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Background: In 2016, an increase in invasive Haemophilus influenzae serotype b (Hib) disease was reported in the Netherlands in children younger than 5 years, which coincided with the introduction of the hexavalent diphtheria, tetanus, and acellular pertussis-hepatitis B virus-inactivated polio virus/Hib vaccine (DTPa-HBV-IPV/Hib) from 2011 onwards. We aimed to estimate the effectiveness of the hexavalent vaccine to assess whether this increase could be explained by decreasing effectiveness., Methods: We did a case-control study in the Netherlands. We selected patients with a Hib infection (cases) by use of the surveillance records of the Netherlands Reference Laboratory for Bacterial Meningitis (Amsterdam). Cases with a Hib infection that began from Jan 1, 2003, to Dec 31, 2016, and who were younger than age 5 years were included. Ten controls from the national vaccination register (Praeventis) were selected for each case, matched by date of birth. Vaccination status was ascertained by use of Praeventis, which details the vaccination records of children living in the Netherlands. The last recorded vaccine dose was used to classify the child as having received the hexavalent DTPa-HBV-IPV/Hib vaccine or a pentavalent vaccine (which excludes the hepatitis B virus component) or another vaccine. We estimated the effectiveness of these vaccines by use of conditional logistic regression., Findings: We included 159 (94%) of 170 cases reported and 1590 matched controls, who had a median age of 1·5 years (IQR 0·8-2·9). The remaining 11 cases could not be cross-matched with vaccination records from Praeventis. 91 (57%) of 159 cases had been vaccinated, compared with 1408 (89%) of 1590 controls. The overall vaccine effectiveness was 92·8% (95% CI 88·7-95·4), with no differences between the year of disease onset (p=0·9670). There were no differences conferred by type of vaccine given: vaccine effectiveness of the pentavalent and other vaccines was 91·8% (95% CI 86·1-95·1) versus 94·0% (89·0-96·8) for the hexavalent vaccine (OR 0·72, 95% CI 0·36-1·45; p=0·3591). Vaccine effectiveness was highest in children aged 1-2 years at disease onset (97·1-99·0%) and was lowest in children aged 3-4 years at disease onset (60·7-82·3%; p=0·0008)., Interpretation: Our results support the current vaccination programme, since Hib vaccine effectiveness has not decreased over time or by the introduction of the hexavalent DTPa-HBV-IPV/Hib vaccine. Vaccine effectiveness was high but waned with age. Alternative explanations for the increase in Hib disease therefore need to be assessed., Funding: Dutch Ministry of Health, Welfare and Sports., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Implementation of 7-valent pneumococcal conjugate vaccine (PCV7) in the Dutch national immunization program for infants led to a shift from vaccine to non-vaccine serotypes in invasive pneumococcal disease (IPD) in all age groups. We studied the impact of the serotype shift on clinical syndromes and outcomes., Methods: Pneumococcal isolates from hospitalized IPD patients obtained from nine sentinel microbiology laboratories, covering 25% of the Dutch population, were serotyped. Clinical syndromes, outcomes and patient characteristics in the post-PCV7 (2008-2012) period were compared with the pre-PCV7 period (2004-2006). Serotype specific propensity of the association with empyema, meningitis and death was calculated., Results: Invasive pneumonia incidence significantly decreased in children <5 years and elderly ≥65 years, but increased in 5-64 years old from 4.92 to 5.58 cases/100.000/year (RR 1.13 95% CI 0.99-1.29). Empyema incidence significantly increased in elderly 65 years and older from 0.61 to 2.60 cases/100.000/year (RR 4.28 95% CI 1.97-9.33), mainly due to serotype 1. The incidence of meningitis only declined significantly in children <5 years. IPD case-fatality decreased in children <5 years from 5% to 3%, in 5-64 years old from 9% to 7% and in elderly ≥65 years significantly from 22% to 17%, due to lower case-fatality rates for most emerging non-PCV7 serotypes., Conclusions: An increase in empyema incidence was observed in persons ≥65 years old in the post-PCV7 era, mainly due to the emergence of serotype 1, although overall IPD case-fatality decreased. Extended conjugate vaccines that target serotype 1 or serotypes with high case-fatality may offer further reduction of pneumococcal disease burden., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Three years after a 7-valent pneumococcal conjugate vaccine was replaced by a 10-valent pneumococcal conjugate vaccine in the Netherlands, we observed a decrease in incidence of invasive pneumococcal disease caused by Streptococcus pneumoniae serotypes 1, 5, and 7F. Our data do not support or exclude cross-protection against serotype 19A.

