Consultations for Influenza-Like Illness in Primary Care in The Netherlands: A Regression Approach.

OBJECTIVES: To estimate the general practitioner (GP) consultation rate attributable to influenza in The Netherlands. METHODS: Regression analysis was performed on the weekly numbers of influenza-like illness (ILI) GP consultations and laboratory reports for influenza virus types A and B and 8 other pathogens over the period 2003-2014 (11 influenza seasons; week 40-20 of the following year). RESULTS: In an average influenza season, 27% and 11% of ILI GP consultations were attributed to infection by influenza virus types A and B, respectively. Influenza is therefore responsible for approximately 107 000 GP consultations (651/100 000) each year in The Netherlands. GP consultation rates associated with influenza infection were highest in children under 5 years of age, at 667 of 100 000 for influenza A and 258 of 100 000 for influenza B. Influenza virus infection was found to be the predominant cause of ILI-related GP visits in all age groups except children under 5, in which respiratory syncytial virus (RSV) infection was found to be the main contributor. CONCLUSIONS: The burden of influenza in terms of GP consultations is considerable. Overall, influenza is the main contributor to ILI. Although ILI symptoms in children under 5 years of age are most often associated with RSV infection, the majority of visits related to influenza occur among children under 5 years of age.

Cost-Effectiveness of Pediatric Influenza Vaccination in The Netherlands.

OBJECTIVE: This study evaluates the cost-effectiveness of extending the Dutch influenza vaccination program for elderly and medical high-risk groups to include pediatric influenza vaccination, taking indirect protection into account. METHODS: An age-structured dynamic transmission model was used that was calibrated to influenza-associated GP visits over 4 seasons (2010-2011 to 2013-2014). The clinical and economic impact of different pediatric vaccination strategies were compared over 20 years, varying the targeted age range, the vaccine type for children or elderly and high-risk groups. Outcome measures include averted symptomatic infections and deaths, societal costs and quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Costs and QALYs were discounted at 4% and 1.5% annually. RESULTS: At an assumed coverage of 50%, adding pediatric vaccination for 2- to 17-year-olds with quadrivalent live-attenuated vaccine to the current vaccination program for elderly and medical high-groups with quadrivalent inactivated vaccine was estimated to avert, on average, 401 820 symptomatic cases and 72 deaths per year. Approximately half of averted symptomatic cases and 99% of averted deaths were prevented in other age groups than 2- to 17-year-olds due to herd immunity. The cumulative discounted 20-year economic impact was 35 068 QALYs gained and €1687 million saved, that is, the intervention was cost-saving. This vaccination strategy had the highest probability of being the most cost-effective strategy considered, dominating pediatric strategies targeting 2- to 6-year-olds or 2- to 12-year-olds or strategies with trivalent inactivated vaccine. CONCLUSION: Modeling indicates that introducing pediatric influenza vaccination in The Netherlands is cost-saving, reducing the influenza-related disease burden substantially.

Economic Analysis of Vaccination Programs: An ISPOR Good Practices for Outcomes Research Task Force Report.

This report provides recommendations for budget holders and decision makers in high-, middle, and low-income countries requiring economic analyses of new vaccination programs to allocate scarce resources given budget constraints. ISPOR's Economic Evaluation of Vaccines Designed to Prevent Infectious Disease: Good Practices Task Force wrote guidelines for three analytic methods and solicited comments on them from external reviewers. Cost-effectiveness analyses use decision-analytic models to estimate cumulative changes in resource use, costs, and changes in quality- or disability-adjusted life-years attributable to changes in disease outcomes. Constrained optimization modeling uses a mathematical objective function to be optimized (e.g. disease cases avoided) for a target population for a set of interventions including vaccination programs within established constraints. Fiscal health modeling estimates changes in net present value of government revenues and expenditures attributable to changes in disease outcomes. The task force recommends that those designing economic analyses for new vaccination programs take into account the decision maker's policy objectives and country-specific decision context when estimating: uptake rate in the target population; vaccination program's impact on disease cases in the population over time using a dynamic transmission epidemiologic model; vaccination program implementation and operating costs; and the changes in costs and health outcomes of the target disease(s). The three approaches to economic analysis are complementary and can be used alone or together to estimate a vaccination program's economic value for national, regional, or subregional decision makers in high-, middle-, and low-income countries.

Cost-Effectiveness of Quadrivalent versus Trivalent Influenza Vaccine in the United States.

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.

A cost-effectiveness analysis of reduced viral transmission with baloxavir marboxil versus oseltamivir or no treatment for seasonal and pandemic influenza management in the United Kingdom.

