Seasonal influenza vaccine effectiveness in asthma
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Introduction Influenza is a seasonal viral respiratory infection that causes considerable morbidity and mortality, particularly in individuals with chronic medical conditions such as asthma. Vaccination is one of the most effective available preventive measures against influenza and is recommended for children and adults with asthma. Despite the longstanding recommendation in developed countries that people with asthma be vaccinated against influenza, less than half of the asthma population eligible for the vaccine are immunised every year. Some of the reasons for this suboptimal coverage include doubts about the benefits of the vaccines and safety concerns amongst both healthcare providers and asthma patients. In 2012, a Cochrane systematic review concluded that evidence from randomised controlled trials (RCTs) on the effect of influenza vaccines on asthma-related clinical outcomes from influenza infection is unclear. However, the review confirmed that influenza vaccination was safe. Therefore, this doctoral research program had the following main aims: 1. To conduct rigorous secondary research in the form of a systematic review to identify, appraise and integrate evidence, not limited by study design, for vaccine protection in asthma against influenza infection and influenza-related clinical outcomes. This review also included and appraised evidence on vaccination safety in people with asthma. 2. To conduct primary research work to fill evidence gaps identified in the systematic review by providing more accurate estimates of the protective effects of influenza vaccines against influenza infection in people with asthma over multiple influenza seasons using routinely collected data from Scotland. 3. To estimate the effectiveness of influenza vaccination in preventing laboratory-confirmed influenza in people with asthma, and variation in vaccine effectiveness (VE) between influenza seasons, influenza types/subtypes, influenza vaccine types and other asthma individuals’ characteristics. To measure the vaccine uptake and explore the main characteristics of people with asthma related to influenza vaccination uptake using routinely collected data from community and secondary healthcare level settings. Methods A programme of work was undertaken which included three complementary phases. In the Phase One, I conducted a systematic review of the literature and searched for published and unpublished studies assessing the efficacy, effectiveness and safety of influenza vaccines over a 46-year period (1970 to 2016). Study selection, data extraction and quality appraisal of studies was carried out independently by two reviewers who followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting checklist. Meta-analysis of clinical and epidemiological similar studies was also performed. In Phase Two, I conducted a test-negative design (TND) case-control study to assess the VE against real-time polymerase chain reaction (RT-PCR) laboratory confirmed influenza in people with asthma. For this study, I used Scottish health administrative data from the Seasonal Influenza Vaccine Effectiveness II (SIVE II) project over 14 influenza seasons (2000/01 to 2015/16). The SIVE II project used healthcare data collected from routinely available datasets and created a large national primary care and laboratory-linked dataset. The main aim of the SIVE II project was to assess the effectiveness of the live attenuated and trivalent inactivated influenza vaccines of all at-risk groups for influenza (e.g. asthma) in Scotland. Some of the SIVE project’s objectives were the evaluation of VE against RT-PCR laboratory-confirmed influenza and influenza-related clinical outcomes (e.g. influenza and asthma-related general practice consultations, hospitalisations and death). Therefore, my work in this phase was part of the SIVE II project as it focused on people with asthma. Additional stratified VE estimates related to various viral strains, vaccines types and asthma individuals’ characteristics were also provided, but from seasons 2010/11 onwards. A generalised additive logistic regression model was used for the calculation of all the VE estimates. Finally, in the Phase Three, I undertook a vaccine uptake analysis exploring factors related to vaccine uptake in the asthma population using data from primary care centres and hospitalisation over 16 influenza seasons (2000/01 to 2016/17) in Scotland. A multivariate logistic regression model was performed to identity any relation between characteristics of the asthma population and vaccine uptake levels in the community. Results The Systematic review identified 20,396 papers, and 35 studies met the inclusion criteria. It was possible to carry out meta-analyses of data from four of these studies. The review found that the influenza vaccination protects children and adults with asthma against influenza infection and influenza-related complications such as asthma exacerbations. However, the overall quality of evidence was rated as very low for all outcomes. The