Background: Several countries consider the implementation of a meningococcal serogroup B vaccine for young children and/or serogroup C or ACWY conjugate vaccine for adolescents. Representative information on clinical course of invasive meningococcal disease (IMD) is useful to evaluate cost-effectiveness of vaccination. Information on the relation between infecting meningococcal clonal complex (CC), disease course and outcome of IMD is scarce., Methods: A retrospective study using Dutch surveillance data on IMD from June 1999 to June 2011. Clinical information was retrieved from hospital records. The effect of age, comorbidity, clinical manifestation, serogroup, and CC on disease course and outcome was assessed in multivariable analyses. Meningococcal CCs were assessed by multilocus sequence typing., Results: Clinical information was retrieved for 879 IMD cases: 48% of patients presented with meningitis, 17% with septic shock, and 22% with septic shock plus meningitis. Development of septic shock was not related to CC or serogroup. Median (interquartile range) duration of hospital admission was 10 (8-13) days. Intensive care unit admittance (38%) was higher for patients aged ≥10 years and patients with septic shock (P-values ≤.001). Case-fatality rate (8%) and development of sequelae (29%) was dependent on age and clinical manifestation (P-values ≤.001) and not affected by comorbidity, CC, or serogroup., Conclusions: IMD still coincides with a considerable disease burden and mortality. Disease course and outcome depend mainly on age and clinical manifestation and less on meningococcal CC or serogroup., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Rationale: Many bacterial pathogens causing respiratory infections in children are common residents of the respiratory tract. Insight into bacterial colonization patterns and microbiota stability at a young age might elucidate healthy or susceptible conditions for development of respiratory disease., Objectives: To study bacterial succession of the respiratory microbiota in the first 2 years of life and its relation to respiratory health characteristics., Methods: Upper respiratory microbiota profiles of 60 healthy children at the ages of 1.5, 6, 12, and 24 months were characterized by 16S-based pyrosequencing. We determined consecutive microbiota profiles by machine-learning algorithms and validated the findings cross-sectionally in an additional cohort of 140 children per age group., Measurements and Main Results: Overall, we identified eight distinct microbiota profiles in the upper respiratory tract of healthy infants. Profiles could already be identified at 1.5 months of age and were associated with microbiota stability and change over the first 2 years of life. More stable patterns were marked by early presence and high abundance of Moraxella and Corynebacterium/Dolosigranulum and were positively associated with breastfeeding in the first period of life and with lower rates of parental-reported respiratory infections in the consecutive periods. Less stable profiles were marked by high abundance of Haemophilus or Streptococcus., Conclusions: These findings provide novel insights into microbial succession in the respiratory tract in infancy and link early-life profiles to microbiota stability and respiratory health characteristics. New prospective studies should elucidate potential implications of our findings for early diagnosis and prevention of respiratory infections. Clinical trial registered with www.clinicaltrials.gov (NCT00189020).

Analysis of the Dutch national invasive pneumococcal disease (IPD) surveillance data by sex reveals an increase in the incidence of serotype-1 disease in young female adults in The Netherlands after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the national immunization schedule. This has led to an overall increase in IPD in women aged 20-45 years, which was not observed in men of the same age. No other differences in serotype shifts possibly induced by the introduction of PCV7 were observed between the sexes in this age group. Serotype 1 is a naturally fluctuating serotype in Europe and it has been associated with disease in young healthy adults before. It remains uncertain whether or not there is an association between the observed increase in serotype-1 disease in young female adults and the implementation of PCV7 in The Netherlands.