BACKGROUND: Baloxavir marboxil is an oral, single-dose, cap-dependent endonuclease inhibitor that reduces the duration of influenza symptoms and rapidly stops viral shedding. We developed a susceptible, exposed, infected, recovered (SEIR) model to inform a cost-effectiveness model (CEM) of baloxavir versus oseltamivir or no antiviral treatment in the UK. RESEARCH DESIGN AND METHODS: The SEIR model estimated the attack rates among otherwise healthy and high-risk individuals in seasonal and pandemic settings. The CEM assumed that a proportion of infected patients would receive antiviral treatment. Results were reported at the population level (per 10,000 at risk of infection). RESULTS: The SEIR model estimated greater reductions in infections with baloxavir. In a seasonal setting, baloxavir provided incremental cost-effectiveness ratios (ICERs) of £1884 per quality-adjusted life-year (QALY) gained versus oseltamivir and a dominant cost-effectiveness position versus no antiviral treatment in the total population; ICERs of £2574/QALY versus oseltamivir and £128/QALY versus no antiviral treatment were seen in the high-risk population. Baloxavir was also cost-effective versus oseltamivir or no antiviral treatment and reduced population-level health system occupancy concerns during a pandemic. CONCLUSION: Baloxavir treatment resulted in the fewest influenza cases and was cost-effective versus oseltamivir or no antiviral treatment from a UK National Health Service perspective.

Baloxavir marboxil ('baloxavir') is a prescription medicine for people who become ill with influenza (or 'the flu') that can reduce how long flu symptoms last and the likelihood of complications from the flu that may require going to the hospital. Baloxavir can also reduce the amount and duration of virus shed by infected individuals thus potentially slow or stop the flu from spreading to healthy people. We studied differences in reducing predicted flu infections between baloxavir and another flu treatment, known as oseltamivir, or no flu treatment at all. Treatment with baloxavir resulted in fewer flu infections in the UK population than oseltamivir or no treatment. We then studied how these differences might affect costs between baloxavir and oseltamivir or no treatment at a population level in the UK. Overall, in the majority of scenarios explored in the model, baloxavir was cost-effective as an antiviral treatment for people with the flu in the UK.

Dynamic transmission modeling: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force--5.

The transmissible nature of communicable diseases is what sets them apart from other diseases modeled by health economists. The probability of a susceptible individual becoming infected at any one point in time (the force of infection) is related to the number of infectious individuals in the population, will change over time, and will feed back into the future force of infection. These nonlinear interactions produce transmission dynamics that require specific consideration when modeling an intervention that has an impact on the transmission of a pathogen. Best practices for designing and building these models are set out in this article.

Cost-effectiveness of duloxetine: the Stress Urinary Incontinence Treatment (SUIT) study.

OBJECTIVE: To assess the cost-effectiveness of duloxetine compared with conservative therapy in women with stress urinary incontinence (SUI). METHODS: Cost and outcome data were taken from the Stress Urinary Incontinence Treatment (SUIT) study, a 12-month, prospective, observational, naturalistic, multicenter, multicountry study. Costs were assessed in UK pound and outcomes in quality adjusted life years using responses to the EuroQol (EQ-5D); numbers of urine leaks were also estimated. Potential selection bias was countered using multivariate regression and propensity score analysis. RESULTS: Duloxetine alone, duloxetine in combination with conservative treatment, and conservative treatment alone were associated with roughly two fewer leaks per week compared with no treatment. Duloxetine alone and with conservative treatment for SUI were associated with incremental quality-adjusted life-years (QALYs) of about 0.03 over a year compared with no treatment or with conservative treatment alone. Conservative treatment alone did not show an effect on QALYs. None of the interventions appeared to have marked impacts on costs over a year. Depending on the form of matching, duloxetine either dominated or had an incremental cost-effectiveness ratio (ICER) below pound900 per QALY gained compared with no treatment and with conservative treatment alone. Duloxetine plus conservative therapy had an ICER below pound5500 compared with no treatment or conservative treatment alone. Duloxetine compared with duloxetine plus conservative therapy showed similar outcomes but an additional cost for the combined intervention. CONCLUSIONS: Although the limitations of the use of SUIT's observational data for this purpose need to be acknowledged, the study suggests that initiating duloxetine therapy in SUI is a cost-effective treatment alternative.

Intestinal heat shock protein 110 regulates expression of CD1d on intestinal epithelial cells.

