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author:("Hak, elko")
1.  Effects and cost-effectiveness of pharmacogenetic screening for CYP2D6 among older adults starting therapy with nortriptyline or venlafaxine: study protocol for a pragmatic randomized controlled trial (CYSCEtrial) 
Trials  2015;16:37.
Nortriptyline and venlafaxine are commonly used antidepressants for treatment of depression in older patients. Both drugs are metabolized by the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme and guidelines for dose adaptations based on the CYP2D6 genotype have been developed. The CYP2D6 Screening Among Elderly (CYSCE) trial is designed to address the potential health and economic value of genotyping for CYP2D6 in optimizing dose-finding of nortriptyline and venlafaxine.
In a pragmatic randomized controlled trial, patients diagnosed with a major depressive disorder according to the DSM-IV and aged 60 years or older will be recruited from psychiatric centers across the Netherlands. After CYP2D6 genotyping determined in peripheral blood obtained by finger-prick, patients will be grouped into poor, intermediate, extensive, or ultrarapid metabolizers. Patients with deviant genotype (that is poor, intermediate or ultrarapid genotype) will be randomly allocated to an intervention group in which the genotype and dosing advice is communicated to the treating physician, or to a control group in which patients receive care as usual. Additionally, an external reference group of patients with the extensive metabolizer genotype is included. Primary outcome in all groups is time needed to obtain an adequate blood level of the antidepressant drug. Secondary outcomes include adverse drug reactions measured by a shortened Antidepressant Side-Effects Checklist (ASEC), and cost-effectiveness of the screening.
Results of this trial will guide policy-making with regard to pharmacogenetic screening prior to treatment with nortriptyline or venlafaxine among older patients with depression.
Trial registration NCT01778907; registration date: 22 January 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0561-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4328880  PMID: 25636328
CYP2D6; Pharmacogenetics; Depression; Nortriptyline; Venlafaxine
2.  Efficacy of Standard and Intensive Statin Treatment for the Secondary Prevention of Cardiovascular and Cerebrovascular Events in Diabetes Patients: A Meta-Analysis 
PLoS ONE  2014;9(11):e111247.
To estimate the efficacy of standard and intensive statin treatment in the secondary prevention of major cardiovascular and cerebrovascular events in diabetes patients.
A systematic search was conducted in Medline over the years 1990 to September 2013. Randomized, double-blind, clinical trials comparing a standard-dose statin with placebo or a standard-dose statin with an intensive-dose statin for the secondary prevention of cardiovascular and cerebrovascular events in diabetes patients were selected. Trial and patient characteristics were extracted independently by two researchers. The combined effect on the composite primary endpoint was measured with a fixed-effect model. Potential publication bias was examined with a funnel plot.
Five trials were included in the analysis comparing standard-dose statins with placebo with a total of 4 351 participants. Four trials were included for comparing standard-dose with intensive-dose statins, including 4 805 participants. Compared with placebo, standard-dose statin treatment resulted in a significant relative risk (RR) reduction of 15% in the occurrence of any major cardiovascular or cerebrovascular event (RR 0.85, 95% CI 0.79–0.91). Compared with standard-dose statin treatment, intensive-dose statin treatment resulted in an additional 9% relative risk reduction (RR 0.91, 95% CI 0.84–0.98).
Treatment with standard-dose statins to prevent cardiovascular or cerebrovascular events in diabetes patients with manifest cardiovascular disease results in an estimated 15% relative risk reduction and intensive-dose statin treatment adds 9%. If proven cost-effective, more intensive statin treatment should be recommended for diabetes patients at high cardiovascular risk.
PMCID: PMC4220992  PMID: 25372483
3.  Cost-effectiveness of vaccination against meningococcal B among Dutch infants 
Human Vaccines & Immunotherapeutics  2013;9(5):1129-1138.
Objective: Recently, a vaccine with the capacity to protect against serogroup B meningococcal (MenB) disease received a positive opinion of the European Medicines Agency. Previously, such a vaccine was estimated to be cost-effective. However, since then, the MenB disease incidence has declined drastically in the Netherlands. Therefore, we re-assessed the potential incremental cost-effectiveness ratio (ICER) of vaccinating infants in the Netherlands with a MenB vaccine.
Methods: A cohort of 185,000 Dutch newborns was followed in a Markov model to compare routine vaccination against MenB disease with no vaccination. The ICER was estimated for different disease incidences. The study was performed from a societal perspective.
Results: Routine infant vaccination (2, 3, 4+11 mo) could prevent 39 cases of MenB disease in a single birth cohort, corresponding to a total gain of 133 quality-adjusted life years (QALYs). However, this strategy is unlikely to be cost-effective if the vaccine costs €40 per dose (€243,778 per QALY). At a disease incidence of 5.7 per 100,000 person-years or a vaccine price of €10 per dose including administration costs, the ICER becomes more acceptable and remains below a threshold of €50,000 per QALY.
