RSV Disease Burden in Primary Care in Italy: A Multi-Region Pediatric Study, Winter Season 2022-2023.

INTRODUCTION: Human respiratory syncytial virus (RSV) is one of the most frequent causes of respiratory infections in children under 5 years of age, but its socioeconomic impact and burden in primary care settings is still little studied. METHODS: During the 2022/2023 winter season, 55 pediatricians from five Italian regions participated in our community-based study. They collected a nasal swab for RSV molecular test from 650 patients under the age of 5 with acute respiratory infections (ARIs) and performed a baseline questionnaire. The clinical and socioeconomic burden of RSV disease in primary care was evaluated by two follow-up questionnaires completed by the parents of positive children on Days 14 and 30. RESULTS: RSV laboratory-confirmed cases were 37.8% of the total recruited ARI cases, with RSV subtype B accounting for the majority (65.4%) of RSV-positive swabs. RSV-positive children were younger than RSV-negative ones (median 12.5 vs. 16.5 months). The mean duration of symptoms for all children infected by RSV was 11.47 ± 6.27 days. We did not observe substantial differences in clinical severity between the two RSV subtypes, but RSV-A positive patients required more additional pediatric examinations than RSV-B cases. The socioeconomic impact of RSV infection was considerable, causing 53% of children to be absent from school, 46% of parents to lose working days, and 25% of families to incur extra costs. CONCLUSIONS: Our findings describe a baseline of the RSV disease burden in primary care in Italy before the introduction of upcoming immunization strategies.

The FLURESP European commission project: cost-effectiveness assessment of ten public health measures against influenza in Italy: is there an interest in COVID-19 pandemic?

BACKGROUND: The FLURESP project is a public health research funded by the European Commission, with the objective to design a methodological framework to assess the cost-effectiveness of existing public health measures against human influenza pandemics. A dataset has been specifically collected in the frame of the Italian health system. As most of interventions against human influenza are relavant against other respiratory diseases pandemics, potential interests in COVID-19 are discussed. METHODS: Ten public health measures against human influenza pandemics pandemic were selected to be also relevant to other respiratory virus pandemics such as COVID 19: individual (hand washing, using masks), border control (quarantine, fever screening, border closure), community infection (school closure, class dismissal, social distancing, limitation of public transport), reduction of secondary infections (implementation of antibiotic therapy guidelines), pneumococcal vaccination for at-risk people, development of Intensive Care Unit (ICU) capacity, implementation of life support equipments in ICU, screening interventions, vaccination programs targeting health professional and targeting general population. RESULTS: Using mortality reduction as effectiveness criteria, the most cost-effective strategies are "reduction of secondary infections" and "implementation of life support equipment in ICU". The least cost-effective option whatever the level of pandemic events are screening interventions and mass vaccination. CONCLUSIONS: A number of intervention strategies against human influenza pandemics appears relevant against every respiratory virus, including the COVID-19 event. Measures against pandemics should be considered according to their expected effectiveness but also their costs for the society because they impose substantial burden to the population, confirming the interest of considering cost-effectiveness of public health measures to enlighten decision making.

Cost-effectiveness of monoclonal antibody and maternal immunization against respiratory syncytial virus (RSV) in infants: Evaluation for six European countries.

BACKGROUND: Respiratory syncytial virus (RSV) imposes a substantial burden on pediatric hospital capacity in Europe. Promising prophylactic interventions against RSV including monoclonal antibodies (mAb) and maternal immunizations (MI) are close to licensure. Therefore, we aimed to evaluate the cost-effectiveness of potential mAb and MI interventions against RSV in infants, for six European countries. METHODS: We used a static cohort model to compare costs and health effects of four intervention programs to no program and to each other: year-round MI, year-round mAb, seasonal mAb (October to April), and seasonal mAb plus a catch-up program in October. Input parameters were obtained from national registries and literature. Influential input parameters were identified with the expected value of partial perfect information and extensive scenario analyses (including the impact of interventions on wheezing and asthma). RESULTS: From the health care payer perspective, and at a price of €50 per dose (mAb and MI), seasonal mAb plus catch-up was cost-saving in Scotland, and cost-effective for willingness-to-pay (WTP) values ≥€20,000 (England, Finland) or €30,000 (Denmark) per quality adjusted life-year (QALY) gained for all scenarios considered, except when using ICD-10 based hospitalization data. For the Netherlands, seasonal mAb was preferred (WTP value: €30,000-€90,000) for most scenarios. For Veneto region (Italy), either seasonal mAb with or without catch-up or MI was preferred, depending on the scenario and WTP value. From a full societal perspective (including leisure time lost), the seasonal mAb plus catch-up program was cost-saving for all countries except the Netherlands. CONCLUSION: The choice between a MI or mAb program depends on the level and duration of protection, price, availability, and feasibility of such programs, which should be based on the latest available evidence. Future research should focus on measuring accurately age-specific RSV-attributable hospitalizations in very young children.

