health impact, budget impact, and incremental cost-effectiveness of QIV versus TIV in the United States. Methods: A dynamic transmission model was used to predict the annual incidence of influenza over the 20-year-period of 2014 to 2034 under either a TIV program or a QIV program. A decision tree model was interfaced with the transmission model to estimate the public health impact and the cost-effectiveness of replacing TIV with QIV from a societal perspective. Our models were informed by published data from the United States on influenza complication probabilities and relevant costs. The incremental vaccine price of QIV as compared with that of TIV was set at US $5.40 per dose. Results: Over the next 20 years, replacing TIV with QIV may reduce the number of influenza B cases by 27.2% (16.0 million cases), resulting in the prevention of 137,600 hospitalizations and 16,100 deaths and a gain of 212,000 quality-adjusted life-years (QALYs). The net societal budget impact would be US $5.8 billion and the incremental cost-effectiveness ratio US $27,411/QALY gained. In the probabilistic sensitivity analysis, 100% and 96.5% of the simulations fell below US $100,000/QALY and US $50,000/QALY, respectively. Conclusions: Introducing QIV into the US immunization program may prevent a substantial number of hospitalizations and deaths. QIV is also expected to be a cost-effective alternative option to TIV.
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Purpose: The objective of the study is to evaluate the effect of antiviral treatment, pre-existing diseases, and sociodemographic factors on the risk of influenza-related complications and healthcare utilization. Methods: Case data were obtained from US MarketScan Research Databases. Cases had a clinical diagnosis of influenza between 2006 and 2010 and continuous healthcare insurance from 90 days before to 30 days after diagnosis. Logistic regression models were applied to explore the impact of antiviral treatment on complications and healthcare utilization. Modified generalized estimating equation regression models in propensity score matched samples were used to address the robustness of the study. Results: Analyses included 1,557, 437 cases from four influenza seasons. In each season, 34.82%- 43.42% of patients received antiviral treatment, mostly oseltamivir. On average, 1.86% of patients were hospitalized, 9.56% visited the emergency room and 41.14% made ≥2 outpatient visits. The incidence of complications ranged from 17.62 to 19.67 per 100 patient-months. The relative risk of complications was increased in patients aged 0-4 years and those with pre-existing diseases, including asthma, Parkinson's disease, and cystic fibrosis. Overall, patients receiving antiviral treatment had an 11% reduction in the risk of complications. Among oseltamivir-treated patients, the risk of complications was significantly reduced by 81% in those treated ≤two days after diagnosis compared with later. Antiviral treatment significantly reduced the risk of hospitalization, emergency room visits and need for ≥2 outpatient visits by 29%, 24% and 11%, respectively. Propensity score matching method improved the strength of the study. Conclusions: Early treatment with antivirals, and specifically oseltamivir, significantly reduced the risk of influenza-related complications and healthcare utilization. However, lacking information about diseases severity and the time from onset of symptoms to fulfillment of a prescription may bias the outcomes.
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Background: Influenza causes significant morbidity and mortality with considerable economic costs, including lost work productivity. Influenza vaccines may reduce the economic burden through primary prevention of influenza and reduction in illness severity. Methods: We examined illness severity and work productivity loss among working adults with medically-attended acute respiratory illnesses, and compared outcomes for patients with and without laboratory-confirmed influenza, and by influenza vaccination status among patients with influenza during the 2012-2013 influenza season. Results: Illnesses laboratory-confirmed as influenza (i.e. Cases) were subjectively assessed as more severe than illnesses not caused by influenza (i.e. Non-Cases) based on multiple measures, including current health status at study enrollment (<7 days from illness onset), and current activity and sleep quality status relative to usual. Influenza Cases reported missing 45% more work hours (20.5 vs. 15.0, P<.001) than Non-Cases, and subjectively assessed their work productivity as impeded to a greater degree (6.0 vs. 5.4, P<.001). Current health status and current activity relative to usual were subjectively assessed as modestly, but significantly, better for vaccinated influenza Cases compared with unvaccinated Cases; however, no significant modifications of sleep quality, missed work hours, or work productivity loss were noted for vaccinated subjects. Conclusions: . Influenza illnesses were more severe and resulted in more missed work hours and productivity loss than illnesses not confirmed as influenza. Modest reductions in illness severity for vaccinated influenza cases were observed. These findings highlight the burden of influenza illnesses and illustrate the importance of laboratory-confirmation of influenza outcomes in evaluations of vaccine effectiveness.