Conclusions: At the current low level of disease incidence, introduction of routine infant vaccination, following a 2, 3, 4+11 mo schedule, against MenB disease is unlikely cost-effective in the Netherlands. If the MenB disease incidence increases or the vaccine price is substantially lower than €40, routine infant vaccination has the potential to be cost-effective.
PMCID: PMC3899149  PMID: 23406816
meningococcal B; cost-effectiveness; vaccine; infants; disease incidence
4.  Effect of pravastatin and fosinopril on recurrent urinary tract infections 
Recurrent urinary tract infections (UTIs) are a problem affecting both women and men. Animal experiments and in vitro studies indicate that statins might prevent recurrent UTIs. We assessed the effects of pravastatin on UTI antibiotic prescribing among adults.
A post hoc analysis was conducted with data from PREVEND IT, a trial among participants randomized to receive pravastatin, fosinopril or placebo in a 2 × 2 factorial design over 4 years. Trial data were linked to the pharmacy prescription database The primary outcome was the number of prescriptions with a nitrofuran derivate, a sulphonamide or trimethoprim as a proxy for UTI antibiotic prescribing. Generalized estimating equations were used to estimate the effect on the number of UTI antibiotic prescriptions. Cox regression was used to determine the effect on first and second (recurrent) UTI antibiotic prescriptions.
Of the 864 trial participants, 655 were eligible for analysis. During an average follow-up of 3.8 years, 112 (17%) participants received at least one UTI antibiotic prescription. Intention-to-treat analyses showed that pravastatin was associated with a reduced total number of UTI antibiotic prescriptions (relative risk, 0.43; 95% CI, 0.21–0.88) and occurrence of second UTI antibiotic prescriptions [hazard ratio (HR), 0.25; 95% CI, 0.08–0.77]. No significant effect on occurrence of first UTI antibiotic prescriptions was found (HR, 0.83; 95% CI, 0.57–1.20). Fosinopril was associated with an increased occurrence of first UTI antibiotic prescriptions (HR, 1.82; 95% CI, 1.16–2.88). Combination therapy with fosinopril and pravastatin did not significantly influence the number of UTI antibiotic prescriptions.
This study suggests that pravastatin can reduce the occurrence of recurrent UTIs. Larger studies among patients with recurrent UTIs are warranted.
PMCID: PMC3566666  PMID: 23111852
cystitis; statin; bacterial invasion
5.  Use of Acid-Suppressive Drugs in Pregnancy and the Risk of Childhood Asthma: Bidirectional Crossover Study using the General Practice Research Database 
Drug Safety  2013;36(11):1097-1104.
Recent studies have reported an association between maternal use of gastric acid-suppressive drugs during pregnancy and asthma in the offspring, but the association could have been confounded by unmeasured risk factors.
We assessed the association between the use of acid-suppressive drugs during pregnancy and the risk of developing childhood asthma using a bidirectional crossover design.
Mother–infant matched sets in the UK General Practitioners Research Database were used to identify children with a drug-treated asthma diagnosis during the years 2006–2010 who were matched to a sibling without asthma as controls. Primary exposure was use of any anti-suppressive drug during pregnancy, and subgroup analyses were conducted according to drug class (e.g. proton pump inhibitors or histamine 2 receptor antagonists) and trimester. Conditional logistic regression was used to estimate odds ratios (OR) with their corresponding 95 % confidence intervals (CIs).
A total of 1,874 children with asthma and 1,874 control siblings were included in the analysis. The exposure rate among case and control pregnancies was 22 and 20 %, respectively. After adjustments for gender, birth order, mother’s age and general practice visits, the exposure to any gastric-acid suppressive drug during pregnancy slightly increased the risk for developing asthma (OR 1.23, 95 % CI 1.01–1.51; p = 0.042). A trend towards increased risks was observed for those who used proton pump inhibitors and/or histamine 2 receptor antagonists (adjusted OR 1.72, 95 % CI 1.00–2.98; p = 0.048).
These findings lend support to the emerging evidence that exposure to acid-suppressive drugs during pregnancy is associated with childhood asthma. More basic research is now warranted to investigate the mechanisms.
Electronic supplementary material
The online version of this article (doi:10.1007/s40264-013-0093-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3824882  PMID: 24018582
6.  Using Spatial Analysis to Predict Health Care Use at the Local Level: A Case Study of Type 2 Diabetes Medication Use and Its Association with Demographic Change and Socioeconomic Status 
PLoS ONE  2013;8(8):e72730.
