Statistical analysis plan for the multicenter, open, randomized controlled clinical trial to assess the efficacy and safety of intravenous tirofiban vs aspirin in acute ischemic stroke due to tandem lesion, undergoing recanalization therapy by endovascular treatment (ATILA trial).

RATIONALE: In-stent reocclusion after endovascular therapy has a negative impact on outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Optimal antiplatelet therapy approach in these patients to avoid in-stent reocclusion is yet to be elucidated. AIMS: To assess efficacy and safety of intravenous tirofiban versus intravenous aspirin in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. SAMPLE SIZE ESTIMATES: Two hundred forty patients will be enrolled, 120 in every treatment arm. METHODS AND DESIGN: A multicenter, prospective, randomized, controlled (aspirin group), assessor-blinded clinical trial will be conducted. Patients fulfilling the inclusion criteria will be randomized at MT onset to the experimental or control group (1:1). Intravenous aspirin will be administered at a 500-mg single dose and tirofiban at a 500-mcg bolus followed by a 200-mcg/h infusion during the first 24 h. All patients will be followed for up to 3 months. STUDY OUTCOMES: Primary efficacy outcome will be the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. Primary safety outcome will be the rate of symptomatic intracranial hemorrhage. DISCUSSION: This will be the first clinical trial to assess the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. TRIAL REGISTRATION: The trial is registered as NCT05225961. February, 7th, 2022.

The Need for the Closer Monitoring of Novel Drugs in MS: A Siponimod Retrospective Cohort Study (Realhes Study).

BACKGROUND: Severe cases of lymphopenia have been reported during siponimod clinical trials, which may negatively impact its benefit/risk profile. OBJECTIVE: We aimed to evaluate the incidence of lymphopenia following the initiation of siponimod treatment in clinical practice. The secondary objectives included the analysis of factors predisposing to and the clinical relevance of lymphopenia events. METHODS: In this multicenter retrospective cohort study, information collected from the medical records of 129 patients with MS from 15 tertiary hospitals in Spain who initiated treatment with Siponimod were followed-up for at least 3 months, including at least one lymphocyte count evaluation per patient. RESULTS: Of the 129 patients, 121 (93.6%) reported lymphopenia events, including 110 (85.3%) with grade ≤ 3 and 11 (8.5%) with grade 4 lymphopenia, higher than those reported in the pivotal clinical trial (73.3% and 3.3% for grade ≤ 3 and grade 4 lymphopenia, respectively). The study included an unexpectedly high proportion of male subjects (72.9%), which might have led to an underestimation of the actual magnitude of the risk. CONCLUSIONS: In this study, the incidence and severity of lymphopenia after starting siponimod treatment were higher than those reported in previous clinical trials. Therefore, our results reinforce the need for the closer monitoring of novel MS drugs in clinical practice, as well as larger and longer follow-up studies to properly characterize this risk.

Safety and efficacy of tirofiban in acute ischemic stroke due to tandem lesions undergoing mechanical thrombectomy: A multicenter randomized clinical trial (ATILA) protocol.

Background: In-stent thrombosis after mechanical thrombectomy (MT) worsen outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Although an optimal antiplatelet therapy is needed, the best approach to avoid in-stent thrombosis is yet to be elucidated. Hypothesis: Low-dose intravenous tirofiban is superior to intravenous aspirin in avoiding in-stent thrombosis in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. Methods: The ATILA-trial is a multicenter, prospective, phase IV, randomized, controlled (aspirin group as control), assessor-blinded clinical trial. Patients fulfilling inclusion criteria (AIS due to TL, ASPECTS ⩾ 6, pre-stroke modified Rankin Scale ⩽2 and onset <24 h) will be randomized (1:1) at MT onset to experimental (intravenous tirofiban) or control group (intravenous aspirin). Intravenous aspirin will be administered at a 500 mg single dose and tirofiban at a 500 µg bolus followed by a 200 µg/h infusion during first 22 h. All patients will be followed up to 3 months. Sample size estimated is 240 patients. Outcomes: The primary efficacy outcome is the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. The primary safety outcome is the rate of symptomatic intracranial hemorrhage. Secondary outcomes include functional independence defined as modified Rankin Scale 0-2, proportion of patients undergoing rescue therapy due to in-stent aggregation during MT and carotid reocclusion at 30 days. Discussion: ATILA-trial will be the first clinical trial regarding the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. Trial registration: NCT0522596.