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SUMMARY Death certificate reports and laboratory-confirmed influenza deaths probably underestimate paediatric deaths attributable to influenza. Using US mortality data for persons aged <18 years who died during 28 September 2003 to 2 October 2010, we estimated influenza-attributable deaths using a generalized linear regression model based on seasonal covariates, influenza-certified deaths (deaths for which influenza was a reported cause of death), and occurrence during the 2009 pandemic period. Of 32 783 paediatric deaths in the death categories examined, 853 (3%) were influenza-certified. The estimated number of influenza-attributable deaths over the study period was 1·8 [95% confidence interval (CI) 1·3-2·8] times higher than the number of influenza-certified deaths. Influenza-attributable deaths were 2·1 (95% CI 1·5-3·4) times higher than influenza-certified deaths during the non-pandemic period and 1·1 (95% CI 1·0-1·8) times higher during the pandemic. Overall, US paediatric deaths attributable to influenza were almost twice the number reported by death certificate codes in the seasons prior to the 2009 pandemic.
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Limited information on age- and sex-specific estimates of influenza-associated death with different underlying causes is currently available. We regressed weekly age- and sex-specific US mortality outcomes underlying several causes between 1997 and 2007 to incidence proxies for influenza A/H3N2, A/H1N1, and B that combine data on influenzalike illness consultations and respiratory specimen testing, adjusting for seasonal baselines and time trends. Adults older than 75 years of age had the highest average annual rate of influenza-associated mortality, with 141.15 deaths per 100,000 people (95% confidence interval (CI): 118.3, 163.9), whereas children under 18 had the lowest average mortality rate, with 0.41 deaths per 100,000 people (95% CI: 0.23, 0.60). In addition to respiratory and circulatory causes, mortality with underlying cancer, diabetes, renal disease, and Alzheimer disease had a contribution from influenza in adult age groups, whereas mortality with underlying septicemia had a contribution from influenza in children. For adults, within several age groups and for several underlying causes, the rate of influenza-associated mortality was somewhat higher in men than in women. Of note, in men 50-64 years of age, our estimate for the average annual rate of influenza-associated cancer mortality per 100,000 persons (1.90, 95% CI: 1.20, 2.62) is similar to the corresponding rate of influenza-associated respiratory deaths (1.81, 95% CI: 1.42, 2.21). Age, sex, and underlying health conditions should be considered when planning influenza vaccination and treatment strategies.
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Objective To improve the understanding of common health care cost collection, estimation, analysis, and reporting methodologies.Data SourcesOvid MEDLINE (1947 to December 2012), Cochrane Central register of Controlled Trials, Database of Systematic Reviews, Health Technology Assessment, and National Health Service Economic Evaluation Database.Review Methods This article discusses the following cost collection methods: defining relevant resources, quantification of consumed resources, and resource valuation. It outlines the recommendations for cost reporting in economic evaluations and reviews the techniques on how to handle cost data uncertainty. Last, it discusses the controversial topics of future costs and patient productivity losses.Conclusion Health care cost collection and estimation can be challenging, and an organized approach is required to optimize accuracy of economic evaluation outcomes.Implications for PracticeUnderstanding health care cost collection and estimation techniques will improve both critical appraisal and development of future economic evaluations.
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Productivity costs occur when the productivity of individuals is affected by illness, treatment, disability or premature death. The objective of this paper was to review past and current developments related to the inclusion, identification, measurement and valuation of productivity costs in economic evaluations. The main debates in the theory and practice of economic evaluations of health technologies described in this review have centred on the questions of whether and how to include productivity costs, especially productivity costs related to paid work. The past few decades have seen important progress in this area. There are important sources of productivity costs other than absenteeism (e.g. presenteeism and multiplier effects in co-workers), but their exact influence on costs remains unclear. Different measurement instruments have been developed over the years, but which instrument provides the most accurate estimates has not been established. Several valuation approaches have been proposed. While empirical research suggests that productivity costs are best included in the cost side of the cost-effectiveness ratio, the jury is still out regarding whether the human capital approach or the friction cost approach is the most appropriate valuation method to do so. Despite the progress and the substantial amount of scientific research, a consensus has not been reached on either the inclusion of productivity costs in economic evaluations or the methods used to produce productivity cost estimates. Such a lack of consensus has likely contributed to ignoring productivity costs in actual economic evaluations and is reflected in variations in national health economic guidelines. Further research is needed to lessen the controversy regarding the estimation of health-related productivity costs. More standardization would increase the comparability and credibility of economic evaluations taking a societal perspective.