Rationale: Breastfeeding elicits significant protection against respiratory tract infections in infancy. Modulation of respiratory microbiota might be part of the natural mechanisms of protection against respiratory diseases induced by breastfeeding., Objectives: To study the association between breastfeeding and nasopharyngeal microbial communities, including all cultivable and noncultivable bacteria., Methods: In this observational study, we analyzed the microbiota of infants that had received exclusive breastfeeding (n = 101) and exclusive formula feeding (n = 101) at age 6 weeks and 6 months by 16S-based GS-FLX-titanium-pyrosequencing., Measurements and Main Results: At 6 weeks of age the overall bacterial community composition was significantly different between breastfed and formula-fed children (nonmetric multidimensional scaling, P = 0.001). Breastfed children showed increased presence and abundance of the lactic acid bacterium Dolosigranulum (relative effect size [RES], 2.61; P = 0.005) and Corynebacterium (RES, 1.98; P = 0.039) and decreased abundance of Staphylococcus (RES, 0.48; P 0.03) and anaerobic bacteria, such as Prevotella (RES, 0.25; P < 0.001) and Veillonella (RES, 0.33; P < 0.001). Predominance (>50% of the microbial profile) of Corynebacterium and Dolosigranulum was observed in 45 (44.6%) breastfed infants compared with 19 (18.8%) formula-fed infants (relative risk, 2.37; P = 0.006). Dolosigranulum abundance was inversely associated with consecutive symptoms of wheezing and number of mild respiratory tract infections experienced. At 6 months of age associations between breastfeeding and nasopharyngeal microbiota composition had disappeared., Conclusions: Our data suggest a strong association between breastfeeding and microbial community composition in the upper respiratory tract of 6-week-old infants. Observed differences in microbial community profile may contribute to the protective effect of breastfeeding on respiratory infections and wheezing in early infancy. Clinical trial registered with www.clinicaltrials.gov (NCT 00189020).

While nasopharyngeal sampling is the gold standard for the detection of Streptococcus pneumoniae carriage, historically seen, saliva sampling also seems highly sensitive for pneumococcal detection. We investigated S. pneumoniae carriage in saliva from fifty schoolchildren by conventional and molecular methods. Saliva was first culture-enriched for pneumococci, after which, DNA was extracted from all bacterial growth and tested by quantitative-PCR (qPCR) for pneumococcus-specific genes lytA and piaA. Next, serotype composition of the samples was determined by serotype-specific qPCRs, conventional-PCRs (cPCR) and sequencing of cPCR amplicons. Although only 2 (4%) of 50 samples were positive by conventional diagnostic culture, 44 (88%) were positive for pneumococci by qPCR. In total, we detected the presence of at least 81 pneumococcal strains representing 20 serotypes in samples from 44 carriers with 23 carriers (52%) positive for multiple (up to 6) serotypes. The number of serotypes detected per sample correlated with pneumococcal abundance. This study shows that saliva could be used as a tool for future pneumococcal surveillance studies. Furthermore, high rates of pneumococcal carriage and co-carriage of multiple pneumococcal strains together with a large number of serotypes in circulation suggests a ubiquitous presence of S. pneumoniae in saliva of school-aged children. Our results also suggest that factors promoting pneumococcal carriage within individual hosts may weaken competitive interactions between S. pneumoniae strains.

Background: Meningococcal serogroup C (MenC) specific antibody levels decline rapidly after a single primary MenC conjugate (MenCC) vaccination in preschool children. A second MenCC vaccination during (pre)adolescence might attain longer lasting individual and herd protection. We aimed to establish an appropriate age for a (pre)adolescent MenCC booster vaccination., Methods: A phase-IV trial with healthy 10-year-olds (n = 91), 12-year-olds (n = 91) and 15-year-olds (n = 86) who were primed with a MenCC vaccine nine years earlier. All participants received a booster vaccination with the same vaccine. Serum bactericidal antibody assay titers (SBA, using baby rabbit complement), MenC-polysaccharide (MenC-PS) specific IgG, IgG subclass and avidity and tetanus-specific IgG levels were measured prior to (T0) and 1 month (T1) and 1 year (T2) after the booster. An SBA titer ≥8 was the correlate of protection., Results: 258 (96.3%) participants completed all three study visits. At T0, 19% of the 10-year-olds still had an SBA titer ≥8, compared to 34% of the 12-year-olds (P = 0.057) and 45% of the 15-year-olds (P<0.001). All participants developed high SBA titers (GMTs>30,000 in all age groups) and MenC-PS specific IgG levels at T1. IgG levels mainly consisted of IgG1, but the contribution of IgG2 increased with age. At T2, 100% of participants still had an SBA titer ≥8, but the 15-year-olds showed the highest protective antibody levels and the lowest decay., Conclusion: Nine years after primary MenCC vaccination adolescents develop high protective antibody levels in response to a booster and are still sufficiently protected one year later. Our results suggest that persistence of individual--and herd--protection increases with the age at which an adolescent booster is administered., Trial Registration: EU Clinical Trials Database 2011-000375-13 Dutch Trial Register NTR3521.