Factors associated with recruitment success in the phase 2a study of aztreonam-avibactam development programme: a descriptive qualitative analysis among sites in Spain.

OBJECTIVE: Successful clinical trials are subject to recruitment. Recently, the REJUVENATE trial, a prospective phase 2a open-label, single-arm interventional clinical trial conducted within the Innovative Medicines Initiative-supported Combatting Bacterial Resistance in Europe-Carbapenem Resistance project, was published, with 85% of the recruitment performed in Spain. We analysed the recruitment success in this trial by establishing a model of recruitment practice. METHODS: A descriptive qualitative study was performed from May 2016 to October 2017 at 10 participating Spanish centres. Data were extracted from: (1) feasibility questionnaires to assess the centre's potential for patient enrolment; (2) delegation of responsibility records; (3) pre-screening records including an anonymised list of potentially eligible and (4) screening and enrolment records. A descriptive analysis of the features was performed by the participating centre. Pearson's and Spearman's correlation coefficients were calculated to determine factors of recruitment success. RESULTS: The highest recruitment rate was observed in Hospitals 3 and 6 (58.8 and 47.0 patients per month, respectively). All the study teams were multidisciplinary with a median of 15 members (range: 7-22). Only Hospitals 3, 5 and 6 had dedicated nursing staff appointed exclusively to this study. Moreover, in those three hospitals and in Hospital 9, the study coordinator performed exclusive functions as a research planner, and did not assume these functions for the other hospitals. The univariate analysis showed a significant association between recruitment success and months of recruitment (p=0.024), number of staff (p<0.001), higher number of pharmacists (p=0.005), infectious disease specialists (p<0.001), the presence of microbiologist in the research team (p=0.018) and specifically dedicated nursing staff (p=0.036). CONCLUSIONS: The existence of broad multidisciplinary teams with staff dedicated exclusively to the study as well as the implementation of a well-designed local patient assessment strategy were the essential optimisation factors for recruitment success in Spain. TRIAL REGISTRATION NUMBER: NCT02655419; EudraCT 2015-002726-39; analysis of pre-screened patients.

Risk factors for unfavorable outcome and impact of early post-transplant infection in solid organ recipients with COVID-19: A prospective multicenter cohort study.

The aim was to analyze the characteristics and predictors of unfavorable outcomes in solid organ transplant recipients (SOTRs) with COVID-19. We conducted a prospective observational cohort study of 210 consecutive SOTRs hospitalized with COVID-19 in 12 Spanish centers from 21 February to 6 May 2020. Data pertaining to demographics, chronic underlying diseases, transplantation features, clinical, therapeutics, and complications were collected. The primary endpoint was a composite of intensive care unit (ICU) admission and/or death. Logistic regression analyses were performed to identify the factors associated with these unfavorable outcomes. Males accounted for 148 (70.5%) patients, the median age was 63 years, and 189 (90.0%) patients had pneumonia. Common symptoms were fever, cough, gastrointestinal disturbances, and dyspnea. The most used antiviral or host-targeted therapies included hydroxychloroquine 193/200 (96.5%), lopinavir/ritonavir 91/200 (45.5%), and tocilizumab 49/200 (24.5%). Thirty-seven (17.6%) patients required ICU admission, 12 (5.7%) suffered graft dysfunction, and 45 (21.4%) died. A shorter interval between transplantation and COVID-19 diagnosis had a negative impact on clinical prognosis. Four baseline features were identified as independent predictors of intensive care need or death: advanced age, high respiratory rate, lymphopenia, and elevated level of lactate dehydrogenase. In summary, this study presents comprehensive information on characteristics and complications of COVID-19 in hospitalized SOTRs and provides indicators available upon hospital admission for the identification of SOTRs at risk of critical disease or death, underlining the need for stringent preventative measures in the early post-transplant period.

Assessing the impact on intestinal microbiome and clinical outcomes of antibiotherapy optimisation strategies in haematopoietic stem cell transplant recipients: study protocol for the prospective multicentre OptimBioma study.