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The primary objective of this study was to assess trends in employer expenditures for both direct medical costs and indirect productivity losses associated with influenza. A retrospective analysis was performed using two of the MarketScan family of databases for 2005-2009. Patients with at least one diagnosis claim for influenza during an influenza season were selected. We estimated seasonal incidence of influenza in the employed population from the MarketScan Commercial Claims and Encounters database. Health care utilization and costs and productivity losses were assessed during the 21-d period following the influenza diagnosis date. Compared with the 2005-2006 season (493 per 100,000 plan members), influenza incidence increased during the 2006-2007 (598 per 100,000 plan members) and 2007-2008 (1,142 per 100,000 plan members) seasons and had a dramatic increase during the pandemic season of 2008-2009 (1,715 per 100,000 plan members) . The total influenza-related employer spending per 100,000 plan members also increased by over 400% during the 2008-2009 influenza season [$623,248; confidence interval (CI]):$601,518-$644,991], compared with 2005-2006 ($145,834; 95% CI: $135,067-$156,603). The primary drivers of the increased costs were emergency room, outpatient and inpatient visits. Total costs associated with influenza-related missed work time per 100,000 plan members increased over 4-fold from $26,479 in the 2005-2006 influenza season to $122,811 in 2008-2009. Overall, as expected, considerably higher direct and indirect costs were observed during the 2008-2009 influenza pandemic season than during other influenza seasons. In recent years, the influenza-related employer burden has increased considerably. In future, employers may need efficient resource allocation in order to address the productivity losses and increasing direct medical costs associated with increased influenza incidence. One of the strategies that employers may consider is increasing influenza vaccination rates among employees, which likely will help lower the influenza incidence and the associated downstream direct and indirect costs.
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Age-specific comparisons of influenza and respiratory syncytial virus (RSV) hospitalization rates can inform prevention efforts, including vaccine development plans. Previous US studies have not estimated jointly the burden of these viruses using similar data sources and over many seasons. We estimated influenza and RSV hospitalizations in 5 age categories (<1, 1-4, 5-49, 50-64, and ≥65 years) with data for 13 states from 1993-1994 through 2007-2008. For each state and age group, we estimated the contribution of influenza and RSV to hospitalizations for respiratory and circulatory disease by using negative binomial regression models that incorporated weekly influenza and RSV surveillance data as covariates. Mean rates of influenza and RSV hospitalizations were 63.5 (95% confidence interval [CI], 37.5-237) and 55.3 (95% CI, 44.4-107) per 100000 person-years, respectively. The highest hospitalization rates for influenza were among persons aged ≥65 years (309/100000; 95% CI, 186-1100) and those aged <1 year (151/100000; 95% CI, 151-660). For RSV, children aged <1 year had the highest hospitalization rate (2350/100000; 95% CI, 2220-2520) followed by those aged 1-4 years (178/100000; 95% CI, 155-230). Age-standardized annual rates per 100000 person-years varied substantially for influenza (33-100) but less for RSV (42-77). Overall US hospitalization rates for influenza and RSV are similar; however, their age-specific burdens differ dramatically. Our estimates are consistent with those from previous studies focusing either on influenza or RSV. Our approach provides robust national comparisons of hospitalizations associated with these 2 viral respiratory pathogens by age group and over time.
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We estimated the possible effects of the next influenza pandemic in the United States and analyzed the economic impact of vaccine-based interventions. Using death rates, hospitalization data, and outpatient visits, we estimated 89,000 to 207,000 deaths; 314,000 to 734,000 hospitalizations; 18 to 42 million outpatient visits; and 20 to 47 million additional illnesses. Patients at high risk (15% of the population) would account for approximately 84% of all deaths. The estimated economic impact would be US$71.3 to $166.5 billion, excluding disruptions to commerce and society. At $21 per vaccinee, we project a net savings to society if persons in all age groups are vaccinated. At $62 per vaccinee and at gross attack rates of 25%, we project net losses if persons not at high risk for complications are vaccinated. Vaccinating 60% of the population would generate the highest economic returns but may not be possible within the time required for vaccine effectiveness, especially if two doses of vaccine are required.