Local health status and health care use may be negatively influenced by low local socio-economic profile, population decline and population ageing. To support the need for targeted local health care, we explored spatial patterns of type 2 diabetes mellitus (T2DM) drug use at local level and determined its association with local demographic, socio-economic and access to care variables. We assessed spatial variability in these associations. We estimated the five-year prevalence of T2DM drug use (2005–2009) in persons aged 45 years and older at four-digit postal code level using the University of Groningen pharmacy database Statistics Netherlands supplied data on potential predictor variables. We assessed spatial clustering, correlations and estimated a multiple linear regression model and a geographically weighted regression (GWR) model. Prevalence of T2DM medicine use ranged from 2.0% to 25.4%. The regression model included the extent of population ageing, proportion of social welfare/benefits, proportion of low incomes and proportion of pensioners, all significant positive predictors of local T2DM drug use. The GWR model demonstrated considerable spatial variability in the association between T2DM drug use and above predictors and was more accurate. The findings demonstrate the added value of spatial analysis in predicting health care use at local level.
PMCID: PMC3758350  PMID: 24023636
7.  Effectiveness of A(H1N1)pdm09 Influenza Vaccine in Adults Recommended for Annual Influenza Vaccination 
PLoS ONE  2013;8(6):e66125.
Because of variability in published A(H1N1)pdm09 influenza vaccine effectiveness estimates, we conducted a study in the adults belonging to the risk groups to assess the A(H1N1)pdm09 MF59-adjuvanted influenza vaccine effectiveness.
VE against influenza and/or pneumonia was assessed in the cohort study (n>25000), and vaccine effectiveness against laboratory-confirmed A(H1N1)pdm09 influenza was assessed in a matched case-control study (16 pairs). Odds ratios (OR) and their 95% confidence intervals (95% CI) were calculated by using multivariate logistic regression; vaccine effectiveness was estimated as (1-odds ratio)*100%.
Vaccine effectiveness against laboratory-confirmed A(H1N1)pdm09 influenza and influenza and/or pneumonia was 98% (84–100%) and 33% (2–54%) respectively. The vaccine did not prevent influenza and/or pneumonia in 18–59 years old subjects, and was 49% (16–69%) effective in 60 years and older subjects.
Even though we cannot entirely rule out that selection bias, residual confounding and/or cross-protection has played a role, the present results indicate that the MF59-adjuvanted A(H1N1)pdm09 influenza vaccine has been effective in preventing laboratory-confirmed A(H1N1)pdm09 influenza and influenza and/or pneumonia, the latter notably in 60 years and older subjects.
PMCID: PMC3688717  PMID: 23840413
8.  Planning and process evaluation of a multi-faceted influenza vaccination implementation strategy for health care workers in acute health care settings 
BMC Infectious Diseases  2013;13:235.
Influenza transmitted by health care workers (HCWs) is a potential threat to frail patients in acute health care settings. Therefore, immunizing HCWs against influenza should receive high priority. Despite recommendations of the World Health Organization, vaccine coverage of HCWs remains low in all European countries. This study explores the use of intervention strategies and methods to improve influenza vaccination rates among HCWs in an acute care setting.
The Intervention Mapping (IM) method was used to systematically develop and implement an intervention strategy aimed at changing influenza vaccination behaviour among HCWs in Dutch University Medical Centres (UMCs). Carried out during the influenza seasons 2009/2010 and 2010/2011, the interventions were then qualitatively and quantitatively evaluated by way of feedback from participating UMCs and the completion of a web-based staff questionnaire in the following spring of each season.
The IM method resulted in the development of a transparent influenza vaccination intervention implementation strategy. The intervention strategy was offered to six Dutch UMCs in a randomized in a clustered Randomized Controlled Trial (RCT), where three UMCs were chosen for intervention, and three UMCs acted as controls. A further two UMCs elected to have the intervention. The qualitative process evaluation showed that HCWs at four of the five intervention UMCs were responsive to the majority of the 11 relevant behavioural determinants resulting from the needs assessment in their intervention strategy compared with only one of three control UMCs. The quantitative evaluation among a sample of HCWs revealed that of all the developed communication materials, HCWs reported the posters as the most noticeable.
Our study demonstrates that it is possible to develop a structured implementation strategy for increasing the rate of influenza vaccination by HCWs in acute health care settings. The evaluation also showed that it is impossible to expose all HCWs to all intervention methods (which would have been the best case scenario). Further study is needed to (1) improve HCW exposure to intervention methods; (2) determine the effect of such interventions on vaccine uptake among HCWs; and (3) assess the impact on clinical outcomes among patients when such interventions are enacted.
PMCID: PMC3680164  PMID: 23701921
Influenza vaccination; Health care workers; Intervention mapping; Intervention implementation; Acute health care
9.  Prevalence and predictors of over-the-counter medication use among pregnant women: a cross-sectional study in the Netherlands 
BMC Public Health  2013;13:185.
Over-the-counter-medication (OTC-medication) use during pregnancy can be potentially harmful for the fetus. To successfully counsel the patient it is important to know if the patient is at risk. In this study possible predictors for OTC-medication use were identified and a model was designed to predict OTC-medication use during pregnancy.