INTRODUCTION: Haematopoietic stem cell transplantation (HSCT) is a life-saving treatment for a number of haematological diseases. Graft versus host disease (GVHD) is its main complication and hampers survival. There is strong evidence that intestinal microbiota diversity of the recipient may increase the risk of GVHD worsening survival. Antibiotic regimens used during the early phase of the transplant may influence clinical outcomes by reducing intestinal microbiota diversity. Present guidelines of European Conference on Infections in Leukaemia exhort to optimising antibiotic use in haematological patients including HSCT recipients. The present study aims to investigate if, in HSCT recipients, the optimisation of antibacterial use may preserve intestinal microbiota composition reducing the incidence and severity of acute GVHD and improving relevant clinical outcomes. METHODS AND ANALYSIS: This is a prospective longitudinal observational study of two cohorts of HSCT recipients: (1) the intervention cohort includes patients treated in centres in which a predefined strategy of antibiotherapy optimisation is implemented, with the objective of optimising and reducing antibiotic administration according to clinical criteria and (2) the control cohort includes patients treated in centres in which a classic permissive strategy of antibiotic prophylaxis and treatment is used. Adult patient receiving a first HSCT as a treatment for any haematological condition are included. Clinical variables are prospectively recorded and up to five faecal samples are collected for microbiota characterisation at prestablished peritransplant time points. Patients are followed since the preconditioning phase throughout 1-year post-transplant and four follow-up visits are scheduled. Faecal microbiota composition and diversity will be compared between both cohorts along with acute GVHD incidence and severity, severe infections rate, mortality and overall and disease-free survival. ETHICS AND DISSEMINATION: The study was approved between 2017 and 2018 by the Ethical Committees of participant centres. Study results will be disseminated through peer-reviewed journals and national and international scientific conferences. TRIAL REGISTRATION NUMBER: NCT03727113.

Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study.

OBJECTIVES: To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/ß-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI). METHODS: This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5-14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31-50 mL/min (Cohorts 2 + 3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed. RESULTS: Thirty-four patients (Cohort 1, n = 16; Cohorts 2 + 3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2 + 3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population). CONCLUSIONS: Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.

Opportunities for antibiotic optimisation and outcome improvement in patients with negative blood cultures: study protocol for a cluster-randomised crossover trial, the NO-BACT study.

INTRODUCTION: Patients with negative blood cultures (BCx) represent 85%-90% of all patients with BCx taken during hospital admission. This population usually includes a heterogeneous group of patients admitted with infectious diseases or febrile syndromes that require a blood culture. There is very little evidence of the clinical characteristics and antibiotic treatment given to these patients. METHODS AND ANALYSIS: In a preliminary exploratory prospective cohort study of patients with BCx taken, the clinical/therapeutic characteristics and outcomes/antimicrobial stewardship opportunities of a population of patients with negative BCx will be analysed. In the second phase, using a cluster randomised crossover design, the implementation of an antimicrobial stewardship intervention targeting patients with negative BCx will be evaluated in terms of quality of antimicrobial use (duration and de-escalation), length of hospital stay and mortality. ETHICS AND DISSEMINATION: This study has been and registered with clinicaltrials.gov. The findings of our study may support the implementation in clinical practice of an antimicrobial stewardship intervention to optimise the use of antibiotics in patients with negative BCx. The results of this study will be published in peer-reviewed journals and disseminated at national and international conferences. TRIAL REGISTRATION NUMBER: NCT03535324.

Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial.

BACKGROUND: Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined. METHODS: A multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7-14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved. RESULTS: A total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of - 2.16 (- 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015). CONCLUSIONS: This study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01292031. Registered 9 February 2011.

Vigilancia del virus respiratorio sincitial en el marco del Sistema de Vigilancia de la Gripe en España, 2006-2014 / Monitoring respiratory syncytial virus through the Spanish influenza surveillance system, 2006-2014

INTRODUCCIÓN: El objetivo del estudio fue analizar la información del virus respiratorio sincitial (VRS) obtenida en el marco del Sistema de Vigilancia de Gripe en España (SVGE) y estudiar su utilidad como información complementaria para la caracterización de las ondas epidémicas de gripe. MÉTODOS: Se analizaron los patrones temporales del VRS y de la gripe comparando la evolución semanal de sus tasas de detección viral entre 2006-2014. RESULTADOS: La circulación del VRS se caracterizó por mostrar un pico máximo entre las semanas 52-1 y fue anterior a la de los virus gripales entre 2-8 semanas. CONCLUSIÓN: La información de VRS obtenida en el marco del SVGE es útil para la caracterización de las ondas epidémicas de gripe