CD1d is expressed on the surface of professional and nonprofessional APCs, including intestinal epithelial cells (IECs), for a role in the presentation of glycolipid-based antigens to subsets of T cells. The mechanisms that regulate CD1d expression in any cell type are unknown. To investigate the possibility that expression of CD1d is influenced by exogenous factors present within the intestinal lumen, CD1d expression was analyzed in several IEC lines after culturing in the presence of lumenal contents (LC) of the normal human intestine. Exposure of the colon-derived cell lines T84, HT-29, and Caco-2 to soluble LC resulted in a marked induction of CD1d expression as determined by RT-PCR, confocal microscopy, cell surface ELISA, and Western blot analysis. Similarly, exposure of human IECs to LC isolated from mice bred in both specific pathogen-free and germfree conditions also resulted in the induction of CD1d expression, with the maximum CD1d-inducing activity observed in the small intestine. Biochemical and biophysical characterization of the human CD1d-inducing activity identified heat shock protein 110 (Hsp110) as a major functional component of the LC that contributes to CD1d surface regulation, and immunolocalization studies revealed Hsp110 expression in subsets of human IECs in vivo. These data support the presence of a novel autocrine pathway of CD1d regulation by Hsp110.

A systematic review of the health economic consequences of quadrivalent influenza vaccination.

BACKGROUND: Quadrivalent influenza vaccines (QIVs) contain antigens derived from an additional influenza type B virus as compared with currently used trivalent influenza vaccines (TIVs). This should overcome a potential reduced vaccine protection due to mismatches between TIV and circulating B viruses. In this study, we systematically reviewed the available literature on health economic evaluations of switching from TIV to QIV. Areas covered: The databases of Medline and Embase were searched systematically to identify health economic evaluations of QIV versus TIV published before September 2016.A total of sixteen studies were included, thirteen cost-effectiveness analyses and three cost-comparisons. Expert commentary: Published evidence on the cost-effectiveness of QIV suggests that switching from TIV to QIV would be a valuable intervention from both the public health and economic viewpoint. However, more research seems mandatory. Our main recommendations for future research include: 1) more extensive use of dynamic models in order to estimate the full impact of QIV on influenza transmission including indirect effects, 2) improved availability of data on disease outcomes and costs related to influenza type B viruses, and 3) more research on immunogenicity of natural influenza infection and vaccination, with emphasis on cross-reactivity between different influenza B viruses and duration of protection.

Delaying the international spread of pandemic influenza.

BACKGROUND: The recent emergence of hypervirulent subtypes of avian influenza has underlined the potentially devastating effects of pandemic influenza. Were such a virus to acquire the ability to spread efficiently between humans, control would almost certainly be hampered by limited vaccine supplies unless global spread could be substantially delayed. Moreover, the large increases that have occurred in international air travel might be expected to lead to more rapid global dissemination than in previous pandemics. METHODS AND FINDINGS: To evaluate the potential of local control measures and travel restrictions to impede global dissemination, we developed stochastic models of the international spread of influenza based on extensions of coupled epidemic transmission models. These models have been shown to be capable of accurately forecasting local and global spread of epidemic and pandemic influenza. We show that under most scenarios restrictions on air travel are likely to be of surprisingly little value in delaying epidemics, unless almost all travel ceases very soon after epidemics are detected. CONCLUSIONS: Interventions to reduce local transmission of influenza are likely to be more effective at reducing the rate of global spread and less vulnerable to implementation delays than air travel restrictions. Nevertheless, under the most plausible scenarios, achievable delays are small compared with the time needed to accumulate substantial vaccine stocks.

The Clinical Impact and Cost Effectiveness of Quadrivalent Versus Trivalent Influenza Vaccination in Finland.

BACKGROUND: Trivalent influenza vaccines encompass one influenza B lineage; however, predictions have been unreliable on which of two antigenically distinct circulating lineages will dominate. Quadrivalent seasonal influenza vaccines contain strains from both lineages. This analysis assesses the cost effectiveness of switching from trivalent inactivated influenza vaccination (TIV) in Finland to quadrivalent vaccination, using inactivated (QIV) or live-attenuated (Q-LAIV) vaccines. METHODS: A transmission model simulated the dynamics of influenza infection while accounting for indirect (herd) protection. Prior distributions for key transmission parameters were repeatedly sampled and simulations that fitted the available information on influenza in Finland were recorded. The resulting posterior parameter distributions were used in a probabilistic sensitivity analysis in which economic parameters were sampled, simultaneously encompassing uncertainty in the transmission and economic parameters. The cost effectiveness of a range of trivalent and quadrivalent vaccine policies over a 20-year time horizon was assessed from both a societal and payer perspective in 2014 Euros. RESULTS: The simulated temporal incidence pattern of symptomatic infections corresponded well with case surveillance data. A switch from the current TIV to Q-LAIV in children (2 to <18 years) and to QIV in other ages was estimated to annually avert approximately 76,100 symptomatic infections (95 % range 36,700-146,700), 11,500 primary care consultations (6100-20,000), 540 hospitalisations (240-1180), and 72 deaths (32-160), and was cost-saving relative to TIV (€374 million averted [€161-€752], in 2014 Euros, discounted at 3 %). This scenario had the highest probability of being the most cost-effective scenario considered. CONCLUSIONS: This analysis demonstrates that quadrivalent vaccination is expected to be highly cost effective, reducing the burden of influenza-related disease.