We performed a post-hoc analysis on data collected for a clustered clinical trial to study a screening strategy for Query fever. Pregnant women under supervision of a midwife were eligible for inclusion. These women filled out questionnaires during their pregnancy and post-partum. These questionnaires were used to determine the prevalence and to select possible predictors for OTC-medication use. These predictors were included in a prediction model using multivariate analysis. The discrimination and calibration of the model were assessed with Receiver Operating Characteristic analysis and the Hosmer and Lemeshow test.
Of the 1348 women enrolling in the clustered clinical trial, we included 1246 women in this analysis. The prevalence of OTC-medication use was 12.5%. The predictors for OTC-medication use in our cohort were: nulliparity, use of prescription medication, the presence of a comorbidity, Body Mass Index between 26 and 30 kg/m2 and General Practitioner visits. These predictors were used to design a prediction model for OTC-medication use. The area under the Receiver Operating Characteristic-curve of the prediction model was 0.667 (95% CI 0.620-0.714 P<0.001) and the predictive probabilities ranged from 6.6% to 57.4%. The Hosmer and Lemeshow goodness-of-fit test indicated good calibration of the model (P = 0.640).
It is possible to indicate women at risk for OTC-medication use during pregnancy, using five maternal characteristics that independently contribute to the prediction model. The predictors are easy to estimate and the model is easy to implement in daily practice.
PMCID: PMC3662163  PMID: 23452432
OTC-medication; Pregnancy; The Netherlands; Epidemiology; Prediction model
10.  Contributing factors to influenza vaccine uptake in general hospitals: an explorative management questionnaire study from the Netherlands 
BMC Public Health  2012;12:1101.
The influenza vaccination rate in hospitals among health care workers in Europe remains low. As there is a lack of research about management factors we assessed factors reported by administrators of general hospitals that are associated with the influenza vaccine uptake among health care workers.
All 81 general hospitals in the Netherlands were approached to participate in a self-administered questionnaire study. The questionnaire was directed at the hospital administrators. The following factors were addressed: beliefs about the effectiveness of the influenza vaccine, whether the hospital had a written policy on influenza vaccination and how the hospital informed their staff about influenza vaccination. The questionnaire also included questions about mandatory vaccination, whether it was free of charge and how delivered as well as the vaccination campaign costs. The outcome of this one-season survey is the self-reported overall influenza vaccination rate of health care workers.
In all, 79 of 81 hospitals that were approached were willing to participate and therefore received a questionnaire. Of these, 42 were returned (response rate 52%). Overall influenza vaccination rate among health care workers in our sample was 17.7% (95% confidence interval: 14.6% to 20.8%). Hospitals in which the administrators agreed with positive statements concerning the influenza vaccination had a slightly higher, but non-significant, vaccine uptake. There was a 9% higher vaccine uptake in hospitals that spent more than €1250,- on the vaccination campaign (24.0% versus 15.0%; 95% confidence interval from 0.7% to 17.3%).
Agreement with positive statements about management factors with regard to influenza vaccination were not associated with the uptake. More economic investments were related with a higher vaccine uptake; the reasons for this should be explored further.
PMCID: PMC3545720  PMID: 23259743
Health care workers; Influenza vaccination; General hospital; Management
11.  Comparatively low attendance during Human Papillomavirus catch-up vaccination among teenage girls in the Netherlands: Insights from a behavioral survey among parents 
BMC Public Health  2012;12:498.
The Dutch Human Papillomavirus (HPV) catch-up vaccination program in 2009 appeared less successful than expected. We aimed to identify the most important determinants of refusing the vaccination.
Two thousand parents of girls born in 1996 targeted for HPV vaccination received an invitation letter to participate in a questionnaire study. Two study groups were defined: the first group consisted of parents of girls who had accepted the vaccine and already received the first dose of HPV vaccination. The second group consisted of parents whose daughters were not vaccinated. The questionnaire consisted of a broad spectrum of possible determinants that were revealed after literature search and discussions with the stakeholders.
Four hundred sixty nine questionnaires (24%) were returned, 307 (31%) from those who accepted and 162 (16%) from those who declined the vaccine. The decision not to accept the vaccine was largely determined by: (i) perception that the information provided by the government about the vaccine was limited or biased (OR 13.27); (ii) limited trust, that the government would stop the vaccination program if there were serious side effects (OR 9.95); (iii) lack of knowledge about the effectiveness of the vaccine (OR 7.67); (iv) concerns about the side effects of the vaccine (OR 4.94); (v) lack of conviction that HPV can be extremely harmful (OR 3.78); (vi) perception that the government is strongly influenced by vaccine producers (OR 3.54); and (vii) religious convictions (OR 2.18).
This study revealed several determinants for HPV vaccination uptake after implementation of the HPV vaccine for adolescent girls. These determinants should be taken into consideration in order to successfully implement HPV vaccination into National Immunization Programs.