Seven-valent pneumococcal conjugate vaccine (PCV-7) is effective against vaccine serotype disease and carriage. Nevertheless, shifts in colonization and disease toward nonvaccine serotypes and other potential pathogens have been described. To understand the extent of these shifts, we analyzed nasopharyngeal microbial profiles of 97 PCV-7-vaccinated infants and 103 control infants participating in a randomized controlled trial in the Netherlands. PCV-7 immunization resulted in a temporary shift in microbial community composition and increased bacterial diversity. Immunization also resulted in decreased presence of the pneumococcal vaccine serotype and an increase in the relative abundance and presence of nonpneumococcal streptococci and anaerobic bacteria. Furthermore, the abundance of Haemophilus and Staphylococcus bacteria in vaccinees was increased over that in controls. This study illustrates the much broader effect of vaccination with PCV-7 on the microbial community than currently assumed, and highlights the need for careful monitoring when implementing vaccines directed against common colonizers.

Respiratory infections are among the most important causes of morbidity and mortality from infectious diseases worldwide. The most common causative bacterium, Streptococcus pneumoniae, frequently colonises the upper respiratory tract, where it resides mostly asymptomatically. Occasionally, however, S pneumoniae can cause severe disease such as pneumonia. Local host immunity is essential to control colonising pathogens by preventing overgrowth, spread, and invasion. However, age-related immune deficits in elderly people, known as immunosenescence, might contribute to increased disease burden. We review present knowledge about immunosenescence in the respiratory tract against Gram-positive bacteria, particularly S pneumoniae. We discuss the possible underdetection of pneumococcal colonisation in elderly people, and suggest changes to present surveillance methods to improve understanding of the relation between colonisation and disease. We conclude that present knowledge about alteration of host-pathogen interactions by immunosenescence in the respiratory tract is insufficient, and that research is needed to enable improved measures for prevention., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Importance: Immunization schedules with pneumococcal conjugate vaccine (PCV) differ among countries regarding the number of doses, age at vaccinations, and interval between doses., Objective: To assess the optimal primary vaccination schedule by comparing immunogenicity of 13-valent PCV (PCV13) in 4 different immunization schedules., Design, Setting, and Participants: An open-label, parallel-group, randomized clinical trial of healthy term infants in a general community in The Netherlands conducted between June 30, 2010, and January 25, 2011, with 99% follow-up until age 12 months., Interventions: Infants (N = 400) were randomly assigned (1:1:1:1) to receive PCV13 either at ages 2, 4, and 6 months (2-4-6); at ages 3 and 5 months (3-5); at ages 2, 3, and 4 months (2-3-4); or at ages 2 and 4 months (2-4), with a booster dose at age 11.5 months., Main Outcomes and Measures: Primary outcome measure was antibody geometric mean concentrations (GMCs) against PCV13-included serotypes 1 month after the booster dose measured by multiplex immunoassay. Secondary outcomes included GMCs measured 1 month after the primary series, at 8 months of age, and before the booster., Results: The primary outcome, GMCs at 1 month after the booster dose, was not significantly different between schedules for 70 of 78 comparisons. The 2-4-6 schedule was superior to the 2-3-4 schedule for serotypes 18C (10.2 µg/mL [95% CI, 8.2-12.7] vs 6.5 µg/mL [95% CI, 5.4-7.8]) and 23F (10.9 µg/mL [95% CI, 9.0-13.3] vs 7.3 µg/mL [95% CI, 5.8-9.2]) and superior to the 2-4 schedule for serotypes 6B (8.5 µg/mL [95% CI, 7.1-10.2] vs 5.1 µg/mL [95% CI 3.8-6.7]), 18C (6.6 µg/mL [95% CI, 5.7-7.7]), and 23F (7.2 µg/mL [95% CI, 5.9-8.8]). For serotype 1, the 3-5 schedule (11.7 µg/mL [95% CI, 9.6-14.3]) was superior to the other schedules. Geometric mean concentrations for all 13 serotypes ranged between 1.6 and 19.9 µg/mL. Secondary outcomes demonstrated differences 1 month after the primary series. The 2-4-6 schedule was superior compared with the 3-5, 2-3-4, and 2-4 schedules for 3, 9, and 11 serotypes, respectively. Differences between schedules persisted until the booster dose., Conclusions and Relevance: The use of 4 different PCV13 immunization schedules in healthy term infants resulted in no statistically significant differences in antibody levels after the booster dose for almost all serotypes. The choice of PCV schedule will require a balance between the need for early protection and maintaining protection between the primary series and the booster., Trial Registration: trialregister.nl Identifier: NTR2316.

