Risk of herpes zoster in adults with SARS-CoV-2 infection in Spain: A population-based, retrospective cohort study.

OBJECTIVES: We aimed to compare the risk of herpes zoster (HZ) in adults with and without laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: This retrospective dynamic cohort study analyzed data from a public healthcare database in Spain between November 2020 and October 2021. The main outcome was incident cases of HZ in individuals ≥18-year-old. Relative risk (RR) of HZ in SARS-CoV-2-confirmed versus SARS-CoV-2-free individuals was estimated by a multivariable negative binomial regression adjusted by age, sex, and comorbidities. RESULTS: Data from 4,085,590 adults were analyzed. The overall HZ incidence rate in adults was 5.76 (95% confidence interval [CI], 5.66-5.85) cases per 1000 person-years. Individuals ≥18-year-old with SARS-CoV-2-confirmed infection had a 19% higher risk of developing HZ versus SARS-CoV-2-free ≥18-year-olds (adjusted RR = 1.19; 95% CI, 1.09-1.29); this percentage was 16% (adjusted RR = 1.16; 95% CI, 1.05-1.29) in ≥50-year-olds. Severe (hospitalized) cases of SARS-CoV-2 infection had a 64% (if ≥18 years old) or 44% (if ≥50 years old) higher risk of HZ versus nonhospitalized cases. CONCLUSION: These results support an association between SARS-CoV-2 infection and HZ, with a greater HZ risk in severe cases of SARS-CoV-2 infection.

Effectiveness of self-financed rotavirus vaccines on acute gastroenteritis primary care episodes using real-world data in Spain: a propensity score-matched analysis of cohort study.

The objective of this study was to estimate, by a novel spatiotemporal approach in an environment of non-funded rotavirus (RV) vaccines, the RV vaccine effectiveness (VE) to prevent acute gastroenteritis primary care (AGE-PC)-attended episodes, demonstrating how indirect protection leads to underestimation of direct VE under high vaccine coverage (VC). This population-based retrospective cohort study used electronic healthcare registries including all children 2 months-5 years old, born from 2009 to 2018 in the Valencia Region (Spain). Direct RV VE preventing AGE-PC episodes was estimated using propensity score matching and Poisson regressions stratified by VC, adjusted by age and calendar season. Indirect VE was estimated by Poisson regression comparing AGE-PC rates in unvaccinated children among the different VC levels. A total of 563,442 children were included for the RV VC estimation; of them, 360,576 were included in the birth-cohort for VE analysis. RV VC showed strong variability among districts and seasons, rising on average from 21% in 2009/2010 to 55% in 2017/2018. The highest direct VE was found in vaccinated children from districts with 0-30% RV VC (16.4%) and the lowest in those from districts with ≥ 70% RV VC (9.7%). The indirect protection in unvaccinated children raised from 6 to 16.6% for those living with 20-30% and ≥ 70% VC, respectively. CONCLUSION: Considering that RV is the causative agent in 20% of AGE cases, a direct effectiveness of 82% preventing AGE-PC episodes due to RV could be deduced using a novel spatiotemporal approach. A reduction of 17% of AGE-PC episodes in unvaccinated was observed in areas with VC over 70% because of indirect protection. WHAT IS KNOWN: • The effectiveness of RV vaccines preventing hospitalizations due to RV-acute gastroenteritis (RV-AGE) has been extensively studied. However, RV also burdens the primary care (PC) setting, and data on vaccine effectiveness (VE) in preventing AGE-PC visits are scarce. • The RV vaccine distribution in Spain (non-funded), with large differences in vaccine coverage (VC) among healthcare districts, provides an ideal scenario to assess the actual VE in preventing AGE-PC consultations, including the direct and indirect protection. WHAT IS NEW: • A direct effectiveness of 82% preventing AGE-PC episodes due to RV could be deduced using a novel spatiotemporal approach. A reduction of 17% of AGE-PC episodes in unvaccinated was observed in areas with high VC because of indirect protection. • These findings, together with existing data on the impact on hospitalizations due to RV-AGE, offer valuable insights for implementing vaccination initiatives in countries that have not yet commenced such programs.

Risk of cardiovascular events after influenza: A population-based Self Controlled Case Series study, Spain 2011-2018.