The New Quadrivalent Adjuvanted Influenza Vaccine for the Italian Elderly: A Health Technology Assessment.

BACKGROUND: The elderly, commonly defined as subjects aged ≥65 years, are among the at-risk subjects recommended for annual influenza vaccination in European countries. Currently, two new vaccines are available for this population: the MF59-adjuvanted quadrivalent influenza vaccine (aQIV) and the high-dose quadrivalent influenza vaccine (hdQIV). Their multidimensional assessment might maximize the results in terms of achievable health benefits. Therefore, we carried out a Health Technology Assessment (HTA) of the aQIV by adopting a multidisciplinary policy-oriented approach to evaluate clinical, economic, organizational, and ethical implications for the Italian elderly. METHODS: A HTA was conducted in 2020 to analyze influenza burden; characteristics, efficacy, and safety of aQIV and other available vaccines for the elderly; cost-effectiveness of aQIV; and related organizational and ethical implications. Comprehensive literature reviews/analyses were performed, and a transmission model was developed in order to address the above issues. RESULTS: In Italy, the influenza burden on the elderly is high and from 77.7% to 96.1% of influenza-related deaths occur in the elderly. All available vaccines are effective and safe; however, aQIV, such as the adjuvanted trivalent influenza vaccine (aTIV), has proved more immunogenic and effective in the elderly. From the third payer's perspective, but also from the societal one, the use of aQIV in comparison with egg-based standard QIV (eQIV) in the elderly population is cost-effective. The appropriateness of the use of available vaccines as well as citizens' knowledge and attitudes remain a challenge for a successful vaccination campaign. CONCLUSIONS: The results of this project provide decision-makers with important evidence on the aQIV and support with scientific evidence on the appropriate use of vaccines in the elderly.

Investigating the procurement system for understanding seasonal influenza vaccine brand availability in Europe.

BACKGROUND: Timely knowledge of which influenza vaccine brands are procured and where is of interest to inform site-selection for brand-specific influenza vaccine effectiveness (VE) studies. Vaccine procurement is a key determinant of brand availability. We therefore sought to understand how the procurement for seasonal influenza vaccine in Europe is organized, how this drives brand availability and how procurement data could enable to determine brand availability pre-season. METHODS: Structured telephone interviews were conducted with 15 experts in 16 European countries between 2017 and 2019 to collect information on the influenza vaccine procurement systems. Sources of (brand-specific) procurement data were identified and assessed on public accessibility. Vaccine type and brand availability and timelines were determined for the 2019-20 season to understand how procurement systems drive brand availability and diversity. RESULTS: Four main types of procurement systems for seasonal influenza vaccination campaigns were identified: national public tenders (Croatia, Denmark, Finland, Ireland, Lithuania, Netherlands, Norway, Scotland, Slovenia), regional public tenders (Italy, Spain, Sweden), direct purchase of vaccines by GPs (England, Wales) or pharmacies (Belgium, France, Germany, Greece) from manufacturers or wholesalers. National public tender outcomes are publicly available and timely; brand availability at clinic level can generally be deduced or narrowed down to two brands. Regional tender outcomes are more difficult to find, known very late or not available. In Italian and Spanish regions tenders may be awarded only a few weeks before the seasonal campaign. No public procurement information is available for countries with direct purchase. CONCLUSION: At the country-level, brand diversity is generally lower for countries with national public tenders than for countries with regional public tenders or direct purchase. In only a few countries, procurement data at the brand level is both publicly available and timely. Therefore the usefulness of procurement data for prospective site-selection for brand-specific VE studies is limited.

Strengthening the Evidence-Based Approach to Guiding Effective Influenza Vaccination Policies.