In the Netherlands, the national immunization program includes 7-valent pneumococcal conjugate vaccine (PCV7) for all newborns born after April 1, 2006. We compared the incidence of invasive pneumococcal disease (IPD) and patient and disease characteristics before PCV7 introduction (June 2004-June 2006) with those after PCV7 introduction (June 2008-June 2010). Culture-confirmed IPD cases were identified by 9 sentinel laboratories covering ≈25% of the Dutch population. Significant declines in overall IPD incidence were observed in children <2 (60%) and in persons >65 (13%) years of age. A trend toward gradual increases in non-PCV7 serotype IPD infections was observed in all age groups; the largest increases were among persons 50-64 (37%) and >65 (25%) years of age. In adults, the proportion of immunocompromised persons increased among IPD patients. Overall, deaths from IPD decreased from 16% to 12% because of a lower case-fatality rate for persons with non-PCV7 serotype IPD.

The burden of respiratory infections is mainly seen in primary healthcare. To evaluate the potential impact of new preventive strategies against respiratory infections, such as the implementation of pneumococcal conjugate vaccines for infants in 2006 in The Netherlands, we conducted a baseline retrospective cohort study of electronic primary-care patient records to assess consultation rates, comorbidities and antibiotic prescription rates for respiratory infections in primary care. We found that between 1995 and 2005, overall registered consultation rates for lower respiratory tract infections had increased by 42·4%, upper respiratory infections declined by 4·9%, and otitis media remained unchanged. Concomitantly, there was a steady rise in overall comorbidity (75·7%) and antibiotic prescription rates (67·7%). Since Dutch primary-care rates for respiratory infections changed considerably between 1995 and 2005, these changes must be taken into account to properly evaluate the effect of population-based preventive strategies on primary-care utilization.

Each year, up to a 1000 splenectomies are performed in the Netherlands. Aside from patients without a spleen, there is also a large group of patients with hyposplenism or functional asplenia due to other primary diseases. All these patients are at risk of developing severe infections, such as post-splenectomy sepsis (PSS), which is associated with very high mortality. However PSS can partly be prevented by taking simple measures such as immunizations and prophylactic or early use of antibiotics. Healthcare professionals in first and secondary care in the Netherlands are generally not well informed about which preventive measures should be taken to prevent these infections, resulting in often suboptimal management of patients. In this article, recommendations are given on vaccination and administration of antibiotics to prevent severe infections such as PSS in this group of patients.

Background: Recent reviews have highlighted the unpredictability of immunologic interference when multivalent conjugated vaccines are coadministered with other pediatric vaccines., Objective: To evaluate immunogenicity, safety, and reactogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix, GlaxoSmithKline Biologicals) and DTPa-IPV-Hib (Pediacel, Sanofi Pasteur MSD) when coadministered as a 3-dose primary vaccination course., Material and Methods: In a single-blind, single-center, randomized controlled trial in the Netherlands, healthy infants (n = 780) were randomly assigned (1:1:1) to receive either (1) PHiD-CV + DTPa-HBV-IPV/Hib (Infanrix Hexa, GlaxoSmithKline Biologicals), (2) PHiD-CV + DTPa-IPV-Hib, or (3) 7-valent pneumococcal conjugate vaccine (Prevenar/Prevnar, Pfizer Inc.) + DTPa-IPV-Hib at 2, 3, and 4 months of age. Blood samples were collected 1 month after dose 3. Diary cards were used to record safety and reactogenicity., Results: Antibody concentrations elicited by PHiD-CV coadministered with DTPa-IPV-Hib were noninferior to those following DTPa-HBV-IPV/Hib coadministration for 9 of 10 vaccines pneumococcal serotypes and protein D. For serotype 18C (conjugated to tetanus toxoid), the antibody concentration was higher with DTPa-HBV-IPV/Hib coadministration (1.73 vs. 1.07 μg/mL). The percentages of infants with antibody concentrations ≥0.2 μg/mL (68.9%-100% in the PHiD-CV + DTPa-HBV-IPV/Hib group vs. 64.9%-100% in the PHiD-CV + DTPa-IPV-Hib group) and with measurable opsonophagocytic activity (56.1%-100% in the PHiD-CV + DTPa-HBV-IPV/Hib group vs. 61.1%-100% in the PHiD-CV + DTPa-IPV-Hib group) were comparable for all serotypes in both PHiD-CV groups. Group differences in antibody responses to the DTPa-IPV-Hib antigens remained within the predefined limit for noninferiority. Safety and reactogenicity profiles were comparable across groups., Conclusions: : PHiD-CV and DTPa-IPV-Hib were immunogenic and well tolerated when coadministered as a 3-dose primary vaccination course.

