Eelko Hak

Is immunising all patients with chronic lung disease in the community against influenza cost effective? Evidence from a general practice based clinical prospective cohort study in Utrecht, the Netherlands

STUDY OBJECTIVE: There is little information on the potential benefit of immunising all patients with chronic lung disease in the community against influenza. The clinical effectiveness and economic benefit was established of the influenza vaccination programme in a general practice based cohort of adult patients with chronic lung disease followed up during the 1995/96 influenza A epidemic. DESIGN: A prospective cohort study from October 1995 to March 1996. SETTING: The study was undertaken in the Utrecht General Practices Network with six large group practices, covering a total population of approximately 50,000 patients in the Netherlands. PATIENTS: Computerised medical records of 1696 patients with chronic lung disease aged over 18 years with an indication for vaccination according to the Dutch GP guidelines were reviewed. MAIN RESULTS: The overall attack rate of any complication, including all cause death, low respiratory tract infection, and acute cardiac disease was 15%. Exacerbations of lung disease were most frequent (13%). Death, pneumonia, and acute cardiac disease were mainly limited to patients > or = 65 years. No effectiveness of the immunisation programme could be established in patients 18-64 years (n = 1066), after controlling for baseline prognosis in multivariable logistic regression analysis. In vaccinees > or = 65 years (n = 630), the occurrence of any complication was reduced by 50% (95% CI 17, 70%). The economic benefit was estimated at 50 Pounds per elderly vaccinee. CONCLUSIONS: This study suggests that in the Netherlands immunisation of elderly patients with chronic lung disease against influenza is effective and cost-saving, hence these patients should be given high priority. More, preferably experimental, studies are needed to establish whether adult lung patients under 65 years in the community will also benefit from vaccination.

Decline in influenza-associated mortality among Dutch elderly following the introduction of a nationwide vaccination program.

With a retrospective nationwide cohort study in the Netherlands over 1992-2003, using mortality and viral surveillance data, the aim was to assess by means of rate difference methods the influenza-associated mortality in the elderly before and after the introduction of a nationwide influenza vaccination program in 1996 (vaccination coverage raised from below 50 to 80%). The average annual influenza-associated mortality declined in the years before and after the introduction from 131 to 105 per 100,000 persons (relative risk 0.80). The decline was largest in the age group 65-69 years (relative risk 0.54) and less in those aged 75 years and older. Validation by Serfling-type regression analysis revealed similar results. In conclusion, routine influenza vaccination among Dutch elderly was associated with a significant decrease in influenza-associated mortality, notably in those aged 65-69 years.

Effectiveness of a co-ordinated nation-wide programme to improve influenza immunisation rates in The Netherlands

OBJECTIVEnTo assess t he effectiveness of a nation-widemultifaceted intervention programme involving general practitioners (GPs) on influenza immunisation practice.nnnDESIGNnPragmatic before-after trial using pre- and post-measurement questionnaires.nnnSETTING AND SUBJECTSnRandom sample of Dutch general practices.nnnINTERVENTIONnDuring a 2.5-year period (1995-1997) a variety of methods was implemented to enhance physician adoption of the immunisation guideline, including employment of facilitators, information-based methods, small-group consensus meetings, individual instructions and introduction of supportive computer software.nnnMAIN OUTCOME MEASURESnInfluenza immunisation practice and influenza vaccine uptake.nnnRESULTSnIn 988 practices all influenza vaccination characteristics markedly improved from 1995 to 1997. The most significant changes were found in computerised marking of high-risk patients (from 54% to 82% of practices), computerised selection (41% to 77%) and sending personal reminders (40% to 77%). Vaccine uptake increased from 9% to 16% of the practice population (78% increase, p < 0.001). Uptake was most prominent in urban and single-handed practices and in those with more patients insured through the National Health Service, low GP workload and low baseline uptake.nnnCONCLUSIONnOur data suggest that a co-ordinated approach involving primary care physicians can succeed in enlarging the public health impact of a population-based preventive measure.

Cost-effectiveness of rotavirus vaccination in the Netherlands; the results of a consensus model

BackgroundEach year rotavirus gastroenteritis results in thousands of paediatric hospitalisations and primary care visits in the Netherlands. While two vaccines against rotavirus are registered, routine immunisation of infants has not yet been implemented. Existing cost-effectiveness studies showed inconsistent results for these vaccines because of lack of consensus on the impact. We aimed to investigate which factors had a major impact on cost-effectiveness and were primarily responsible for the large differences in previously estimated cost-effectiveness ratios.MethodsBased on updated data on health outcomes and cost estimates, we re-assessed the cost-effectiveness of routine paediatric rotavirus vaccination within the National Immunization Program for the Netherlands. Two consensus meetings were organised with national and international experts in the field to achieve consensus and resolve potential controversies.ResultsIt was estimated that rotavirus vaccination in the Netherlands could avert 34,214 cases of rotavirus gastroenteritis in children aged less than 5 years. Notably, 2,779 hospitalisations were averted of which 315 were extensions of existing hospital stays due to nosocomial rotavirus infection. With a threshold varying from 20K€ - 50K€ per QALY and according to the base-case scenario, the full vaccination costs per child leading to cost-effectiveness was €57.76 -€77.71. Results were sensitive to the inclusion of potential vaccine induced herd protection, QALY losses and number of deaths associated with rotavirus gastroenteritis.ConclusionsOur economic analysis indicates that inclusion of rotavirus vaccination in the Dutch National Immunization Program might be cost-effective depending on the cost of the vaccine and the impact of rotavirus gastroenteritis on childrens quality of life.