This study explores the relationship between influenza infection, both clinically diagnosed in primary-care and laboratory confirmed in hospital, and atherothrombotic events (acute myocardial infarction and ischemic stroke) in Spain. A population-based self-controlled case series design was used with individual-level data from electronic registries (n = 2,230,015). The risk of atherothrombotic events in subjects ≥50 years old increased more than 2-fold during the 14 days after the mildest influenza cases in patients with fewer risk factors and more than 4-fold after severe cases in the most vulnerable patients, remaining in them more than 2-fold for 2 months. The transient increase of the association, its gradient after influenza infection and the demonstration by 4 different sensitivity analyses provide further evidence supporting causality. This work reinforces the official recommendations for influenza prevention in at-risk groups and should also increase the awareness of even milder influenza infection and its possible complications in the general population.

Early estimates of nirsevimab immunoprophylaxis effectiveness against hospital admission for respiratory syncytial virus lower respiratory tract infections in infants, Spain, October 2023 to January 2024.

The monoclonal antibody nirsevimab was at least 70% effective in preventing hospitalisations in infants with lower respiratory tract infections (LRTI) positive for respiratory syncytial virus (RSV) in Spain (Oct 2023-Jan 2024), where a universal immunisation programme began late September (coverage range: 79-99%). High protection was confirmed by two methodological designs (screening and test-negative) in a multicentre active surveillance in nine hospitals in three regions. No protection against RSV-negative LRTI-hospitalisations was shown. These interim results could guide public-health decision-making.

Bronchiolitis, Regardless of Its Etiology and Severity, Is Associated With Increased Risk of Asthma: A Population-Based Study.

An association exists between severe respiratory syncytial virus (RSV)-bronchiolitis and a subsequent increased risk of recurrent wheezing (RW) and asthma. However, a causal relationship remains unproven. Using a retrospective population-based cohort study (339 814 children), bronchiolitis during the first 2 years of life (regardless of etiology and severity) was associated with at least a 3-fold increased risk of RW/asthma at 2-4 years and an increased prevalence of asthma at ≥5 years of age. The risk was similar in children with mild bronchiolitis as in those with hospitalized RSV-bronchiolitis and was higher in children with hospitalized non-RSV-bronchiolitis. The rate of RW/asthma was higher when bronchiolitis occurred after the first 6 months of life. Our results seem to support the hypothesis of a shared predisposition to bronchiolitis (irrespective of etiology) and RW/asthma. However, 60% of hospitalized bronchiolitis cases in our setting are due to RSV, which should be paramount in decision-making on imminent RSV prevention strategies.

Human papillomavirus vaccines effectiveness to prevent genital warts: A population-based study using health system integrated databases, 2009-2017.

OBJECTIVES: To assess the effectiveness of the HPV vaccines in preventing genital warts (GW) in women aged 14-23 years and to estimate the incidence of GW in the whole population aged from 14 to 65. DESIGN: Population-based retrospective cohort study using real-world data from the Valencia health system Integrated Databases (VID). STUDY POPULATION: All subjects aged 14-65 years residing in the Valencia Region during 2009-2017 (n = 4,492,724), including a cohort of 563,240 females aged 14-23 years followed-up for the vaccine effectiveness (VE) estimations. MAIN OUTCOME MEASURES: Incident cases of GW defined as the first activation of GW-related codes (ICD-9-CM 078.11 or ICD-10-CM A63.0) in hospital, primary and specialized care during the study period. Adjusted VE was estimated as (1-Relative Risk (RR)) × 100 by a negative binomial Bayesian model. RESULTS: There were 23,049 cases of GW in the overall population and 2,565 in the females' cohort 14-23 years old. The incidence rate (IR) (in 100,000 persons-year) was 69.1 (95% CI 68.21-69.99) in the population overall, being higher in men (72.73; 95% CI 71.45-74.04). The IR of GW was 104.08 (95% CI 100.79-108.94) in the cohort of young women. The RR of GW increased with age from 14 to 21 years, reaching a plateau from 21 to 23. The VE of a complete schedule was 74% (95% CrI 68-79) for quadrivalent HPV vaccine (HPV4v). No effectiveness was seen with a full vaccination course with the bivalent HPV vaccine (HPV2v) in girls up to 21 years old. GW IR tends to be higher in unvaccinated cohorts covered by HPV4v vaccine than in unvaccinated cohorts not covered by HPV4v vaccine. CONCLUSIONS: A complete HPV4v vaccination schedule was 74% effective in reducing GW in our population. Our results also suggest an indirect protection to unvaccinated and HPV2v vaccinated girls.