Background: Nontypeable (unencapsulated) strains of Haemophilus influenzae (ntHi) are usually involved in respiratory tract infections and otitis media but may also cause invasive disease. The epidemiology, the course of disease, and the outcome of ntHi invasive disease are not well established. For prevention, risk groups that might benefit from vaccination have to be defined., Methods: All patients with ntHi invasive disease confirmed by culture of samples collected by the Netherlands Reference Laboratory for Bacterial Meningitis from 41 sentinel hospitals and representative of ∼45% of all Dutch hospitalized ntHi case patients over the period from 2001 through 2008 were included in the study. Data on clinical presentation, course of disease, and outcome as well as patient characteristics and comorbidity were retrospectively retrieved from hospital records., Results: Clinical presentations of 396 cases included mainly invasive pneumonia (190 cases [48%]) and bacteremia without a clinical focus (75 cases [19%]). Comorbidities were present in 327 [83%] and immunodeficiency in 173 [44%] of all cases. The overall case fatality rate within the first month after diagnosis was 12% and the lowest (2%) was among patients aged 5-54 years. The highest extrapolated age-specific incidence rates occurred within the first 6 weeks of life (19.0 cases per 100,000 persons), concerning mostly prematurely born infants with bacteremia within 24 h after birth, and in the first year of life (5.6 cases per 100,000 persons). The highest rate in adults was among elderly patients aged >65 years (2.2 cases per 100,000 persons)., Conclusions: This study provides a detailed overview of invasive ntHi disease cases in the Netherlands. Risk groups are prematurely born infants, elderly patients aged >65 years, and immunocompromised patients., (© The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.)

Background: In the Netherlands, incidence of physician's consultations and hospitalizations for varicella is low compared to other countries. Better knowledge about the severity of varicella among Dutch hospitalized patients is needed. Therefore, a medical record research was conducted among hospitalized patients with diagnosis varicella., Methods: Hospital admissions due to varicella in 2003-2006 were obtained from the National Medical Register. Retrospectively, additional data were retrieved from the medical record of patients hospitalized with varicella in 23 Dutch hospitals using a standardized form. Analyses were performed using descriptive statistics., Results: The study population (N = 296) was representative for all varicella admissions in the Netherlands (N = 1,658) regarding age, sex, duration of admission and type of diagnosis. Complications were recorded in 76% of the patients (37% had at least one relatively severe complication). Bacterial super infections of skin lesions (28%), (imminent) dehydration (19%), febrile convulsions (7%), pneumonia (7%) and gastroenteritis (7%) were most frequently reported. No varicella-related death occurred within the study population and 3% of the patients had serious rest symptoms., Conclusions: It is not likely that the severity of varicella among hospitalized patients in the Netherlands differs from other countries. A considerable part of the varicella complications among hospitalized patients was rather moderate and can be treated effectively, although in a third of the hospitalized cases with complications, severe complications occurred. These data are relevant in the decision-making process regarding whether or not to introduce routine varicella vaccination in the Netherlands.

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.

Background: Whooping cough is a respiratory disease caused by Bordetella pertussis, which induces mucosal IgA antibodies that appear to be relevant in protection. Serum IgA responses are measured after pertussis infection and might provide an additional role in pertussis diagnostics. However, the possible interfering role for pertussis vaccinations in the induction of serum IgA antibodies is largely unknown., Methods/principal Findings: We compared serum IgA responses in healthy vaccinated children between 1 and 10 years of age with those in children who despite vaccinations recently were infected with Bordetella pertussis. All children have been vaccinated at 2, 3, 4 and 11 months of age with either the Dutch whole-cell pertussis (wP) vaccine or an acellular pertussis (aP) vaccine and additionally received an aP booster vaccination at 4 years of age. Serum IgA responses to pertussis toxin (PT), filamentous heamagglutinin (FHA) and pertactin (Prn) were measured with a fluorescent multiplex bead-based immuno-assay. An ELISPOT-assay was used for the detection of IgA-memory B-cells specific to these antigens. Serum IgA levels to all pertussis vaccine antigens were significantly higher in infected children compared with healthy children. High correlations between anti-PT, anti-FHA or anti-Prn IgA and IgG levels were found in infected children and to some degree in wP primed children, but not at all in aP primed children. Highest numbers of IgA-pertussis-specific memory B-cells were observed after infection and generally comparable numbers were found after wP and aP vaccination., Conclusions: This study provides new insight in the diagnostic role for serum IgA responses against PT in vaccinated children. Since aP vaccines induce high serum IgG levels that interfere with pertussis diagnostics, serum IgA-PT levels will provide an additional diagnostic role. High levels of serum IgA for PT proved specific for recent pertussis infection with reasonable sensitivity, whereas the role for IgA levels against FHA and Prn in diagnosing pertussis remains controversial.