meta-analysis of two TND studies found a moderate VE of 45.0% (95% confidence interval (CI): 31.0 to 56.0) against influenza infection over two seasons in the United States (US) population. The protective effects of the vaccine against asthma exacerbations was also identified based on another US based study over a 3-year period in children with asthma. Specifically, the incidence rate ratio of the vaccine against asthma hospitalizations and emergency department visits ranged from 0.6 (95% CI: 0.4 to 0.8) to 0.8 (95% CI: 0.6 to 1.1). The safety of the inactivated vaccines was also shown. Specifically, a large RCT study in US found an absolute difference of 1.1 percent (95% CI: -1.4 to 3.6) for asthma exacerbations between 2,032 inactivated vaccine and placebo recipients. However, more evidence is needed to assess the safety of the live attenuated vaccines against asthma-related adverse events in preschool children. The TND case-control study included 6,921 swab samples tested for influenza and identified an overall VE of 49.4% (95% CI: 39.7 to 57.5) in 5,824 asthma patients over a 14-year period in Scotland. Higher and significant VE estimates were observed in seasons with good antigenic match between the viral and vaccine strains. The highest VE (76.1%; 95% CI: 55.6 to 87.1) was found in 2010/11 season where the A(H1N1) strain dominated and a good antigenic match with the vaccine was found. Significant protection was observed against the A(H1N1) and B strains, with non-significant protection for the A(H3N2) strain. Significant VE estimates were found in younger adults aged 18-54 years old (VE: 54.0%; 95% CI: 39.2 to 65.2) where protection was found against all circulating influenza strains. The live vaccines offered protection against the influenza B type in children < 17 years old (VE: 96.4%; 95% CI: 46.0 to 100.0). The vaccine uptake analysis revealed characteristics in the asthma population that are related to higher uptake of the vaccine. The overall uptake was 33.6% among 194,319 individuals with asthma identified from 223 general practices and 65.9% among 6,232 patients with asthma with an emergency hospital admission due to influenza or pneumonia over a 16-year period. In the community and at hospital settings higher uptake levels were observed for females (38.7% and 37.0%), younger children aged 5-11 years old (24.5% and 0.8%), older adults aged >75 years old (82.8% and 31.0%) and influenza vaccination history (80.5% and 56.8%). History of primary and secondary care visits (70.4% and 52.8%) and the presence of multiple medical conditions (83.2%) were also related with higher uptake in the community. Higher vaccination rates (65.2%) were observed in individuals using medications, particularly inhaled and oral corticosteroids. Females, adults aged >65 years old, individuals living in remote rural areas, with comorbidities, with history of influenza or pneumococcal vaccination, ex-smokers and with history of five primary care visits and two emergency hospital admissions were more likely to have been vaccinated in the current season. Conclusions This program of work has identified evidence supporting the protective effects of influenza vaccination asthma from previous studies and has contributed new evidence supporting the use of influenza vaccination in the asthma population. In addition, factors related to vaccine uptake in people with asthma were explored. Thus, the current suboptimal uptake levels seen in the UK and globally might be improved by more effective targeting interventions to subgroups of people with asthma defined by specific demographic, clinical and other characteristics that are associated with a lower propensity for vaccination. The systematic review and the TND case-control study confirm that a moderate protection against laboratory diagnosed influenza infection can be achieved with current vaccines in people with asthma. Evidence from the systematic review also showed beneficial effects of the vaccination against clinical outcomes such as influenza-related asthma exacerbations and healthcare visits or hospital admissions. In addition, the primary research work provided stratified VE estimates across multiple influenza seasons and confirmed that vaccination prevents influenza incidence and complication in children and adults with asthma. This thesis has therefore contributed to filling important gaps in the evidence base regarding the benefits of the influenza vaccination in people with asthma. It has also identified the need for additional evidence: specifically, studies should now focus on providing VE estimates for older adults (e.g. 55 years old), for children with LAIV administration and for asthma-related clinical outcomes. Vaccination policymakers can now use my research findings (for example, providing better estimates of safety and effectiveness to inform shared decision making and how to better target interventions to promote uptake) to enhance evidence-based recommendations for clinical practice that could result in improved health of people with asthma by preventing or reducing the burden of influenza virus during each influenza season.