Cholera toxin potentiates influences of IFN-gamma through activation of NF-kappaB and release of tumor necrosis factor-alpha.

Cholera toxin (Ctx) is a potent adjuvant in the mucosal immune system. Previous studies have indicated that Ctx induces intestinal interferon-gamma (IFN-gamma) production and that adjuvant properties require activation of the IFN-gamma receptor (IFNGR). Thus, we hypothesized that Ctx potentiates IFN-gamma responses in intestinal epithelia. Initial studies suggested that Ctx enhances IFN-gamma-mediated barrier disruption in cultured intestinal epithelia. This response was attributable to liberation of a soluble mediator into conditioned supernatants, subsequently identified as tumor necrosis factor-alpha (TNF-alpha). Extensions of these findings revealed that the Ctx A subunit induces transcriptional activation of proinflammatory genes in addition to TNF-alpha (interleukin-8 [IL- 8], intracellular adhesion molecule-1 [ICAM-1], and IL-6) and that such transactivation is mediated by the transcriptional regulator NF-kappaB. We conclude that Ctx elicits a proinflammatory phenotype in intestinal epithelia and that potentiation of IFN-gamma-mediated barrier disruption by TNF-alpha may contribute to the overall adjuvant properties of Ctx.

Origins and properties of Mycobacterium tuberculosis isolates in London.

Using similarities of IS6110 banding patterns, isolates of Mycobacterium tuberculosis from a population-based study in London were assigned to 12 large groups termed 'superfamilies' (sfams). Analysis of patient data showed a marked geographical association in the distribution of these sfams. In particular, isolates from patients born in Europe were from different sfams than those born elsewhere, indicating that there had been relatively little transmission of tuberculosis in London from immigrant communities into the endogenous population. Multivariate analysis showed that certain sfams were significantly associated with pulmonary rather than extrapulmonary disease, or with sputum smear negativity, independently of country of birth or ethnicity, suggesting that the properties of the infecting organism play a role in the nature of the disease process.

Retrospective public health impact of a quadrivalent influenza vaccine in the United States.

INTRODUCTION: Vaccination is an effective preventive strategy against influenza. However, current trivalent influenza vaccines (TIVs) contain only one of the two influenza B lineages that circulate each year. Vaccine mismatches are frequent because predicting which one will predominate is difficult. Recently licensed quadrivalent influenza vaccines (QIVs) containing the two B lineages should address this issue. Our study estimates their impact by assessing what would have been the US public health benefit of routinely vaccinating with QIV in 2000-2013. METHODS: We developed a dynamic compartmental model that accounts for interactions between influenza B lineages (natural or vaccine-induced) and simulates the multiyear influenza dynamics for 2000-2013. Age-structured population dynamics, vaccine efficacy (VE) per strain, and weekly ramp-up of vaccination coverage are modeled. Sensitivity analyses were performed on VE, duration of immunity, and levels of vaccine-induced cross-protection between B lineages. RESULTS: Assuming a cross-protection of 70% of the VE of the matched vaccine, the model predicts 16% more B lineage cases prevented by QIV. Elderly (≥65 years) and young seniors (50-64 years) benefit most from QIV, with 21% and 18% reductions in B lineage cases. Reducing cross-protection to 50%, 30%, and 0% of the VE of the matched vaccine improves the relative benefit of QIV to 25%, 30%, and 34% less B lineage cases. CONCLUSION: Using a dynamic retrospective framework with real-life vaccine mismatch, our analysis shows that QIV routine vaccination in the United States has the potential to substantially reduce the number of influenza infections, even with relatively high estimates of TIV-induced cross-protection.

The hidden burden of adult allergic rhinitis: UK healthcare resource utilisation survey.