Conventional Influenza Vaccination Is Not Associated with Complications in Working-Age Patients with Asthma or Chronic Obstructive Pulmonary Disease

Abstract By using a nested case-control design, the authors studied the effectiveness of the influenza vaccine in reducing severe and fatal complications in 4,241 and 5,966 primary care, working-age patients aged 18–64 years who had asthma or chronic obstructive pulmonary disease during the 1998–1999 and 1999–2000 influenza epidemics in the Netherlands. Patients developing fatal or nonfatal exacerbations of lung disease, pneumonia, congestive heart failure, or myocardial infarction during either epidemic were considered cases. For each case, four age- and sex-matched controls were randomly sampled, and patient records were reviewed. Conditional logistic regression and propensity scores were used to assess vaccine effectiveness after adjustment for confounding factors. In seasons one and two, respectively, 87% (47/54) and 85% (171/202) of the cases and 74% (155/210) and 75% (575/766) of the controls had been vaccinated. After adjustments, vaccination was not associated with reductions in complications (season one: odds ratio = 0.95, 95% confidence interval (CI): 0.26, 3.48; season two: odds ratio = 1.07, 95% CI: 0.59, 1.96; pooled odds ratio = 1.07, 95% CI: 0.63, 1.80). Because influenza vaccination appeared not to be associated with a clinically relevant reduction in severe morbidity, other measures need to be explored.

Design of the Dutch prevention of influenza, surveillance and management (PRISMA) study

Rationale and design of a study on the cost-effectiveness of the Dutch influenza vaccination campaign are described. During two influenza epidemics, about 75,000 primary care patients recommended for influenza vaccination are included. Cases have fatal or non-fatal influenza, pneumonia, otitis media, acute respiratory disease (ARD), heart failure, myocardial infarction, depression or diabetes dysregulation. Per case four controls are sampled, frequency matched on age and high-risk co-morbidity (<18 years, 18-64, >/=65 healthy, >/=65 with co-morbidity). Baseline and outcome data are retrieved from patient records. During the 1999-2000 influenza A epidemic 5891 (7.9%) high-risk children, 24,848 (33.2%) high-risk adults aged 18-64 years, 18,484 (24.7%) elderly with co-morbidity and 25,527 (34.1%) healthy elderly had been included. The mortality rate was 5.2 per 1000 and 2035 non-fatal outcome events were recorded (incidence rate 27.2/1000).

Monitoring the safety of influenza A (H1N1) vaccine using web-based intensive monitoring.

BACKGROUNDnWhen adjuvant vaccines against the pandemic influenza A (H1N1) virus became available after an accelerated registration process, safety issues dominated the public debate. As part of the immunisation campaign, the Dutch government installed an active monitoring of possible adverse events following immunisation (AEFIs). As part of the monitoring we conducted an anonymous prospective cohort study to identify and quantify the occurrence of AEFIs related to pandemic vaccination among the population immunised in general practice.nnnMETHODnAdults aged 60 years and older or persons with a risk-elevating medical condition recommended for vaccination in general practice were eligible for participation. After receipt of the first pandemic vaccine the administrator handed over an information flyer of the web-based monitoring program. The patient could sign up for study participation online. Within one week, three weeks and three months after the first immunisation questions were asked about demographics and health, immunisations, injections site reactions and labeled reactions as well as other possible new AEFIs.nnnRESULTSnIn all, 3569 participants filled in the first questionnaire. Corresponding figures for the second and third questionnaires were 3395 (95.1%) and 3162 (88.6%). Mean age was 58 years (SD 15) and 50.1% was female. Main indication was 60 years or older followed by presence of pulmonary or cardiovascular disease. Of all participants, 1311 (37%) reported an AEFI. Unexpected serious reactions were not reported nor were there signals of possible new AEFIs. The occurrence of an AEFI was determined by gender, age and type of co-morbidity.nnnCONCLUSIONnThe web-based intensive monitoring system among patients immunised in general practice revealed AEFIs due to pandemic vaccination in one-third of participants. There were no unexpected serious adverse events in this population. This advanced methodology can be further developed to monitor real-time use and AEFIs of vaccines.