INTRODUCTION: The aim of the study is to analyze the information on respiratory syncytial virus (RSV) obtained through the Spanish Influenza Surveillance System (SISS) and to study its usefulness as supplementary information for the characterization of influenza epidemics. METHODS: The temporal patterns of both RSV and influenza viruses were analyzed by patterns comparing the weekly viral detection rates from 2006 to 2014. RESULTS: In general, the RSV circulation was characterized by showing a peak between 52-1 weeks, and circulated from 2 to 8 weeks before/prior to influenza viruses. CONCLUSION: RSV information obtained from the SISS is useful for the characterization of influenza epidemics in Spain

[Monitoring respiratory syncytial virus through the Spanish influenza surveillance system, 2006-2014]. / Vigilancia del virus respiratorio sincitial en el marco del Sistema de Vigilancia de la Gripe en España, 2006-2014.

INTRODUCTION: The aim of the study is to analyze the information on respiratory syncytial virus (RSV) obtained through the Spanish Influenza Surveillance System (SISS) and to study its usefulness as supplementary information for the characterization of influenza epidemics. METHODS: The temporal patterns of both RSV and influenza viruses were analyzed by patterns comparing the weekly viral detection rates from 2006 to 2014. RESULTS: In general, the RSV circulation was characterized by showing a peak between 52-1 weeks, and circulated from 2 to 8 weeks before/prior to influenza viruses. CONCLUSION: RSV information obtained from the SISS is useful for the characterization of influenza epidemics in Spain.

Exceso de mortalidad relacionado con la gripe en España en el invierno de 2012 / Excess mortality associated with influenza in Spain in winter 2012

Objetivo: El sistema de monitorización de la mortalidad diaria en España y el programa European monitoring of excess mortality for public health action detectaron un exceso de mortalidad en España en febrero y marzo de 2012. El objetivo de este trabajo es estudiar el papel que puede atribuirse a la gripe como factor de sobremortalidad en ese periodo. Métodos: Se estudiaron los excesos de mortalidad por todas las causas en el periodo 2006-2012 utilizando series temporales en el sistema de vigilancia de la mortalidad diaria español y mediante regresión de Poisson en el sistema de vigilancia de la mortalidad europeo y en un modelo que estima la mortalidad atribuible a la gripe. Los excesos de mortalidad por gripe y neumonía atribuibles a la gripe se estudiaron con un modelo Serfling modificado. Para detectar los periodos de exceso se comparó la mortalidad observada con la esperada. Resultados: En febrero y marzo de 2012, en los sistemas de monitorización de mortalidad español y europeo se detectó un exceso de mortalidad de 8110 y 10.872 defunciones (razón de mortalidad: 1,22, intervalo de confianza del 95% [IC95%]: 1,21-1,23, y 1,32, IC95%: 1,29-1,31, respectivamente). El modelo que estima la mortalidad atribuible a la gripe identificó en la temporada 2011-2012 el máximo porcentaje (97%) de defunciones atribuibles a la gripe en mayores de 64 años con respecto al total de la mortalidad asociada a la gripe (13.822 defunciones). La tasa de excesos de defunciones por gripe y neumonía y causas respiratorias en mayores de 64 años, obtenida con el modelo Serfling, fue máxima en la temporada 2011-2012: 18,07 y 77,20 defunciones por 100.000 habitantes, respectivamente. Conclusiones: Uno de los principales incrementos significativos de la mortalidad acontecidos en España en los inviernos de los últimos años, en mayores de 64 años, fue detectado por los sistemas de monitorización de mortalidad español y europeo en la temporada 2011-2012, coincidiendo en el tiempo con una tardía temporada gripal, con predominio de virus A(H3N2), y una ola de bajas temperaturas. Este estudio muestra que la gripe pudo ser uno de los principales factores contribuyentes al exceso de mortalidad observado en el invierno de 2012 en España (AU)