PMCID: PMC3461412  PMID: 22748022
12.  Effect of Seven-Valent Pneumococcal Conjugate Vaccine on Staphylococcus aureus Colonisation in a Randomised Controlled Trial 
PLoS ONE  2011;6(6):e20229.
Heptavalent pneumococcal conjugate vaccine (PCV7) shifts nasopharyngeal colonisation with vaccine serotype pneumococci towards nonvaccine serotypes. Because of the reported negative association of vaccine serotype pneumococci and Staphylococcus aureus in the nasopharynx, we explored the effect of PCV7 on nasopharyngeal colonisation with S. aureus in children and parents.
Methodology/Principal Findings
This study was part of a randomised controlled trial on the effect of PCV7 on pneumococcal carriage, enrolling healthy newborns who were randomly assigned (1∶1∶1) to receive PCV7 (1) at 2 and 4 months of age (2) at 2, 4 and 11 months or (3) no PCV7 (controls). Nasopharyngeal colonisation of S. aureus was a planned secondary outcome. Nasopharyngeal swabs were obtained from all children over a 2-year period with 6-months interval and from one parent at the child's age of 12 and 24 months and cultured for Streptococcus pneumoniae and S. aureus. Between July 2005 and February 2006, 1005 children were enrolled and received either 2-doses of PCV7 (n = 336), 2+1-doses (336) or no dose (n = 333) before PCV7 implementation in the Dutch national immunization program. S. aureus colonisation had doubled in children in the 2+1-dose group at 12 months of age compared with unvaccinated controls (10.1% versus 5.0%; p = 0.019). A negative association for co-colonisation of S. pneumoniae and S. aureus was observed for both vaccine serotype (adjusted odds ratio (aOR) 0.53, 95% confidence interval (CI) 0.38–0.74) and nonvaccine serotype pneumococci (aOR 0.67, 95% CI 0.52–0.88).
PCV7 induces a temporary increase in S. aureus colonisation in children around 12 months of age after a 2+1-dose PCV7 schedule. The potential clinical consequences are unknown and monitoring is warranted.
Trial Registration NCT00189020
PMCID: PMC3112202  PMID: 21695210
13.  Cost-effectiveness of rotavirus vaccination in the Netherlands; the results of a consensus model 
BMC Public Health  2011;11:462.
Each 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.
Based 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.
It 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.
Our 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 children's quality of life.
PMCID: PMC3129591  PMID: 21663620
14.  How to develop a program to increase influenza vaccine uptake among workers in health care settings? 
Apart from direct protection and reduced productivity loss during epidemics, the main reason to immunize healthcare workers (HCWs) against influenza is to provide indirect protection of frail patients through reduced transmission in healthcare settings. Because the vaccine uptake among HCWs remains far below the health objectives, systematic programs are needed to take full advantage of such vaccination. In an earlier report, we showed a mean 9% increase of vaccine uptake among HCWs in nursing homes that implemented a systematic program compared with control homes, with higher rates in those homes that implemented more program elements. Here, we report in detail the process of the development of the implementation program to enable researchers and practitioners to develop intervention programs tailored to their setting.
We applied the intervention mapping (IM) method to develop a theory- and evidence-based intervention program to change vaccination behaviour among HCWs in nursing homes.
After a comprehensive needs assessment, we were able to specify proximal program objectives and selected methods and strategies for inducing behavioural change. By consensus, we decided on planning of three main program components, i.e., an outreach visit to all nursing homes, plenary information meetings, and the appointment of a program coordinator -- preferably a physician -- in each home. Finally, we planned program adoption, implementation, and evaluation.
The IM methodology resulted in a systematic, comprehensive, and transparent procedure of program development. A potentially effective intervention program to change influenza vaccination behaviour among HCWs was developed, and its impact was assessed in a clustered randomised controlled trial.
PMCID: PMC3115899  PMID: 21595877
15.  Carriage of Streptococcus pneumoniae 3 Years after Start of Vaccination Program, the Netherlands 
Emerging Infectious Diseases  2011;17(4):584-591.
To evaluate the effectiveness of the 7-valent pneumococcal conjugate vaccine (PCV7) program, we conducted a cross-sectional observational study on nasopharyngeal carriage of Streptococcus pneumoniae 3 years after implementation of the program in the Netherlands. We compared pneumococcal serotypes in 329 prebooster 11-month-old children, 330 fully vaccinated 24-month-old children, and 324 parents with age-matched pre-PCV7 (unvaccinated) controls (ages 12 and 24 months, n = 319 and n = 321, respectively) and 296 of their parents. PCV7 serotype prevalences before and after PCV7 implementation, respectively, were 38% and 8% among 11-month-old children, 36% and 4% among 24-month-old children, and 8% and 1% among parents. Non-PCV7 serotype prevalences were 29% and 39% among 11-month-old children, 30% and 45% among 24-month-old children, and 8% and 15% among parents, respectively; serotypes 11A and 19A were most frequently isolated. PCV7 serotypes were largely replaced by non-PCV7 serotypes. Disappearance of PCV7 serotypes in parents suggests strong transmission reduction through vaccination.