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Respiratory viral infections are responsible for a large number of hospitalizations in the United States each year. To estimate annual influenza-associated hospitalizations in the United States by hospital discharge category, discharge type, and age group. National Hospital Discharge Survey (NHDS) data and World Health Organization Collaborating Laboratories influenza surveillance data were used to estimate annual average numbers of hospitalizations associated with the circulation of influenza viruses from the 1979-1980 through the 2000-2001 seasons in the United States using age-specific Poisson regression models. We estimated influenza-associated hospitalizations for primary and any listed pneumonia and influenza and respiratory and circulatory hospitalizations. Annual averages of 94,735 (range, 18,908-193,561) primary and 133,900 (range, 30,757-271,529) any listed pneumonia and influenza hospitalizations were associated with influenza virus infections. Annual averages of 226,54 (range, 54,523-430,960) primary and 294,128 (range, 86,494-544,909) any listed respiratory and circulatory hospitalizations were associated with influenza virus infections. Persons 85 years or older had the highest rates of influenza-associated primary respiratory and circulatory hospitalizations (1194.9 per 100,000 persons). Children younger than 5 years (107.9 primary respiratory and circulatory hospitalizations per 100,000 persons) had rates similar to persons aged 50 through 64 years. Estimated rates of influenza-associated hospitalizations were highest during seasons in which A(H3N2) viruses predominated, followed by B and A(H1N1) seasons. After adjusting for the length of each influenza season, influenza-associated primary pneumonia and influenza hospitalizations increased over time among the elderly. There were no significant increases in influenza-associated primary respiratory and circulatory hospitalizations after adjusting for the length of the influenza season. Significant numbers of influenza-associated hospitalizations in the United States occur among the elderly, and the numbers of these hospitalizations have increased substantially over the last 2 decades due in part to the aging of the population. Children younger than 5 years had rates of influenza-associated hospitalizations similar to those among individuals aged 50 through 64 years. These findings highlight the need for improved influenza prevention efforts for both young and older US residents.
Article
Background: The seasonal incidence of influenza is often approximated as "5% to 20%". Methods: We used two methods to estimate the seasonal incidence of symptomatic influenza in the United States. First, we made a statistical estimate extrapolated from influenza-associated hospitalization rates for 2010-11 to 2015-16, collected as part of national surveillance, covering approximately 9% of the United States, and including the existing mix of vaccinated and unvaccinated persons. Second, we performed a literature search and meta-analysis of published manuscripts that followed cohorts of subjects during 1996-2016 to detect laboratory-confirmed symptomatic influenza among unvaccinated persons; we adjusted this result to the United States median vaccination coverage and effectiveness during 2010-2016. Results: The statistical estimate of influenza incidence among all ages ranged from 3.0-11.3% among seasons, with median values of 8.3 (95% confidence interval [CI] 7.3%, 9.7%) for all ages, 9.3% (CI 8.2%, 11.1%) for children <18 years and 8.9% (CI 8.2%, 9.9%) for adults 18-64 years. Corresponding values for the meta-analysis were 7.1% (CI 6.1, 8.1) for all ages, 8.7% (6.6, 10.5) for children, and 5.1% (3.6, 6.6) for adults. Conclusions: The two approaches produced comparable results for children and persons of all ages. The statistical estimates are more versatile and permit estimation of season-to-season variation. During 2010-2016, the incidence of symptomatic influenza among vaccinated and unvaccinated United States residents, including both medically attended and non-attended infections, was approximately 8% and varied from 3% to 11% among seasons.