Objective: An excess of mortality was detected in Spain in February and March 2012 by the Spanish daily mortality surveillance system and the «European monitoring of excess mortality for public health action» program. The objective of this article was to determine whether this excess could be attributed to influenza in this period. Methods: Excess mortality from all causes from 2006 to 2012 were studied using time series in the Spanish daily mortality surveillance system, and Poisson regression in the European mortality surveillance system, as well as the FluMOMO model, which estimates the mortality attributable to influenza. Excess mortality due to influenza and pneumonia attributable to influenza were studied by a modification of the Serfling model. To detect the periods of excess, we compared observed and expected mortality. Results: In February and March 2012, both the Spanish daily mortality surveillance system and the European mortality surveillance system detected a mortality excess of 8,110 and 10,872 deaths (mortality ratio (MR): 1.22 (95% CI:1.21-1.23) and 1.32 (95% CI: 1.29-1.31), respectively). In the 2011-12 season, the FluMOMO model identified the maximum percentage (97%) of deaths attributable to influenza in people older than 64 years with respect to the mortality total associated with influenza (13,822 deaths). The rate of excess mortality due to influenza and pneumonia and respiratory causes in people older than 64 years, obtained by the Serfling model, also reached a peak in the 2011-2012 season: 18.07 and 77.20, deaths per 100,000 inhabitants, respectively. Conclusion: A significant increase in mortality in elderly people in Spain was detected by the Spanish daily mortality surveillance system and by the European mortality surveillance system in the winter of 2012, coinciding with a late influenza season, with a predominance of the A(H3N2) virus, and a cold wave in Spain. This study suggests that influenza could have been one of the main factors contributing to the mortality excess observed in the winter of 2012 in Spain (AU)

The European I-MOVE Multicentre 2013-2014 Case-Control Study. Homogeneous moderate influenza vaccine effectiveness against A(H1N1)pdm09 and heterogenous results by country against A(H3N2).

BACKGROUND: In the first five I-MOVE (Influenza Monitoring Vaccine Effectiveness in Europe) influenza seasons vaccine effectiveness (VE) results were relatively homogenous among participating study sites. In 2013-2014, we undertook a multicentre case-control study based on sentinel practitioner surveillance networks in six European Union (EU) countries to measure 2013-2014 influenza VE against medically-attended influenza-like illness (ILI) laboratory-confirmed as influenza. Influenza A(H3N2) and A(H1N1)pdm09 viruses co-circulated during the season. METHODS: Practitioners systematically selected ILI patients to swab within eight days of symptom onset. We compared cases (ILI positive to influenza A(H3N2) or A(H1N1)pdm09) to influenza negative patients. We calculated VE for the two influenza A subtypes and adjusted for potential confounders. We calculated heterogeneity between sites using the I(2) index and Cochrane's Q test. If the I(2) was <50%, we estimated pooled VE as (1 minus the OR)×100 using a one-stage model with study site as a fixed effect. If the I(2) was >49% we used a two-stage random effects model. RESULTS: We included in the A(H1N1)pdm09 analysis 531 cases and 1712 controls and in the A(H3N2) analysis 623 cases and 1920 controls. For A(H1N1)pdm09, the Q test (p=0.695) and the I(2) index (0%) suggested no heterogeneity of adjusted VE between study sites. Using a one-stage model, the overall pooled adjusted VE against influenza A(H1N1)pdm2009 was 47.5% (95% CI: 16.4-67.0). For A(H3N2), the I(2) was 51.5% (p=0.067). Using a two-stage model for the pooled analysis, the adjusted VE against A(H3N2) was 29.7 (95% CI: -34.4-63.2). CONCLUSIONS: The results suggest a moderate 2013-2014 influenza VE against A(H1N1)pdm09 and a low VE against A(H3N2). The A(H3N2) estimates were heterogeneous among study sites. Larger sample sizes by study site are needed to prevent statistical heterogeneity, decrease variability and allow for two-stage pooled VE for all subgroup analyses.

Interim influenza vaccine effectiveness: A good proxy for final estimates in Spain in the seasons 2010-2014.