Background: 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)., Conclusions/significance: 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: ClinicalTrials.gov NCT00189020.

Background: In 2002 a Meningococcal serogroup C (MenC) conjugate vaccine, with tetanus toxoid as carrier protein, was introduced in the Netherlands as a single-dose at 14 months of age. A catch-up campaign was performed targeting all individuals aged 14 months to 18 years. We determined the MenC-specific immunity before and after introduction of the MenC conjugate (MenCC) vaccine., Methods and Findings: Two cross-sectional population-based serum banks, collected in 1995/1996 (n = 8539) and in 2006/2007 (n = 6386), were used for this study. The main outcome measurements were the levels of MenC polysaccharide(PS)-specific IgG and serum bactericidal antibodies (SBA) after routine immunization, 4-5 years after catch-up immunization or by natural immunity. There was an increasing persistence of PS-specific IgG and SBA with age in the catch-up immunized cohorts 4-5 years after their MenCC immunization (MenC PS-specific IgG, 0.25 microg/ml (95%CI: 0.19-0.31 microg/ml) at age 6 years, gradually increasing to 2.34 microg/ml,(95%CI: 1.70-3.32 microg/ml) at age 21-22 years). A comparable pattern was found for antibodies against the carrier protein in children immunized above 9 years of age. In case of vaccination before the age of 5 years, PS-specific IgG was rapidly lost. For all age-cohorts together, SBA seroprevalence (> or =8) increased from 19.7% to 43.0% in the pre- and post-MenC introduction eras, respectively. In non-immunized adults the SBA seroprevalence was not significantly different between the pre- and post-MenC introduction periods, whereas PS-specific IgG was significantly lower in the post-MenC vaccination (GMT, age > or =25 years, 0.10 microg/ml) era compared to the pre-vaccination (GMT, age > or =25 years, 0.43 microg/ml) era., Conclusion: MenCC vaccination administered above 5 years of age induced high IgG levels compared to natural exposure, increasing with age. In children below 14 months of age and non-immunized cohorts lower IgG levels were observed compared to the pre-vaccination era, whereas functional levels remained similar in adults. Whether the lower IgG poses individuals at increased risk for MenC disease should be carefully monitored. Large-scale introduction of a MenCC vaccine has led to improved protection in adolescents, but in infants a single-dose schedule may not provide sufficient protection on the long-term and therefore a booster-dose early in adolescence should be considered.

Objectives: To update cost effectiveness estimates for the four dose (3+1) schedule of the seven valent pneumococcal conjugated vaccine (PCV-7) in the Netherlands and to explore the impact on cost effectiveness of reduced dose schedules and implementation of 10 valent and 13 valent pneumococcal vaccines (PCV-10 and PCV-13)., Design: Economic evaluation comparing PCV-7, PCV-10, and PCV-13 with no vaccination using a decision tree analytic model built from data in previous studies., Setting: The Netherlands. Population A cohort of 180,000 newborns followed until 5 years of age., Main Outcome Measures: Costs; gains in life years and quality adjusted life years (QALYs); and incremental cost effectiveness ratios., Results: Under base case assumptions-that is, assuming a five year protective period of the vaccine and no assumed net indirect effects (herd protection minus serotype replacement) among children aged over 5 years-vaccination with PVC-7 in a four dose (3+1) schedule was estimated to prevent 71 and 5778 cases of invasive and non-invasive pneumococcal disease, respectively, in children aged up to 5 years. This corresponds with a total net gain of 173 life years or 277 QALYs. The incremental cost effectiveness ratio of PCV-7 was estimated at euro113,891 ( pound98,300; $145,000) per QALY, well over the ratio of euro50,000 per QALY required for PCV-7 to be regarded as potentially cost effective. A three dose (2+1) schedule of PCV-7 reduced the incremental cost effectiveness ratio to euro82,975 per QALY. For various assumptions and including 10% of the maximum net indirect effects among individuals aged 5 years and over, PCV-10 and PCV-13 had incremental cost effectiveness ratios ranging from euro31,250 to euro52,947 per QALY., Conclusions: The current Dutch infant vaccination programme of four doses of PCV-7 is not cost effective because of increases in invasive disease caused by non-vaccine serotypes, which reduces the overall direct effects of vaccination and offsets potential positive herd protection benefits in unvaccinated individuals. The 10 valent and 13 valent pneumococcal vaccines could have better net health benefits than PCV-7 through less replacement disease and increased herd protection. Both these effects could substantially reduce the incremental cost effectiveness ratio to possibly acceptable levels, if total programme costs can be lowered by reduced schedules, reductions in vaccine prices, or both.