PMCID: PMC3377405  PMID: 21470445
Streptococcus pneumoniae; nasopharyngeal colonization; heptavalent pneumococcal conjugate vaccine; infectious disease transmission; herd immunity; parents; infants; bacteria; research
16.  Cost-effectiveness of a screening strategy for Q fever among pregnant women in risk areas: a clustered randomized controlled trial 
BMC Women's Health  2010;10:32.
In The Netherlands the largest human Q fever outbreak ever reported in the literature is currently ongoing with more than 2300 notified cases in 2009. Pregnant women are particularly at risk as Q fever during pregnancy may cause maternal and obstetric complications. Since the majority of infected pregnant women are asymptomatic, a screening strategy might be of great value to reduce Q fever related complications. We designed a trial to assess the (cost-)effectiveness of a screening program for Q fever in pregnant women living in risks areas in The Netherlands.
We will conduct a clustered randomized controlled trial in which primary care midwife centres in Q fever risk areas are randomized to recruit pregnant women for either the control group or the intervention group. In both groups a blood sample is taken around 20 weeks postmenstrual age. In the intervention group, this sample is immediately analyzed by indirect immunofluorescence assay for detection of IgG and IgM antibodies using a sensitive cut-off level of 1:32. In case of an active Q fever infection, antibiotic treatment is recommended and serological follow up is performed. In the control group, serum is frozen for analysis after delivery. The primary endpoint is a maternal (chronic Q fever or reactivation) or obstetric complication (low birth weight, preterm delivery or fetal death) in Q fever positive women. Secondary aims pertain to the course of infection in pregnant women, diagnostic accuracy of laboratory tests used for screening, histo-pathological abnormalities of the placenta of Q fever positive women, side effects of therapy, and costs. The analysis will be according to the intention-to-screen principle, and cost-effectiveness analysis will be performed by comparing the direct and indirect costs between the intervention and control group.
With this study we aim to provide insight into the balance of risks of undetected and detected Q fever during pregnancy.
Trial registration, protocol record NL30340.042.09.
PMCID: PMC2987891  PMID: 21040534
17.  Effects of Pneumococcal Conjugate Vaccine 2 Years after Its Introduction, the Netherlands 
Emerging Infectious Diseases  2010;16(5):816-823.
Vaccine-serotype disease decreased, but non–vaccine-serotype disease increased.
In the Netherlands, the 7-valent pneumococcal conjugate vaccine (PCV-7) was implemented in a 3+1-dose schedule in the national immunization program for infants born after April 1, 2006. To assess the vaccine’s effectiveness, we compared disease incidence before and after vaccine implementation (June 2004–June 2006 and June 2006–June 2008, respectively). We serotyped 2,552 invasive pneumococcal isolates from throughout the Netherlands, covering 25% of the country’s population. Clinical characteristics were extracted from hospital records. After June 2006, vaccine-serotype invasive pneumococcal disease (IPD) decreased 90% (95% confidence interval [CI] 68%–97%) in children age eligible for PCV-7; simultaneously, however, non–vaccine-serotype IPD increased by 71% (not significant), resulting in a 44% total net IPD reduction (95% CI 7%–66%). IPD rates did not change for other age groups. In the Netherlands, PCV-7 offered high protection against vaccine-serotype IPD in vaccinated children, but increases of non–vaccine-serotype IPD reduced net vaccine benefits.
PMCID: PMC2953990  PMID: 20409372
Heptavalent pneumococcal conjugate vaccine; pneumococcal vaccines; pneumococcal infections; surveillance; bacteria; research
18.  Prognosis of primary care patients aged 80 years and older with lower respiratory tract infection 
The British Journal of General Practice  2009;59(561):e110-e115.
Predictors for a complicated course of a lower respiratory tract infection (LRTI) episode among patients aged ≥80 years are unknown.
To determine prognostic factors for hospital admission or death within 30 days after first onset of LRTI among primary care patients aged ≥80 years.
Design of study
Retrospective cohort study.
Utrecht General Practitioner Research Network.
Data were obtained using the computerised database of the research network over the years 1997 to 2003. Multivariable logistic regression analysis was applied to estimate the independent association of predictors with 30-day hospitalisation or death.
In all, 860 episodes of LRTI were observed in 509 patients; 13% of patients were hospitalised or died within 30 days. Type of LRTI, diabetes, use of oral glucocorticoids, use of antibiotics in the previous month, and hospitalisation in the previous 12 months were independently associated with the combined outcome. Patients with insulin-dependent diabetes mellitus had a greater risk of 30-day hospitalisation or death compared with patients with non-insulin-dependent diabetes.