Article
Background: Immune responses to influenza vaccines decline with age, reducing clinical effectiveness. We compared the effect of the more immunogenic high-dose trivalent influenza vaccine with a standard-dose vaccine to identify the effect on reducing hospital admissions of nursing home residents in the USA. Methods: We did a single-blind, pragmatic, comparative effectiveness, cluster-randomised trial with a 2 × 2 factorial design. Medicare-certified nursing homes in the USA located within 50 miles of a Centers for Disease Control and Prevention influenza reporting city were recruited, so long as the facilities were not located in a hospital, had more than 50 long-stay residents, had less than 20% of the population aged under 65 years, and were not already planning to administer the high-dose influenza vaccine to residents. Enrolled nursing homes were randomised to a facility-wide standard of care for the residents of either high dose or standard dose as the vaccine for the 2013-14 influenza season and half of each group were randomly allocated to free vaccines for staff. Individual residents were included in the analysis group if they were aged 65 years or older and were long-stay residents (ie, had been in the facility 90 days or more before commencing the influenza vaccination programme). The analysts and investigators with access to the raw data were masked to study group by coding the groups until after the analyses were complete. The primary outcome was hospital admissions related to pulmonary and influenza-like illness between Nov 1, 2013, and May 31, 2014, identified from Medicare hospital claims available for residents who were without private health insurance (ie, those who were considered Medicare fee-for-service). We obtained data from the Centers for Medicare & Medicaid Services (CMS) and enrolled facilities. The analyses used marginal Poisson and Cox proportional hazards regression, accounting for clustering of residents within homes, on an intention-to-treat basis, adjusting for facility clustering and prespecified covariates. Safety data were voluntarily reported according to the standard of care. This trial is registered with ClinicalTrials.gov, number NCT01815268. Findings: 823 facilities were recruited to the study between March and August, 2013, to participate in the trial, of which 409 facilities were randomised for residents to receive high-dose vaccine, and 414 facilities for residents to receive standard-dose vaccine. The facilities housed 92 269, of whom 75 917 were aged 65 years or older and 53 008 were also long-stay residents, and 38 256 were matched to Medicare hospital claims as of Nov 1, 2013. Staff vaccination rates did not differ between groups, so analyses focused on the high-dose versus standard-dose vaccine comparison. On the basis of Medicare fee-for-service claims, the incidence of respiratory-related hospital admissions was significantly lower in facilities where residents received high-dose influenza vaccines than in those that received standard-dose influenza vaccines (0·185 per 1000 resident-days or 3·4% over 6 months vs 0·211 per 1000 resident-days or 3·9% over 6 months; unadjusted relative risk of 0·888, 95% CI 0·785-1·005, 0=0·061, and adjusted relative risk 0·873, 0·776-0·982, p=0·023). Interpretation: When compared with standard-dose vaccine, high-dose influenza vaccine can reduce risk of respiratory-related hospital admissions from nursing home residents aged 65 years and older. Funding: Sanofi Pasteur, Swiftwater, PA, USA.
Article
Background: There is a paucity of data on the clinical and economic impact of seasonal influenza in children. This study estimated the incidence of diagnosed influenza and related complications, and associated healthcare resource utilization (HRU) and costs in US children. Methods: Children ≥6 months and <18 years old diagnosed with influenza using ICD-9 codes and enrolled in a health plan during at least one influenza season between 2010-2014 were matched to similar patients without diagnosed influenza (GSK study identifier: HO-15-15728). Outcomes included incidence of influenza and complications, HRU frequency, and healthcare costs during 21 days of follow-up. Adjusted costs were estimated using generalized linear models. Results: Incidence (per 1,000) of influenza was 20.3 (commercially-insured) and 32.6 (Medicaid), with the highest incidence among 6 to 35-month olds (Commercial: 26.8; Medicaid: 47.9). Approximately 12-17% of influenza patients experienced complications, with the 6-35 months group having the highest percentage (25-30%). The 6-35-month-old influenza patients with complications had the highest proportion with hospitalizations (5-6%) and emergency room visits (Commercial: 19%; Medicaid: 36%). Influenza patients with (vs. without) complications had greater adjusted mean influenza-specific costs (Commercial: $1,161 vs. $337; Medicaid: $1,199 vs. $354; p<0.05), and influenza cases (vs. controls) had greater adjusted mean all-cause costs (Commercial: $688 vs. $470; Medicaid: $818 vs. $453; p<0.05). Conclusions: Pediatric patients with influenza incurred higher healthcare costs compared with matched controls, and influenza-specific costs were greater among those with complications.
Article
Although researchers have demonstrated that influenza illness has affected societies for many centuries, in more recent decades, the World Health Organization and the Centers for Disease Control and Prevention have developed sophisticated means of tracking the virus' activity around the globe. The importance of tracking influenza activity lies not only in detecting what is circulating in other countries, but also in enabling global manufacturers of vaccine to prepare the appropriate A and B compositions for the impending epidemic. Tracking influenza also allows quantification of its great toll in terms of morbidity and mortality. Influenza has broad societal and financial impact, with as much as $12 to $14 billion in indirect economic impact in the United States annually and a significant increase in physician visits for febrile respiratory illness. For example, during many influenza outbreaks visits to family care physicians and internal medicine specialists earl increase by 150% to 450%. Influenza presents an ongoing public health issue because of the virus' ability to continually reinvent itself. Antigenic drift, caused by subtle changes in influenza's surface proteins, partially accounts for annual epidemic outbreaks of the illness. Antigenic shift that occurs because of major changes in the viral hemagglutinin and sometimes in the neuraminidase, the other surface protein, results in the more widespread and lethal pandemic forms of influenza. Moreover, type A influenza is not an exclusively human infection. By understanding how both of these types of changes occur in waterfowl, the virus' primary nonhuman hosts, scientists can develop both drugs and epidemiological strategies to avert or minimize the most severe effects of influenza.