INTRODUCTION: The agreement between interim and final influenza vaccine effectiveness (VE) estimates would support the use of interim assessments as a proxy for final VE results to guide health authorities in influenza prevention. We aimed to compare interim/final VE estimates in Spain. METHODS: We used a test-negative case-control study (cycEVA) for 2010/11-2013/14 seasons. Sensitivity analyses were carried out by type/subtype of influenza virus and by target groups for vaccination. RESULTS: In general, interim estimates were higher compared to end-season estimates. Interim and final VE differences were higher for the target groups compared to all population. Subtype-specific interim/final VE estimates showed greater concordance (3-13%) than for any virus (7-24%). CONCLUSION: In Spain, interim influenza VE estimates over 2010-2014 were a good proxy of the final protection of the vaccine. Interim and final estimates showed greater concordance for all population and if performed subtype-specific.

[Excess mortality associated with influenza in Spain in winter 2012]. / Exceso de mortalidad relacionado con la gripe en España en el invierno de 2012.

OBJECTIVE: An excess of mortality was detected in Spain in February and March 2012 by the Spanish daily mortality surveillance system and the «European monitoring of excess mortality for public health action¼ program. The objective of this article was to determine whether this excess could be attributed to influenza in this period. METHODS: Excess mortality from all causes from 2006 to 2012 were studied using time series in the Spanish daily mortality surveillance system, and Poisson regression in the European mortality surveillance system, as well as the FluMOMO model, which estimates the mortality attributable to influenza. Excess mortality due to influenza and pneumonia attributable to influenza were studied by a modification of the Serfling model. To detect the periods of excess, we compared observed and expected mortality. RESULTS: In February and March 2012, both the Spanish daily mortality surveillance system and the European mortality surveillance system detected a mortality excess of 8,110 and 10,872 deaths (mortality ratio (MR): 1.22 (95% CI:1.21-1.23) and 1.32 (95% CI: 1.29-1.31), respectively). In the 2011-12 season, the FluMOMO model identified the maximum percentage (97%) of deaths attributable to influenza in people older than 64 years with respect to the mortality total associated with influenza (13,822 deaths). The rate of excess mortality due to influenza and pneumonia and respiratory causes in people older than 64 years, obtained by the Serfling model, also reached a peak in the 2011-2012 season: 18.07 and 77.20, deaths per 100,000 inhabitants, respectively. CONCLUSION: A significant increase in mortality in elderly people in Spain was detected by the Spanish daily mortality surveillance system and by the European mortality surveillance system in the winter of 2012, coinciding with a late influenza season, with a predominance of the A(H3N2) virus, and a cold wave in Spain. This study suggests that influenza could have been one of the main factors contributing to the mortality excess observed in the winter of 2012 in Spain.

[cycEVA study: case control study measuring influenza vaccine effectiveness in Spain, 2008-2013]. / Estudio cycEVA: casos y controles para la estimación de la efectividad de la vacuna antigripal en España, 2008-2013.

BACKGROUND: In Spain, influenza vaccine effectiveness (EV) is estimated since 2008-09 season through the cycEVA case-control study, the Spanish component of the European I-MOVE (Monitoring Influenza Vaccine Effectiveness in the EU/EEA) network. We aimed at describing cycEVA performance in its five consolidated editions 2008/09 -; 2012/13. METHODS: During the study period the following indicators were analysed: 1) the participation of sentinel general practitioners and pediatricians (MP), 2) the population studied and the study period, 3) the data quality and 4) the dissemination of the cycEVA results. Trend analysis of the indicators was done using the Cochran-Armitage test to compute the Annual Percentage Change (PCA). RESULTS: The number of participating MP increased from 164 in 2008-09 to 246 in the following editions. The percentage of MP recruiting at least one patient increased significantly annually (PCA = 15.33%). The percentage of recruited patients included into the analysis increased (PCA=5.91%) from 77% in 2008-09 to more than 95% in the following editions. The percentage of cycEVA patients contributing to the I-MOVE study ranged between 23% and 30% in the pilot and 2011-12 editions respectively.. Final results were disseminated in quartile 2 peer-reviewed journals and 2010-11 and 2011-12 preliminary EV estimates were published in quartile 1 journals. cycEVA publications received 97 citations. CONCLUSION: cycEVA study achieved more quality information, timely EV estimates and a higher impact of the results.