Effectiveness of seasonal influenza vaccination in community-dwelling elderly people: an individual participant data meta-analysis of test-negative design case-control studies

BACKGROUNDnSeveral aggregate data meta-analyses have provided estimates of the effectiveness of influenza vaccination in community-dwelling elderly people. However, these studies ignored the effects of patient-level confounders such as sex, age, and chronic diseases that could bias effectiveness estimates. We aimed to assess the confounder-adjusted effectiveness of influenza vaccines on laboratory-confirmed influenza among elderly people by conducting a global individual participant data meta-analysis.nnnMETHODSnIn this individual participant data meta-analysis, we considered studies included in a previously conducted aggregate data meta-analysis that included test-negative design case-control studies published up to July 13, 2014. We contacted all authors of the included studies on Dec 1, 2014, to request individual participant data. Patients were excluded if their unique identifier was missing, their vaccination status was unknown, their outcome status was unknown, or they had had suspected influenza infection more than once in the same influenza season. Cases were patients with influenza-like illness symptoms who tested positive for at least one of A H1N1, A H1N1 pdm09, A H3N2, or B viruses; controls were patients with influenza-like illness symptoms who tested negative for these virus types or subtypes. Influenza vaccine effectiveness against overall and subtype-specific laboratory-confirmed influenza were the primary and secondary outcomes. We used a generalised linear mixed model to calculate adjusted vaccine effectiveness according to vaccine match to the circulating strains of influenza virus and intensity of the virus activity (epidemic or non-epidemic). Vaccine effectiveness was defined as the relative reduction in risk of laboratory-confirmed influenza in vaccinated patients compared with unvaccinated patients. We did subgroup analyses to estimate vaccine effectiveness according to hemisphere, age category, and health status.nnnFINDINGSnWe received 23 of the 53 datasets included in the aggregate data meta-analysis. Furthermore, six additional datasets were provided by data collaborators, which resulted in individual participant data for a total of 5210 participants. A total of 4975 patients had the required data for analysis. Of these, 3146 (63%) were controls and 1829 (37%) were cases. Influenza vaccination was significantly effective during epidemic seasons irrespective of vaccine match status (matched adjusted vaccine effectiveness 44·38%, 95% CI 22·63-60·01; mismatched adjusted vaccine effectiveness 20·00%, 95% CI 3·46-33·68; analyses in the imputed dataset). Seasonal influenza vaccination did not show significant effectiveness during non-epidemic seasons. We found substantial variation in vaccine effectiveness across virus types and subtypes, with the highest estimate for A H1N1 pdm09 (53·19%, 10·25-75·58) and the lowest estimate for B virus types (-1·52%, -39·58 to 26·16). Although we observed no significant differences between subgroups in each category (hemisphere, age, and health status), influenza vaccination showed a protective effect among elderly people with cardiovascular disease, lung disease, or aged 75 years and younger.nnnINTERPRETATIONnInfluenza vaccination is moderately effective against laboratory-confirmed influenza in elderly people during epidemic seasons. More research is needed to investigate factors affecting vaccine protection (eg, brand-specific or type-specific vaccine effectiveness and repeated annual vaccination) in elderly people.nnnFUNDINGnUniversity Medical Center Groningen.

Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction: A systematic review on CYP2C9, CYP2C19 and CYP2D6

Currently, most guidelines on drug-drug interaction (DDI) neither consider the potential effect of genetic polymorphism in the strength of the interaction nor do they account for the complex interaction caused by the combination of DDI and drug-gene interaction (DGI) where there are multiple biotransformation pathways, which is referred to as drug-drug-gene interaction (DDGI). In this systematic review, we report the impact of pharmacogenetics on DDI and DDGI in which three major drug-metabolizing enzymes - CYP2C9, CYP2C19 and CYP2D6 - are central. We observed that several DDI and DDGI are highly gene-dependent, leading to a different magnitude of interaction. Precision drug therapy should take pharmacogenetics into account when drug interactions in clinical practice are expected.

Safety and tolerability evaluation of the use of Montanide ISA™51 as vaccine adjuvant: A systematic review

Montanide ISA™51 (ISA 51) is a vaccine adjuvant which has been tested in therapeutic and prophylactic vaccine trials. The aim of this review is to present a comprehensive examination of the safety and tolerability of ISA 51 containing vaccines. A systematic literature search was conducted in PubMed, EMBASE and clinicaltrials.gov. Eligible studies were categorized into: (A) uncontrolled studies with non-healthy subjects, (B) controlled studies with non-healthy subjects, and (C) controlled studies with healthy subjects. Reported adverse events (AEs) were assessed. 91 studies were included in our review. Generally observed AEs included injection site reaction; injection site pain; myalgia; headache; gastro-intestinal disorders; fatigue and fever - regardless of the administration route and subject characteristic. Specific AEs, e.g. injection site reactions and rash, were more frequently reported from subjects receiving ISA 51-adjuvanted vaccines than from subjects receiving antigen or ISA 51 only. The reported AEs were mainly mild to moderate in intensity. Serious AEs (SAEs) were reported in 27% of the uncontrolled trials and 2 trials conducted with healthy subjects. Notably, 2 other trials conducted with healthy subjects were stopped due to unacceptable AEs. Some studies indicate that the mixing procedure of antigen and adjuvant might influence the occurrence of AEs. Reports on SAEs and premature termination of 2 trials advise caution when using ISA 51. Yet, AEs might be preventable by proper mixing of vaccine and adjuvant to a stable emulsion. Trials including an active control group are needed for a fair evaluation of adjuvant safety.