Article
Background Seasonal influenza causes considerable morbidity and mortality across all age groups, and influenza vaccination was recommended in 2010 for all persons aged 6 months and above. We estimated the averted costs due to influenza vaccination, taking into account the seasonal economic burden of the disease. Methods We used recently published values for averted outcomes due to influenza vaccination for influenza seasons 2005-06, 2006-07, 2007-08, and 2008-09, and age cohorts 6 months-4 years, 5-19 years, 20-64 years, and 65 years and above. Costs were calculated according to a payer and societal perspective (in 2009 US$), and took into account medical costs and productivity losses. Results When taking into account direct medical costs (payer perspective), influenza vaccination was cost saving only for the older age group (65≥) in seasons 2005-06 and 2007-08. Using the same perspective, influenza vaccination resulted in total costs of $US 1.7 billion (95%CI: $US 0.3–4.0 billion) in 2006-07 and $US 1.8 billion (95%CI: $US 0.1–4.1 billion) in 2008-09. When taking into account a societal perspective (and including the averted lost earnings due to premature death) averted deaths in the older age group influenced the results, resulting in cost savings for all ages combined in season 07-08. Discussion Influenza vaccination was cost saving in the older age group (65≥) when taking into account productivity losses and, in some seasons, when taking into account medical costs only. Averted costs vary significantly per season; however, in seasons where the averted burden of deaths is high in the older age group, averted productivity losses due to premature death tilt overall seasonal results towards savings. Indirect vaccination effects and the possibility of diminished case severity due to influenza vaccination were not considered, thus the averted burden due to influenza vaccine may be even greater than reported.
Article
Since the introduction of pandemic influenza A (H1N1) to the USA in 2009, the Influenza Incidence Surveillance Project has monitored the burden of influenza in the outpatient setting through population-based surveillance. From Oct 1, 2009, to July 31, 2013, outpatient clinics representing 13 health jurisdictions in the USA reported counts of influenza-like illness (fever including cough or sore throat) and all patient visits by age. During four years, staff at 104 unique clinics (range 35-64 per year) with a combined median population of 368 559 (IQR 352 595-428 286) attended 35 663 patients with influenza-like illness and collected 13 925 respiratory specimens. Clinical data and a respiratory specimen for influenza testing by RT-PCR were collected from the first ten patients presenting with influenza-like illness each week. We calculated the incidence of visits for influenza-like illness using the size of the patient population, and the incidence attributable to influenza was extrapolated from the proportion of patients with positive tests each week. The site-median peak percentage of specimens positive for influenza ranged from 58·3% to 77·8%. Children aged 2 to 17 years had the highest incidence of influenza-associated visits (range 4·2-28·0 per 1000 people by year), and adults older than 65 years had the lowest (range 0·5-3·5 per 1000 population). Influenza A H3N2, pandemic H1N1, and influenza B equally co-circulated in the first post-pandemic season, whereas H3N2 predominated for the next two seasons. Of patients for whom data was available, influenza vaccination was reported in 3289 (28·7%) of 11 459 patients with influenza-like illness, and antivirals were prescribed to 1644 (13·8%) of 11 953 patients. Influenza incidence varied with age groups and by season after the pandemic of 2009 influenza A H1N1. High levels of influenza virus circulation, especially in young children, emphasise the need for additional efforts to increase the uptake of influenza vaccines and antivirals. US Centers for Disease Control and Prevention. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
A high-dose trivalent inactivated influenza vaccine was licensed in 2009 by the US Food and Drug Administration (FDA) on the basis of serological criteria. We sought to establish whether high-dose inactivated influenza vaccine was more effective for prevention of influenza-related visits and hospital admissions in US Medicare beneficiaries than was standard-dose inactivated influenza vaccine. In this retrospective cohort study, we identified Medicare beneficiaries aged 65 years and older who received high-dose or standard-dose inactivated influenza vaccines from community pharmacies that offered both vaccines during the 2012-13 influenza season. Outcomes were defined with billing codes on Medicare claims. The primary outcome was probable influenza infection, defined by receipt of a rapid influenza test followed by dispensing of the neuraminidase inhibitor oseltamivir. The secondary outcome was a hospital or emergency department visit, listing a Medicare billing code for influenza. We estimated relative vaccine effectiveness by comparing outcome rates in Medicare