Estudio cycEVA: caos y controles para la estimación de la efectividad de la vacuna antigripal en España, 2008-2013 / cycEVA study: case control study Measuring influenza vaccine effectiveness in Spain, 2008-2013

Fundamentos: Desde 2008-09 la efectividad de la vacuna (EV) antigripal en España se estima con el estudio de casos y controles para la evaluación de la EV antigripal (cycEVA), componente español de la red europea (Influenza- Monitoring Vaccine Effectiveness (I-MOVE). El objetivo es describir la evolución del estudio cycEVAdurante las cinco temporadas del período 2008/09-2012/13. Métodos: Se analizaron los siguientes indicadores: 1) participación de los médicos/pediatras centinela (MP); 2) población y periodo de estudio, 3) calidad de los datos y 4) difusión de los resultados mediantes publicaciones. Se calculó el porcentaje anual de cambio constante de los indicadores analizándose su tendencia mediante el test de Cochran-Armitage. Resultados: El número de MP participantes aumentó de 164 en 2008-09 hasta 246 en ediciones posteriores. El porcentaje de médicos que reclutaron al menos un paciente experimentó un cambio anual significativo (PCA) del 15,33%. El porcentaje de pacientes reclutados incluidos en el análisis aumentó del 77% en 2008-09 a más del 95% en las siguientes ediciones (PCA=5,91%). El porcentaje de casos y controles participantes en cycEVA sobre el total de pacientes que contribuyeron al estudio europeo I-MOVE osciló entre el 23% en la edición piloto y 30% en la temporada 2011-12. Los resultados finales se difundieron en revistas científicas con un factor de impacto situado en el cuartil 2 y en 2010-11 y 2011-12 se publicaron resultados preliminares en revistas con un factor de impacto situado en el cuartil 1 (97 citas). Conclusiones: La experiencia del estudio cycEVA se reflejó en una mejora en la oportunidad e impacto de sus resultados, cruciales para orientar las recomendaciones anuales de vacunación antigripal (AU)

Background: In Spain, influenza vaccine effectiveness (EV) is estimated since 2008-09 season through the cycEVAcase-control study, the Spanish component of the European I-MOVE (Monitoring Influenza Vaccine Effectiveness in the EU/EEA) network.We aimed at describing cycEVAperformance in its five consolidated editions 2008/09 - 2012/13. Methods: During the study period the following indicators were analysed: 1) the participation of sentinel general practitioners and pediatricians (MP), 2) the population studied and the study period, 3) the data quality and 4) the dissemination of the cycEVA results. Trend analysis of the indicators was done using the Cochran-Armitage test to compute theAnnual Percentage Change (PCA). Results: The number of participatingMP increased from 164 in 2008-09 to 246 in the following editions. The percentage of MP recruiting at least one patient increased significantly annually (PCA = 15.33%). The percentage of recruited patients included into the analysis increased (PCA=5.91%) from 77% in 2008-09 to more than 95% in the following editions. The percentage of cycEVA patients contributing to the I-MOVE study ranged between 23% and 30% in the pilot and 2011-12 editions respectively.. Final results were disseminated in quartile 2 peer-reviewed journals and 2010-11 and 2011-12 preliminary EV estimates were published in quartile 1 journals. cycEVA publications received 97 citations. Conclusion: cycEVA study achieved more quality information, timely EV estimates and a higher impact of the results (AU)

Higher vaccine effectiveness in seasons with predominant circulation of seasonal influenza A(H1N1) than in A(H3N2) seasons: test-negative case-control studies using surveillance data, Spain, 2003-2011.

BACKGROUND: We used data provided by the Spanish influenza surveillance system to measure seasonal influenza vaccine effectiveness (VE) against medically attended cases, laboratory confirmed with the predominately circulating influenza virus over eight seasons (2003-2011). METHODS: Using the test-negative case-control design, we compared the vaccination status of swabbed influenza-like illnesses (ILI) patients who were laboratory confirmed with predominantly circulating influenza strain in the season (cases) to that of ILI patients testing negative for any influenza (controls). Data on age, sex, vaccination status and laboratory results were available for all seasons. We used logistic regression to calculate adjusted influenza VE for age, week of swabbing, Spanish region and season. We calculated the influenza VE by each season and pooling the seasons with the same predominant type/subtype. RESULTS: Overall influenza VE against infection with A(H3N2) subtype (four seasons) was 31 (95% confidence interval (CI):10; 48). For seasonal influenza A(H1N1) (two seasons), the effectiveness was 86% (95% CI: 65; 94). Against B infection (three seasons), influenza VE was 47% (95% CI: 27; 62). CONCLUSIONS: The Spanish influenza surveillance system allowed estimating influenza VE in the studied seasons for the predominant strain. Strengthening the influenza surveillance will result in more precise VE estimates for decision making.