The availability of several effective and safe vaccines enables health systems to counteract annual influenza epidemics. However, the criteria of appropriateness and sustainability require that each citizen should receive the right vaccine. The value of each vaccine can be assessed within well-known frameworks, such as the Health Technology Assessment (HTA), a step that is fundamental to the process of allocating resources to vaccination strategies. The paper describes how HTA has been incorporated as an evidence-based tool to support the definition of Italian vaccination strategies, reports the results of the HTA report on the most recently available influenza vaccine in Italy (cell-based quadrivalent vaccine (QIVc)-Flucelvax® Tetra) and elaborates on current and future recommendations in the field of influenza vaccination. Recommendations issued by the Italian Ministry of Health foster the appropriate use of influenza vaccines from 2018-2019 onwards. Evidence of the value of newly available vaccines will hopefully support future decisions and promote the appropriate use of these vaccines on the basis of the characteristics of the target population. However, the success of influenza vaccination will also depend on citizens' empowerment and engagement in the decision-making process.

Cost-effectiveness of public health interventions against human influenza pandemics in France: a methodological contribution from the FLURESP European Commission project.

BACKGROUND: The FLURESP project is a public health project funded by the European Commission with the objective to design a methodological approach in order to compare the cost-effectiveness of existing public health measures against human influenza pandemics in four target countries: France, Italy, Poland and Romania. This article presents the results relevant to the French health system using a data set specifically collected for this purpose. METHODS: Eighteen public health interventions against human influenza pandemics were selected. Additionally, two public-health criteria were considered: 'achieving mortality reduction ≥40%' and 'achieving morbidity reduction ≥30%'. Costs and effectiveness data sources include existing reports, publications and expert opinions. Cost distributions were taken into account using a uniform distribution, according to the French health system. RESULTS: Using reduction of mortality as an effectiveness criterion, the most cost-effective options was 'implementation of new equipment of Extracorporeal membrane oxygenation (ECMO) equipment'. Targeting vaccination to health professionals appeared more cost-effective than vaccination programs targeting at risk populations. Concerning antiviral distribution programs, curative programs appeared more cost-effective than preventive programs. Using reduction of morbidity as effectiveness criterion, the most cost-effective option was 'implementation of new equipment ECMO'. Vaccination programs targeting the general population appeared more cost-effective than both vaccination programs of health professionals or at-risk populations. Curative antiviral programs appeared more cost-effective than preventive distribution programs, whatever the pandemic scenario. CONCLUSION: Intervention strategies against human influenza pandemics impose a substantial economic burden, suggesting a need to develop public-health cost-effectiveness assessments across countries.

The impact of demographic changes, exogenous boosting and new vaccination policies on varicella and herpes zoster in Italy: a modelling and cost-effectiveness study.

BACKGROUND: The present study aims to evaluate the cost-effectiveness of the newly introduced varicella and herpes zoster (HZ) vaccination programmes in Italy. The appropriateness of the introduction of the varicella vaccine is highly debated because of concerns about the consequences on HZ epidemiology and the expected increase in the number of severe cases in case of suboptimal coverage levels. METHODS: We performed a cost-utility analysis based on a stochastic individual-based model that considers realistic demographic processes and two different underlying mechanisms of exogenous boosting (temporary and progressive immunity). Routine varicella vaccination is given with a two-dose schedule (15 months, 5-6 years). The HZ vaccine is offered to the elderly (65 years), either alone or in combination with an initial catch-up campaign (66-75 years). The main outcome measures are averted cases and deaths, costs per quality-adjusted life years gained, incremental cost-effectiveness ratios, and net monetary benefits associated with the different vaccination policies. RESULTS: Demographic processes have contributed to shaping varicella and HZ epidemiology over the years, decreasing varicella circulation and increasing the incidence of HZ. The recent introduction of varicella vaccination in Italy is expected to produce an enduring reduction in varicella incidence and, indirectly, a further increase of HZ incidence in the first decades, followed by a significant reduction in the long term. However, the concurrent introduction of routine HZ vaccination at 65 years of age is expected to mitigate this increase and, in the longer run, to reduce HZ burden to its minimum. From an economic perspective, all the considered policies are cost-effective, with the exception of varicella vaccination alone when considering a time horizon of 50 years. These results are robust to parameter uncertainties, to the two different hypotheses on the mechanism driving exogenous boosting, and to different demographic projection scenarios. CONCLUSIONS: The recent introduction of a combined varicella and HZ vaccination programme in Italy will produce significant reductions in the burden of both diseases and is found to be a cost-effective policy. This programme will counterbalance the increasing trend of zoster incidence purely due to demographic processes.

Parental vaccine hesitancy in Italy - Results from a national survey.