The impact of childhood RSV infection on children's and parents' quality of life: a prospective multicenter study in Spain.

BACKGROUND:  Several immunisation candidates against RSV are in late-stage clinical trials. To evaluate the benefits of a potential vaccination programme, both economic and health benefits will be needed. Health benefits are usually measured in Health-related Quality of Life (HRQoL) loss using standardised questionnaires. However, there are no RSV-specific questionnaires validated for children under 2 years, in whom most RSV episodes occur. Therefore, HRQoL estimates are taken from literature or inadequate tools. We determined HRQoL loss and direct costs due to an RSV episode in children younger than 2 years and their caregivers during a month of follow up, using a new questionnaire administered online. METHODS:  An observational prospective multicentre surveillance study was conducted in children aged younger than two years. Children were recruited from 8 primary care centres and 1 hospital in the Valencia region and Catalonia (Spain). RSV-positive cases were obtained by immunochromatographic test. HRQoL was assessed using a new ad-hoc 38 item-questionnaire developed. Parents of infected children completed 4 questionnaires at four timepoints (day 0, 7, 14 and 30) after diagnosis. RESULTS:  117 children were enrolled in the study and 86 (73.5%) were RSV + . Median (interquartile range; IQR) scores were 0.52 (0.42-0.68), 0.65 (0.49-0.79), 0.82 (0.68-0.97) and 0.94 (0.81-1), for days 0, 7, 14 and 30, respectively. Compared to total recovery (Q30), HRQoL loss was 37.5%, 31.5% and 8.9% on days 0, 7 and 14 since diagnosis of the disease. The total median cost per patient (including treatments) was €598.8 (IQR: 359.63-2425.85). CONCLUSIONS:  RSV had almost 40% impact on HRQoL during the first week since onset of symptoms and the median cost per episode and patient was about €600. These results represent a substantial input for health-economic evaluations of future RSV-related interventions such as vaccination.

Brand-specific influenza vaccine effectiveness estimates during 2019/20 season in Europe - Results from the DRIVE EU study platform.

DRIVE (Development of Robust and Innovative Vaccine Effectiveness) is an IMI funded public-private platform that aims to annually estimate brand-specific influenza vaccine effectiveness (IVE), for public health and regulatory purposes. IVE analyses and reporting are conducted by public partners in the consortium. In 2019/20, four primary care-based test-negative design (TND) studies (Austria, England, Italy (n = 2)), eight hospital-based TND studies (Finland, France, Italy, Romania, Spain (n = 4)), and one population-based cohort study (Finland) were conducted. The COVID-19 pandemic affected influenza surveillance in all participating study sites, therefore the study period was truncated on February 29, 2020. Age-stratified (6 m-17y, 18-64y, ≥65y), confounder-adjusted, site-specific adjusted IVE estimates were calculated and pooled through meta-analysis. Parsimonious confounder-adjustment was performed, adjusting the estimates for age, sex and calendar time. TND studies included 3531 cases (351 vaccinated) and 5546 controls (1415 vaccinated) of all ages. IVE estimates were available for 8/11 brands marketed in Europe in 2019. Most children and adults < 64y were captured in primary care setting and the most frequently observed vaccine brand was Vaxigrip Tetra. The estimate against any influenza for Vaxigrip Tetra in primary care setting was 61% (95%CI 38-77) in children and 32% (95%CI -13-59) in adults up to 64y. Most adults ≥ 65y were captured in hospital setting and the most frequently observed brand was Fluad, with an estimate of 52% (95%CI 27-68). The population-based cohort covered 511,854 person-years and two vaccine brands. In children aged 2-6y, the IVE against any influenza was 68% (95%CI 58-75) for Fluenz Tetra and 71% (56-80) for Vaxigrip Tetra. In adults ≥ 65y, IVE against any influenza was 29% (20-36) for Vaxigrip Tetra. DRIVE is a growing platform. Public health institutes with surveillance data and hospitals in countries with high influenza vaccine coverage are encouraged to join DRIVE.