BACKGROUND: The affliction of allergic rhinitis (AR) has been trivialised in the past. Recent initiatives by the European Academy of Allergy & Clinical Immunology and by the EU parliament seek to rectify that situation. The aim of this study was to provide a comprehensive picture of the burden and unmet need of AR patients. METHODS: This was a cross-sectional, online, questionnaire-based study (June-July 2011) including symptomatic seasonal AR (SAR) patients (≥18 years) from a panel. SAR episode pattern, severity, medication/co-medication usage, residual symptoms on treatment, number of healthcare visits, absenteeism and presenteeism were collected. RESULTS: One thousand patients were recruited (mild: n = 254; moderate/severe: n = 746). Patients with moderate/severe disease had significantly more symptomatic episodes/year (8.0 vs 6.0/year; p = 0.025) with longer episode-duration (12.5 vs 9.8 days; p = 0.0041) and more commonly used ≥2 AR therapies (70.5 vs 56.1 %; OR 1.87; p = 0.0001), looking for better and faster nasal and ocular symptom relief. The reported symptom burden was high irrespective of treatment, and significantly (p < 0.0001) higher in the moderate/severe group. Patients with moderate/severe AR were more likely to visit their GP (1.61 vs 1.19 times/year; OR: 1.49; p = 0.0061); due to dissatisfaction with therapy in 35.4 % of cases. Patients reported SAR-related absenteeism from work on 4.1 days/year (total cost to UK: £1.25 billion/year) and noted presenteeism for a mean of 37.7 days/year (vs 21.0 days/year; OR 1.71; p = 0.0048). Asthma co-morbid patients reported the need to increase their reliever- (1 in 2 patients) and controller-medication (1 in 5 patients) if they did not take their rhinitis medication. CONCLUSIONS: This study differentiated between patients with mild and moderate/severe AR, demonstrating a burden of poorly controlled symptoms and high co-medication use. The deficiency in obtaining symptom control with what are currently considered firstline treatments suggests the need for a novel therapeutic approach.

Dynamic transmission modeling: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force Working Group-5.

The transmissible nature of communicable diseases is what sets them apart from other diseases modeled by health economists. The probability of a susceptible individual becoming infected at any one point in time (the force of infection) is related to the number of infectious individuals in the population, will change over time, and will feed back into the future force of infection. These nonlinear interactions produce transmission dynamics that require specific consideration when modeling an intervention that has an impact on the transmission of a pathogen. Best practices for designing and building these models are set out in this paper.

Estimating the impact of childhood influenza vaccination programmes in England and Wales.

There is increasing interest in routine vaccination of children against influenza. We use an age-structured model to demonstrate that the long-term incidence of influenza A could decrease by 11-21% in the overall population by vaccinating individuals aged 6 to <24 months, and by 22-38% and 65-97% through targeting those aged 6 to <60 months and 6 months to 16 years, respectively. The corresponding reductions predicted for influenza B were 25-35%, 44-69% and 85-96%, respectively. These results are sensitive to assumptions about contact patterns and several parameters, including the vaccine efficacy among those aged <24 months, require further study. Consistently high levels of vaccination coverage among pre-school children has the potential to bring benefits to both those vaccinated and the community.

CD8+ T cell apoptosis induced by Escherichia coli heat-labile enterotoxin B subunit occurs via a novel pathway involving NF-kappaB-dependent caspase activation.

The B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is a potent immunomodulatory molecule capable of treating and preventing autoimmune disease. These properties result from its ability to bind to glycolipid receptors, principally G(M1) ganglioside, and modulate immune cell function. EtxB receptor binding causes B cell activation, modulates monocyte cytokine secretion and triggers apoptosis of CD8+ T cells. These wide-ranging effects suggest that B subunit receptor interaction triggers signaling events affecting cellular differentiation. We have investigated the processes by which EtxB induces CD8+ T cell apoptosis. We show that receptor interaction by EtxB activates caspase-3 in CD8+ but not in CD4+ T cells. Inhibition of caspase-3 blocks the apoptotic process. EtxB induces the activation of NF-kappaB in both CD8+ and CD4+ T cells. The findings that (i) SN50, a peptide inhibitor of NF-kappaB nuclear translocation, prevents caspase-3 activation and subsequent apoptosis, and (ii) CD8+CD4- thymocytes from transgenic mice expressing a dominant-negative form of the IkappaBalpha protein were markedly less susceptible to EtxB-induced apoptosis than cells from wild-type mice, indicate that NF-kappaB is important in the induction of the apoptotic pathway. Further investigations revealed that while caspase-8 activity is detected concomitant to caspase-3, caspase-9 activation, following mitochondrial cytochrome c release, is detectable later on. These observations are consistent with death receptor-mediated signaling, however, experiments using lpr/lpr and p55 TNFR -/- mice rule out the involvement of Fas and the p55 TNF receptor, respectively. The data therefore indicate that EtxB-mediated apoptosis occurs via a novel pathway involving NF-kappaB.