In Italy, in 2016, we conducted a cross-sectional survey to estimate vaccine hesitancy and investigate its determinants among parents of children aged 16-36 months. Data on parental attitudes and beliefs about vaccinations were collected through a questionnaire administered online or self-administered at pediatricians' offices and nurseries. Parents were classified as pro-vaccine, vaccine-hesitant or anti-vaccine, according to self-reported tetanus and measles vaccination status of their child. Multivariable logistic regression was used to investigate factors associated with hesitancy. A total of 3130 questionnaires were analysed: 83.7% of parents were pro-vaccine, 15.6% vaccine-hesitant and 0.7% anti-vaccine. Safety concerns are the main reported reason for refusing (38.1%) or interrupting (42.4%) vaccination. Anti-vaccine and hesitant parents are significantly more afraid than pro-vaccine parents of short-term (85.7 and 79.7% vs 60.4%) and long-term (95.2 and 72.3% vs 43.7%) vaccine adverse reactions. Most pro-vaccine and hesitant parents agree about the benefits of vaccinations. Family pediatricians are considered a reliable source of information by most pro-vaccine and hesitant parents (96.9 and 83.3% respectively), against 45% of anti-vaccine parents. The main factors associated with hesitancy were found to be: not having received from a paediatrician a recommendation to fully vaccinate their child [adjusted odds ratio (AOR): 3.21, 95% CI: 2.14-4.79], having received discordant opinions on vaccinations (AOR: 1.64, 95% CI: 1.11-2.43), having met parents of children who experienced serious adverse reactions (AOR: 1.49, 95% CI: 1.03-2.15), and mainly using non-traditional medical treatments (AOR: 2.05, 95% CI: 1.31-3.19). Vaccine safety is perceived as a concern by all parents, although more so by hesitant and anti-vaccine parents. Similarly to pro-vaccine parents, hesitant parents consider vaccination an important prevention tool and trust their family pediatricians, suggesting that they could benefit from appropriate communication interventions. Training health professionals and providing homogenous information about vaccinations, in line with national recommendations, are crucial for responding to their concerns.

Age-prioritized use of antivirals during an influenza pandemic.

BACKGROUND: The WHO suggested that governments stockpile, as part of preparations for the next influenza pandemic, sufficient influenza antiviral drugs to treat approximately 25% of their populations. Our aim is two-fold: first, since in many countries the antiviral stockpile is well below this level, we search for suboptimal strategies based on treatment provided only to an age-dependent fraction of cases. Second, since in some countries the stockpile exceeds the suggested minimum level, we search for optimal strategies for post-exposure prophylactic treatment of close contacts of cases. METHODS: We used a stochastic, spatially structured individual-based model, considering explicit transmission in households, schools and workplaces, to simulate the spatiotemporal spread of an influenza pandemic in Italy and to evaluate the efficacy of interventions based on age-prioritized use of antivirals. RESULTS: Our results show that the antiviral stockpile required for treatment of cases ranges from 10% to 35% of the population for R0 in 1.4 - 3. No suboptimal strategies, based on treatment provided to an age-dependent fraction of cases, were found able to remarkably reduce both clinical attack rate and antiviral drugs needs, though they can contribute to largely reduce the excess mortality. Treatment of all cases coupled with prophylaxis provided to younger individuals is the only intervention resulting in a significant reduction of the clinical attack rate and requiring a relatively small stockpile of antivirals. CONCLUSION: Our results strongly suggest that governments stockpile sufficient influenza antiviral drugs to treat approximately 25% of their populations, under the assumption that R0 is not much larger than 2. In countries where the number of antiviral stockpiled exceeds the suggested minimum level, providing prophylaxis to younger individuals is an option that could be taken into account in preparedness plans. In countries where the number of antivirals stockpiled is well below 25% of the population, priority should be decided based on age-specific case fatality rates. However, late detection of cases (administration of antivirals 48 hours after the clinical onset of symptoms) dramatically affects the efficacy of both treatment and prophylaxis.

Epidemic patch models applied to pandemic influenza: contact matrix, stochasticity, robustness of predictions.

Due to the recent emergence of H5N1 virus, the modelling of pandemic influenza has become a relevant issue. Here we present an SEIR model formulated to simulate a possible outbreak in Italy, analysing its structure and, more generally, the effect of including specific details into a model. These details regard population heterogeneities, such as age and spatial distribution, as well as stochasticity, that regulates the epidemic dynamics when the number of infectives is low. We discuss and motivate the specific modelling choices made when building the model and investigate how the model details influence the predicted dynamics. Our analysis may help in deciding which elements of complexity are worth including in the design of a deterministic model for pandemic influenza, in a balance between, on the one hand, keeping the model computationally efficient and the number of parameters low and, on the other hand, maintaining the necessary realistic features.