Effectiveness of influenza vaccine against laboratory-confirmed influenza, in the late 2011-2012 season in Spain, among population targeted for vaccination.

BACKGROUND: In Spain, the influenza vaccine effectiveness (VE) was estimated in the last three seasons using the observational study cycEVA conducted in the frame of the existing Spanish Influenza Sentinel Surveillance System. The objective of the study was to estimate influenza vaccine effectiveness (VE) against medically attended, laboratory-confirmed influenza-like illness (ILI) among the target groups for vaccination in Spain in the 2011-2012 season. We also studied influenza VE in the early (weeks 52/2011-7/2012) and late (weeks 8-14/2012) phases of the epidemic and according to time since vaccination. METHODS: Medically attended patients with ILI were systematically swabbed to collect information on exposure, laboratory outcome and confounding factors. Patients belonging to target groups for vaccination and who were swabbed <8 days after symptom onset were included. Cases tested positive for influenza and controls tested negative for any influenza virus. To examine the effect of a late season, analyses were performed according to the phase of the season and according to the time between vaccination and symptoms onset. RESULTS: The overall adjusted influenza VE against A(H3N2) was 45% (95% CI, 0-69). The estimated influenza VE was 52% (95% CI, -3 to 78), 40% (95% CI, -40 to 74) and 22% (95% CI, -135 to 74) at 3.5 months, 3.5-4 months, and >4 months, respectively, since vaccination. A decrease in VE with time since vaccination was only observed in individuals aged ≥ 65 years. Regarding the phase of the season, decreasing point estimates were only observed in the early phase, whereas very low or null estimates were obtained in the late phase for the shortest time interval. CONCLUSIONS: The 2011-2012 influenza vaccine showed a low-to-moderate protective effect against medically attended, laboratory-confirmed influenza in the target groups for vaccination, in a late season and with a limited match between the vaccine and circulating strains. The suggested decrease in influenza VE with time since vaccination was mostly observed in the elderly population. The decreasing protective effect of the vaccine in the late part of the season could be related to waning vaccine protection because no viral changes were identified throughout the season.

Epidemiology of the 2009 influenza pandemic in Spain. The Spanish Influenza Surveillance System.

In accordance with European Centre for Disease Prevention and Control recommendations, the Spanish Influenza Surveillance System (SISS) maintained its activity during the summer of 2009, and since July 2009 the pandemic virus activity was monitored by the SISS. In this paper, we describe the epidemiological and virological characteristics of the 2009 pandemic in the Spain through the SISS. Spain experienced a transmission of the new A(H1N1)pdm09 influenza virus during the summer of 2009, which gradually increased, resulting in the pandemic wave in early autumn of that year. The reproductive number R0, estimated during the growth phase of the pandemic wave (1.32; 95% confidence interval [95%CI], 1.29-1.36), showed a transmissibility comparable to preceding pandemics. There was an almost complete replacement of the previous seasonal A(H1N1) influenza virus by the pandemic virus A(H1N1)pdm09. The pandemic virus produced a greater burden of illness than seasonal influenza in children younger than 15 years old, while the incidence in those older than 64 years was lower compared with previous inter-pandemic seasons. Nevertheless, in Spain the 2009 pandemic was characterized as mild, considering the duration of the pandemic period and the influenza detection rate, both in the range of those observed in previous inter-pandemic seasons. Also, the case fatality ratio (CFR) was estimated at 0.58 deaths/1,000 confirmed ILI cases (95%CI, 0.52-0.64), in the range of the two previous pandemics of 1957 and 1968, with the highest CFR observed in the older than 64 years age group. In the 2009 pandemic there was a higher percentage of pandemic confirmed deaths in the younger ages, compared to seasonal influenza, since only 28% of the reported deaths occurred in persons aged 64 years and older.