beneficiaries during periods of high influenza circulation. Univariate and multivariate Poisson regression models were used for analyses. Between Aug 1, 2012 and Jan 31, 2013, we studied 929 730 recipients of high-dose vaccine and 1 615 545 recipients of standard-dose vaccine. Participants enrolled in each cohort were well balanced with respect to age and presence of underlying medical disorders. The high-dose vaccine (1·30 outcomes per 10 000 person-weeks) was 22% (95% CI 15-29) more effective than the standard-dose vaccine (1·01 outcomes per 10 000 person-weeks) for prevention of probable influenza infections (rapid influenza test followed by oseltamivir treatment) and 22% (95% CI 16-27%) more effective for prevention of influenza hospital admissions (0·86 outcomes per 10 000 person-weeks in the high-dose cohort vs 1·10 outcomes per 10 000 person-weeks in the standard-dose cohort). Our retrospective cohort study in US Medicare beneficiaries shows that, in people 65 years of age and older, high-dose inactivated influenza vaccine was significantly more effective than standard-dose vaccine in prevention of influenza-related medical encounters. Additionally, the large population in our study enabled us to show, for the first time, a significant reduction in influenza-related hospital admissions in high-dose compared to standard-dose vaccine recipients, an outcome not shown in randomised studies. These results provide important new information to be considered by policy makers recommending influenza vaccinations for elderly people. FDA and the office of the Assistant Secretary of Planning and Evaluation. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
Human capital estimates of labor productivity are often used to estimate the economic impact of diseases and injuries that cause incapacitation or death. Estimates of average hourly, annual, and lifetime economic productivity, both market and household, were calculated in 2007 US dollars for 5-year age groups for men, women, and both sexes in the United States. Data from the American Time Use Survey were used to estimate hours of paid work and household services and hourly and annual earnings and household productivity. Present values of discounted lifetime earnings were calculated for each age group using the 2004 US life tables and a discount rate of 3% per year and assuming future productivity growth of 1% per year. The estimates of hours and productivity were calculated using the time diaries of 72,922 persons included in the American Time Use Survey for the years 2003 to 2007. The present value of lifetime productivity is approximately $1.2 million in 2007 dollars for children under 5 years of age. For adults in their 20s and 30s, it is approximately $1.6 million and then it declines with increasing age. Productivity estimates are higher for males than for females, more for market productivity than for total productivity. Changes in hours of paid employment and household services can affect economic productivity by age and sex. This is the first publication to include estimates of household services based on contemporary time use data for the US population.
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Healthcare delivery in the USA and abroad has changed dramatically over the last several decades. Along with the growth in diagnostic and therapeutic interventions, the costs of healthcare have escalated out of proportion relative to other aspects of the economy. This growth has fostered careful scrutiny of both the effectiveness and efficiency of healthcare delivery. Because of this emphasis on the economics of healthcare, physicians require an understanding not only of the efficacy and clinical utility of their interventions, but also of the relative value in an economic sense of their efforts. In other words, physicians in the modern era must now appreciate the concept of cost-effectiveness. Cost-effectiveness and cost-utility analyses are critical evaluative tools. Explicit data on comparative cost-effectiveness are useful for allocating the increasingly stretched healthcare resources. This article provides a primer for understanding the methods and applications of cost-effectiveness and cost-utility analyses.
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This study aimed to compare systematically approaches to estimating influenza-attributable mortality in older Australians. Using monthly age-specific death data together with viral surveillance counts for influenza and respiratory syncytial virus, we explored two of the most frequently used methods of estimating excess influenza-attributable disease: Poisson and Serfling regression models. These approaches produced consistent age and temporal patterns in estimates of influenza-attributable mortality in older Australians but some variation in the magnitude of the disease burden. Of Australians aged >50 years, average annual estimated influenza-attributable deaths (all cause) ranged from 2314 to 3457 for the Serfling and Poisson regression models, respectively. The excess influenza-attributable disease burden was substantial under all approaches.