Independent of age, serious comorbidity – notably the presence of insulin-dependent diabetes or exacerbation of chronic obstructive pulmonary disease requiring oral glucocorticoids – increases the risk for complications, including hospital admissions, in patients aged ≥80 years with an LRTI.
PMCID: PMC2662122  PMID: 19341546
elderly; primary health care; prognosis; respiratory tract, infections
19.  A Model-based Assessment of Oseltamivir Prophylaxis Strategies to Prevent Influenza in Nursing Homes 
Emerging Infectious Diseases  2009;15(10):1547-1555.
Postexposure prophylaxis can prevent more influenza virus infections among nursing home patients per dose than continuous prophylaxis.
Prophylaxis with neuraminidase inhibitors is important for controlling seasonal influenza outbreaks in long-term care settings. We used a stochastic individual-based model that simulates influenza virus transmission in a long-term care nursing home department to study the protection offered to patients by different strategies of prophylaxis with oseltamivir and determined the effect of emerging resistance. Without resistance, postexposure and continuous prophylaxis reduced the patient infection attack rate from 0.19 to 0.13 (relative risk [RR] 0.67) and 0.05 (RR 0.23), respectively. Postexposure prophylaxis prevented more infections per dose (118 and 323 daily doses needed to prevent 1 infection, respectively) and required fewer doses per season than continuous prophylaxis. If resistance to oseltamivir was increased, both prophylaxis strategies became less efficacious and efficient, but postexposure prophylaxis posed a lower selection pressure for resistant virus strains. Extension of prophylaxis to healthcare workers offered little additional protection to patients.
PMCID: PMC2866379  PMID: 19861044
Influenza; oseltamivir; nursing homes; outbreak control; resistance; prophylaxis; prevention; simulation model; research; expedited
20.  Prediction of complicated lower respiratory tract infections in older patients with diabetes 
Patients with diabetes have an elevated risk of developing complicated lower respiratory tract infections (LRTIs). However, up until now, GPs have not had the tools to assess individual risks.
To assess the applicability of an existing prediction rule for complicated LRTI among patients with diabetes.
Design of study
Retrospective cohort study.
The Utrecht GP Research Network.
An existing rule that was used estimates the risk of 30-day hospitalisation or death following an episode of LRTI. Predictors were exacerbation of chronic obstructive pulmonary disease, or pneumonia, increasing age, heart failure, number of hospitalisations in the previous year, use of antibiotics in the previous month, diabetes medication, and prednisone use. Discriminative capacity of the rule was estimated in patients with diabetes. Other potential predictors from the original study were examined, to test for a potentially improved model.
Of 445 episodes of LRTI in patients with diabetes, 68 had an outcome of hospitalisation or death within 30 days of diagnosis of LRTI (15.3%). Results showed good reliability of the model (goodness of fit test P = 0.16) and discriminative properties (area under the receiver operating characteristic curve: 0.79, 95% confidence interval = 0.73 to 0.86). No other predictors could be added. Patients with a lower-risk assignment (score ≤2) had a probability of 5.2%, and those with higher risks (score ≥7) had a probability of 36.6% for the composite endpoint of hospitalisation or death within 30 days of diagnosis of LRTI.
The use of a prediction rule may help GPs to assess the risk of hospitalisation or death in patients with diabetes who have an episode of LRTI.
PMCID: PMC2486383  PMID: 18682019
diabetes mellitus; patient admission; prediction, primary health care; respiratory tract, infection
21.  The Effects of Influenza Vaccination of Health Care Workers in Nursing Homes: Insights from a Mathematical Model 
PLoS Medicine  2008;5(10):e200.
Annual influenza vaccination of institutional health care workers (HCWs) is advised in most Western countries, but adherence to this recommendation is generally low. Although protective effects of this intervention for nursing home patients have been demonstrated in some clinical trials, the exact relationship between increased vaccine uptake among HCWs and protection of patients remains unknown owing to variations between study designs, settings, intensity of influenza seasons, and failure to control all effect modifiers. Therefore, we use a mathematical model to estimate the effects of HCW vaccination in different scenarios and to identify a herd immunity threshold in a nursing home department.
Methods and Findings
We use a stochastic individual-based model with discrete time intervals to simulate influenza virus transmission in a 30-bed long-term care nursing home department. We simulate different levels of HCW vaccine uptake and study the effect on influenza virus attack rates among patients for different institutional and seasonal scenarios. Our model reveals a robust linear relationship between the number of HCWs vaccinated and the expected number of influenza virus infections among patients. In a realistic scenario, approximately 60% of influenza virus infections among patients can be prevented when the HCW vaccination rate increases from 0 to 1. A threshold for herd immunity is not detected. Due to stochastic variations, the differences in patient attack rates between departments are high and large outbreaks can occur for every level of HCW vaccine uptake.