On the Elimination of Infections Related to Oncogenic Human Papillomavirus: An Approach Using a Computational Network Model.

Cervical cancer is the fourth most common malignancy in women worldwide, although it is preventable with prophylactic HPV vaccination. HPV transmission-dynamic models can predict the potential for the global elimination of cervical cancer. The random network model is a new approach that allows individuals to be followed, and to implement a given vaccination policy according to their clinical records. We developed an HPV transmission-dynamic model on a lifetime sexual partners network based on individual contacts, also accounting for the sexual behavior of men who have sex with men (MSM). We analyzed the decline in the prevalence of HPV infection in a scenario of 75% and 90% coverage for both sexes. An important herd immunity effect for men and women was observed in the heterosexual network, even with 75% coverage. However, HPV infections are persistent in the MSM population, with sustained circulation of the virus among unvaccinated individuals. Coverage around 75% of both sexes would be necessary to eliminate HPV-related conditions in women within five decades. Nevertheless, the variation in the decline in infection in the long term between a vaccination coverage of 75% and 90% is relatively small, suggesting that reaching coverage of around 70-75% in the heterosexual network may be enough to confer high protection. Nevertheless, HPV elimination may be achieved if men's coverage is strictly controlled. This accurate representation of HPV transmission demonstrates the need to maintain high HPV vaccination coverage, especially in men, for whom the cost-effectiveness of vaccination is questioned.

Factors driving choices between types and brands of influenza vaccines in general practice in Austria, Italy, Spain and the UK.

Influenza vaccine effectiveness (IVE) assessment is increasingly stratified by vaccine type or brand, such as done by the European network of DRIVE. In 2019/2020, eleven influenza vaccines were licensed in Europe. If more than one vaccine type is recommended or if more than one vaccine brand is available for a specific risk group, it is not clear which factors affect the choice of a specific vaccine (type or brand) by a health practitioner for individual patients. This is important for IVE assessment. A survey tailored to the 2019/20 local vaccine recommendations was conducted among GPs in four European countries (Austria, Italy, Spain, UK) to understand how influenza vaccine is offered to recommended risk groups and, if GPs have a choice between 2 or more vaccines, what factors influence their vaccine choice for patients. Overall, 360 GPs participated. In Austria, Italy and Spain GPs indicated that influenza vaccines are commonly offered when patients present for consultation, whereas in the UK all GPs indicated that all relevant patients are contacted by letter. In Austria and Italy, roughly 80% of GPs had only one vaccine type available for patients <65y. The use of any specific vaccine type in this age group is mostly determined by the availability of specific vaccine type(s) at the clinic. GPs frequently reported availability of more than one vaccine type for patients ≥65y in Austria (45%), Italy (70%) and Spain (79%). In this group, patient characteristics played a role in choice of vaccine, notably older age and presence of (multiple) comorbidities. Knowing that a non-patient related factor usually determines the vaccine type a patient receives in settings where more than one vaccine type is recommended for risk groups <65y, simplifies IVE assessment in this age group. However, patient characteristics need careful consideration when assessing IVE in those ≥65y.

Challenges and Adaptation of a European Influenza Vaccine Effectiveness Study Platform in Response to the COVID-19 Emergence: Experience from the DRIVE Project.

The Development of Robust and Innovative Vaccine Effectiveness (DRIVE) project is a public-private partnership aiming to build capacity in Europe for yearly estimation of brand-specific influenza vaccine effectiveness (IVE). DRIVE is a five-year project funded by IMI (Innovative Medicines Initiative). It was initiated as a response to the guidance on influenza vaccines by EMA (European Medicines Agency), which advised vaccine manufacturers to work with public health institutes to set up a joint IVE study platform. The COVID-19 pandemic reached Europe in February 2020 and overlapped with the 2019/2020 influenza season only in the last weeks. However, several elements of the DRIVE study network were impacted. The pandemic specifically affected the study sites' routines and the subsequent assessment of the 2019/20 influenza season. Moreover, the current social distancing measures and lockdown policies across Europe are expected to also limit the circulation of influenza for the 2020/21 season, and therefore the impact of COVID-19 will be higher than in the season 2019/20. Consequently, DRIVE has planned to adapt its study platform to the COVID-19 challenge, encompassing several COVID-19 particularities in the study procedures, data collection and IVE analysis for the 2020/21 season. DRIVE will study the feasibility of implementing these COVID-19 components and establish the foundations of future COVID-19 vaccine effectiveness studies.