Article
We measured the relative impact of influenza and respiratory syncytial virus (RSV) infections in young children in terms of emergency department (ED) visits, clinical care requirements, and overall resource use. Patients who were aged <or=7 years and treated in the ED of a tertiary care pediatric hospital for an acute respiratory infection were enrolled during 2 winter seasons between 2003 and 2005. We quantified health care resource use for children with influenza or RSV infections, and extrapolated results to estimate the national resource use associated with influenza and RSV infections. Nationally, an estimated 10.2 ED visits per 1000 children were attributable to influenza and 21.5 visits per 1000 to RSV. Children who were aged 0 to 23 months and infected with RSV had the highest rate of ED visits with 64.4 visits per 1000 children. Significantly more children required hospitalization as a result of an RSV infection compared with influenza, with national hospitalization rates of 8.5 and 1.4 per 1000 children, respectively. The total number of workdays missed yearly by caregivers of children who required ED care was 246965 days for influenza infections and 716404 days for RSV infections. For young children, RSV is associated with higher rates of ED visits, hospitalization, and caregiver resource use than is influenza. Our results provide data on the large number of children who receive outpatient care for influenza and RSV illnesses and serve to inform analyses of prevention programs and treatments for both influenza and RSV disease.
Article
The cost-effectiveness of treating influenzalike illness (ILI) with oseltamivir in the United States was assessed. A decision-analysis model was developed with a one-year time horizon to assess the cost-effectiveness of oseltamivir compared with usual care from societal and payer perspectives for four patient populations: high-risk adults, healthy adults, elderly adults, and children. The model used efficacy data from oseltamivir clinical trials and other published literature and assumed oseltamivir was effective only in individuals infected with influenza virus not resistant to oseltamivir and treated within 48 hours of symptom onset. Direct medical costs were based on resources used; indirect costs were estimated based on time lost from work due to illness and premature mortality. Base-case estimates were tested in one-way sensitivity and variability analyses. From a societal perspective, oseltamivir was cost-effective across all populations modeled, with an incremental cost per quality-adjusted life-year gained of $5,388, $6,317, $7,652, and $16,176 for high-risk adults, children, elderly adults, and healthy adults, respectively. Results were similar from a payer perspective. When indirect costs were included (for all populations except elderly adults), oseltamivir was cost saving. In sensitivity analyses, oseltamivir remained cost-effective across all patient populations for all values tested, except the probability of developing influenza-related pneumonia. Variability analyses showed that oseltamivir remained cost-effective under most scenarios tested. Base-case results and sensitivity analyses from a decision-analysis model found that treatment of ILI with oseltamivir was cost-effective compared with usual care from U.S. payer and societal perspectives in all patient populations studied when only direct costs were considered.
Article
The impact of influenza has been recognized for centuries. Its seasonality in temperate climates has allowed estimates of mortality and severe morbidity, such as hospitalization, to be made statistically, without identifying cases virologically. Most influenza related mortality occurs in older individuals and those with underlying conditions. In addition to those groups, influenza hospitalizations occur in younger children and pregnant women. Morbidity is more difficult to identify and laboratory confirmation is required for precise estimates to be made. Younger individuals experience the highest frequency of illnesses caused by all subtypes. This has resulted in suggested strategies for community control by vaccinating children.
Article
Many respiratory viruses cause morbidity in young children, but a licensed vaccine and effective oral therapy are available only for influenzavirus. To determine the incidence of laboratory-confirmed influenza illness, we prospectively followed up 1665 healthy children aged <5 years who were enrolled in the Vanderbilt Vaccine Clinic at some point from 1974 through 1999. Viral cultures were obtained when the children presented with clinical illness. The isolation of influenzavirus was associated with an estimated 95 health care visits for children with symptoms of influenza, 46 episodes of acute otitis media, and 8 episodes of lower respiratory tract disease per 1000 children yearly. Rates of acute otitis media and lower respiratory tract disease were highest among children aged <2 years. Hospitalizations associated with culture-positive influenza occurred at an annual rate of 3–4 per 1000 children aged <2 years. Influenza is associated with substantial morbidity in otherwise healthy children aged <5 years
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The current healthcare environment requires the evaluation of both the costs and benefits of alternative interventions for a given clinical problem. Given the increased interest in the economic evaluation of healthcare interventions, this article briefly defines various forms of economic evaluations and describes some useful steps for conducting appraisals of cost-effectiveness analyses. Studies of competing methods of treatment of abdominal aortic aneurysms greater than 5 cm are used as a clinical example of interest to the readers of this Journal. Rather than actually conducting such an analysis with existing data, we describe the principles for conducting or reviewing an economic analysis with factitious data.