The absence of herd immunity in nursing homes implies that vaccination of every additional HCW protects an additional fraction of patients. Because of large stochastic variations, results of small-sized clinical trials on the effects of HCW vaccination should be interpreted with great care. Moreover, the large variations in attack rates should be taken into account when designing future studies.
Using a mathematical model to simulate influenza transmission in nursing homes, Carline van den Dool and colleagues find that each additional staff member vaccinated further reduces the risk to patients.
Editors' Summary
Every winter, millions of people catch influenza, a contagious viral disease of the nose, throat, and airways. Most people recover completely from influenza within a week or two but some develop life-threatening complications such as bacterial pneumonia. As a result, influenza outbreaks kill about half a million people—mainly infants, elderly people, and chronically ill individuals—each year. To minimize influenza-related deaths, the World Health Organization recommends that vulnerable people be vaccinated against influenza every autumn. Annual vaccination is necessary because flu viruses continually make small changes to the viral proteins (antigens) that the immune system recognizes. This means that an immune response produced one year provides only partial protection against influenza the next year. To provide maximum protection against influenza, each year's vaccine contains disabled versions of the major circulating strains of influenza viruses.
Why Was This Study Done?
Most Western countries also recommend annual flu vaccination for health care workers (HCWs) in hospitals and other institutions to reduce the transmission of influenza to vulnerable patients. However, many HCWs don't get a regular flu shot, so should efforts be made to increase their rate of vaccine uptake? To answer this question, public-health experts need to know more about the relationship between vaccine uptake among HCWs and patient protection. In particular, they need to know whether a high rate of vaccine uptake by HCWs will provide “herd immunity.” Herd immunity occurs because, when a sufficient fraction of a population is immune to a disease that passes from person to person, infected people rarely come into contact with susceptible people, which means that both vaccinated and unvaccinated people are protected from the disease. In this study, the researchers develop a mathematical model to investigate the relationship between vaccine uptake among HCWs and patient protection in a nursing home department.
What Did the Researchers Do and Find?
To predict influenza virus attack rates (the number of patient infections divided by the number of patients in a nursing home department during an influenza season) at different levels of HCW vaccine uptake, the researchers develop a stochastic transmission model to simulate epidemics on a computer. This model predicts that as the HCW vaccination rate increases from 0 (no HCWs vaccinated) to 1 (all the HCWs vaccinated), the expected average influenza virus attack rate decreases at a constant rate. In the researchers' baseline scenario—a nursing home department with 30 beds where patients come into contact with other patients, HCWs, and visitors—the model predicts that about 60% of the patients who would have been infected if no HCWs had been vaccinated are protected when all the HCWs are vaccinated, and that seven HCWs would have to be vaccinated to protect one patient. This last figure does not change with increasing vaccine uptake, which indicates that there is no level of HCW vaccination that completely stops the spread of influenza among the patients; that is, there is no herd immunity. Finally, the researchers show that large influenza outbreaks can happen by chance at every level of HCW vaccine uptake.
What Do These Findings Mean?
As with all mathematical models, the accuracy of these predictions may depend on the specific assumptions built into the model. Therefore the researchers verified that their findings hold for a wide range of plausible assumptions. These findings have two important practical implications. First, the direct relationship between HCW vaccination and patient protection and the lack of any herd immunity suggest that any increase in HCW vaccine uptake will be beneficial to patients in nursing homes. That is, increasing the HCW vaccination rate from 80% to 90% is likely to be as important as increasing it from 10% to 20%. Second, even 100% HCW vaccination cannot guarantee that influenza outbreaks will not occasionally occur in nursing homes. Because of the large variation in attack rates, the results of small clinical trials on the effects of HCW vaccination may be inaccurate and future studies will need to be very large if they are to provide reliable estimates of the amount of protection that HCW vaccination provides to vulnerable patients.
Additional Information.
Please access these Web sites via the online version of this summary at
Read the related PLoSMedicine Perspective by Cécile Viboud and Mark Miller
A related PLoSMedicine Research Article by Jeffrey Kwong and colleagues is also available
The World Health Organization provides information on influenza and on influenza vaccines (in several languages)
The US Centers for Disease Control and Prevention provide information for patients and professionals on all aspects of influenza (in English and Spanish)
The UK Health Protection Agency also provides information on influenza
MedlinePlus provides a list of links to other information about influenza (in English and Spanish)
The UK National Health Service provides information about herd immunity, including a simple explanatory animation
The European Centre for Disease Prevention and Control provides an overview on the types of influenza
PMCID: PMC2573905  PMID: 18959470
22.  Statins and outcomes in patients with pneumonia 
BMJ : British Medical Journal  2006;333(7578):1124.
PMCID: PMC1661706  PMID: 17124237

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