Herpes zoster risk and burden of disease in immunocompromised populations: a population-based study using health system integrated databases, 2009-2014.

BACKGROUND: Estimate the incidence of herpes zoster (HZ), its complications and healthcare utilization rates in adults (≥ 18-years-old) with a wide range of immunocompromised (IC) conditions compared to IC-free cohort. METHOD: A population-based retrospective study using the Valencia healthcare Integrated Databases (VID) (2009-2014). HZ and IC were defined using ICD-9 codes in primary care (PC) and hospitalization registers. Incidence rates (IR), risk of HZ, HZ-recurrence, HZ-complications and healthcare utilization rates were estimated in the IC-cohort compared to IC-free. RESULTS: The study population consisted of 4,382,590 subjects, of which 578,873 were IC (13%). IR (in 1000 persons-year) of HZ overall, in IC and in IC-free cohort was 5.02, 9.15 and 4.65, respectively. IR of HZ increased with age in both cohorts and it was higher for all IC conditions studied, reaching up to twelvefold in subjects with stem cell transplantation. IC subjects had 51% higher risk of developing HZ, 25% higher HZ-recurrence and the risk of HZ-complications was 2.37 times higher than in IC-free. HZ-related healthcare utilization was higher in the IC-cohort than in IC-free (number of hospitalizations 2.93 times greater, hospital stays 12% longer, 66% more HZ-specialist visits, 2% more PC visits, sick leaves 18% longer and 20% higher antiviral dispensation). CONCLUSIONS: Patients suffering from all the IC conditions studied are at higher risk of developing HZ, HZ-recurrence and post-herpetic complications, which implies a substantial morbidity and a high consumption of resources. These results should be considered for vaccine policy implementation.

Spatio-temporal impact of self-financed rotavirus vaccination on rotavirus and acute gastroenteritis hospitalisations in the Valencia region, Spain.

BACKGROUND: Several studies have shown a substantial impact of Rotavirus (RV) vaccination on the burden of RV and all-cause acute gastroenteritis (AGE). However, the results of most impact studies could be confused by a dynamic and complex space-time process. Therefore, there is a need to analyse the impact of RV vaccination on RV and AGE hospitalisations in a space-time framework to detect geographical-time patterns while avoiding the potential confusion caused by population inequalities in the impact estimations. METHODS: A retrospective population-based study using real-world data from the Valencia Region was performed among children aged less than 3 years old in the period 2005-2016. A Bayesian spatio-temporal model was constructed to analyse RV and AGE hospitalisations and to estimate the vaccination impact measured in averted hospitalisations. RESULTS: We found important spatio-temporal patterns in RV and AGE hospitalisations, RV vaccination coverage and in their associated adverted hospitalisations. Overall, ~ 1866 hospital admissions for RV were averted by RV vaccination during 2007-2016. Despite the low-medium vaccine coverage (~ 50%) in 2015-2016, relevant 36 and 20% reductions were estimated in RV and AGE hospitalisations respectively. CONCLUSIONS: The introduction of the RV vaccines has substantially reduced the number of RV hospitalisations, averting ~ 1866 admissions during 2007-2016 which were space and time dependent. This study improves the methodologies commonly used to estimate the RV vaccine impact and their interpretation.

Risk and impact of herpes zoster among COPD patients: a population-based study, 2009-2014.

BACKGROUND: The objective of this study was to assess the incidence of Herpes Zoster (HZ) among patients with chronic obstructive pulmonary disease (COPD) and the impact of HZ on the underlying COPD. METHODS: A retrospective cohort of all subjects older than 49 years was followed up between 2009 and 2014 using population and health databases of Valencia Region (Spain). HZ and COPD were identified using ICD-9 codes, differentiating COPD patients with inhaled corticosteroids prescriptions (COPD-ICS). The incidence of HZ was compared among 3 groups [non-COPD, COPD and COPD-ICS populations] and use of healthcare resource due to HZ for 6 months following HZ diagnosis through different statistical generalized linear models (GLM). We also compared resources consumption due to COPD before and after HZ. RESULTS: The cohort consisted of 2,289,485 subjects, including 161,317 COPD patients of which 29,708 were COPD-ICS. HZ incidence rates were 11 (95% confidence interval [CI]: 10.7-11.4) and 13 (95% CI: 12.3-13.8) cases/1000 persons-year for COPD and COPD-ICS populations respectively. Incidence increased with age in all groups. The risk of HZ rose by 45 and 61% among COPD and COPD-ICS patients respectively compared to non-COPD (95% credible intervals [CrI]: 1.41-1.5 and 1.52-1.71 respectively). COPD patients consumed more resources due to their HZ than non-COPD. There was no statistically significant impact of the HZ on the resources consumed due to COPD during the 6 months post-HZ compared to the 6 months pre-HZ. CONCLUSIONS: The presence of COPD increases the risk, severity and impact of zoster episodes.

Impact of postherpetic neuralgia: A six year population-based analysis on people aged 50 years or older.

OBJECTIVES: To estimate the incidence and burden of postherpetic neuralgia (PHN) and to investigate risk factors for PHN in the Valencia Region of Spain. METHODS: Data were extracted from population and healthcare databases from the Valencia Region (2009-2014). Herpes zoster (HZ) and PHN were defined using ICD-9 codes and drug prescriptions in people aged ≥50 years. The risk of HZ patients for developing PHN and potential risk factors (diabetes mellitus, COPD and heart failure) were investigated. A survival analysis was developed to estimate the cumulative hazard of developing HZ and PHN between ages 50-90 years. RESULTS: From a total of 2,289,485 subjects, 87,086 cases of HZ were registered, 13,658 (15.7%) of whom developed PHN. PHN risk was higher in women and increased sharply with age and comorbidities as diabetes mellitus, COPD and heart failure. The cumulative risk of developing HZ between ages 50-90 years was 31.7% (95% CI: 31.3-32.1) and 6.9 (95% CI: 6.7-7.1) for PHN. CONCLUSIONS: PHN risk was higher in women and increased with age and comorbidities. At least 32% and 7% of people will develop HZ and PHN, respectively, between ages 50-90 years. These results should be considered for vaccine policy implementation.

Lack of impact of rotavirus vaccines on seizure-related hospitalizations in children under 5 years old in Spain.

INTRODUCTION: Up to date the impact of rotavirus (RV) vaccines on seizures has been poorly evaluated, with some studies but not all, showing different degrees of protection. OBJECTIVES: To assess the impact of RV vaccines on convulsions-related hospitalizations among children under 5 years of age residing in the Region of Valencia, Spain. METHODS: A population-based, ecological study using the hospital discharge record (MBDS), the population-based administrative database (SIP) and the vaccine register (SIV), among Valencia Region's children <5 years old, during 2003 - 2015. Impact of vaccination on seizures-related hospitalization rates (780.3* ICD-9-MC code) was estimated by a multivariate Bayesian mixed Poisson regression model. RESULTS: Since RV vaccines licensure in 2007, its coverage rate increased up to around 42%. When the impact of vaccination against seizures was controlled for potential confounders in the multivariate analysis, there was a non-statistically significant protective effect. CONCLUSIONS: We could not find any impact of RV vaccine coverage on seizure-related hospitalizations in children <5 years.

Letter to the editor regarding "The role of age-sex interaction in the development of post-herpetic neuralgia".

The objective of the study was to evaluate the role of age and sex and their combined effect in the development of post-herpetic neuralgia (PHN) in a large population-based study, in order to confirm the results published previously by Amicizia et al. Data were extracted from population and healthcare databases from the Valencia Region (2009-2014). Logistic regressions were implemented to estimate the effect of increasing age on the probability of developing PHN stratified by sex. From a cohort of 2,289,485 subjects ≥ 50 years, 87,086 cases of HZ were registered and 13,658 (15.7%) of them developed PHN. In our population, PHN cases were more common in women and rose with increasing age independently of the sex.