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.

Background: There is ample evidence that childhood overweight is associated with increased risk of chronic disease in adulthood. The aim of this study was to investigate associations between childhood overweight and common childhood health problems., Methods: Data were used from a general population sample of 3960 8-year-old children, participating in the Dutch PIAMA birth cohort study. Weight and height, measured by the investigators, were used to define BMI status (thinness, normal weight, moderate overweight, obesity). BMI status was studied cross-sectionally in relation to the following parental reported outcomes: a general health index, GP visits, school absenteeism due to illness, health-related functional limitations, doctor diagnosed respiratory infections and use of antibiotics., Results: Obesity was significantly associated with a lower general health score, more GP visits, more school absenteeism and more health-related limitations, (adjusted odds ratios around 2.0 for most outcomes). Obesity was also significantly associated with bronchitis (adjusted odds ratio (aOR) and 95% confidence intervals (95%CI): 5.29 (2.58;10.85) and with the use of antibiotics (aOR (95%CI): 1.79 (1.09;2.93)). Associations with flu/serious cold, ear infection and throat infection were positive, but not statistically significant. Moderate overweight was not significantly associated with the health outcomes studied., Conclusion: Childhood obesity is not merely a risk factor for disease in adulthood, but obese children may experience more illness and health related problems already in childhood. The high prevalence of the outcomes studied implies a high burden of disease in terms of absolute numbers of sick children.

In this cohort study we compared IgG antibody levels between infants immunized with 7-valent CRM197-conjugated pneumococcal vaccine (PCV-7) at 2, 4 and 11 months and at 2, 3, 4 and 11 months of age, as measured by double adsorption ELISA. Pre- and post-booster levels following the 2+1- and 3+1-dose schedule were comparable for 5 out of 7 serotypes except for serotypes 6B and 19F. The proportion of children reaching post-booster antibody thresholds were comparable except for 6B (>or=1.0 microg/ml and >or=5.0 microg/ml) and 19F (>or=5.0 microg/ml). Surveillance studies are warranted for vaccine impact on 6B and 19F disease cases after reduced-dose PCV-7 schedules., ((c) 2009 Elsevier Ltd. All rights reserved.)

In the Netherlands the meningococcal serogroup C conjugate (MenCC) vaccine is administered as a single dose at 14 months. We evaluated the kinetics of isotype-specific antibodies in adults (n=21) after primary immunization with MenCC or secondary immunization with MenCC or plain MenC polysaccharide vaccine. Blood samples were collected prior to immunization and at 6 additional time points, from 3 to 25 days post-immunization. Secondary immunization resulted in 5-10-fold higher IgG titers compared to the primary immunization group, 25 days post-immunization. Prior to the secondary immunization, but 5 years after the first immunization, protective bactericidal antibodies and levels of MenC-specific IgG and IgM were still present. Furthermore, IgG antibodies present before secondary immunization were of higher avidity compared to antibodies produced one month after primary immunization. In addition, secondary immunization with nonconjugated MenC polysaccharide seemed to induce a higher IgG2 response compared to MenCC immunization. The kinetics of the observed secondary immune responses were not really faster than the observed primary responses. However, the rate of increase in antibodies seemed faster than the primary responses, representing a booster response. As the course of infection by Neisseria meningitidis can be very rapid, these data support the idea that sustainment of high antibody levels induced by MenCC are important for immediate protection.

Since whooping cough is reemerging in the Netherlands from 1996 onwards, several changes in the national immunization program have been implemented regarding the pertussis vaccinations. The aim of this study is to investigate IgG responses in whole cell (wP) and acellular (aP) pertussis vaccine primed children following revaccination with different pertussis booster vaccines at 4 years of age. IgG levels to pertussis toxin (Pt), filamentous heamagglutin (FHA), pertactin (Prn) and fimbriae type 2 and 3 (Fim2/3) and avidities of Pt and Prn antibodies were measured using a multiplex immunoassay. Before and after the booster we found significantly higher IgG levels to Pt, FHA and Prn in aP compared to wP primed children. In all children a booster vaccination with a pertussis vaccine containing a high antigen dose (Infanrix) induced higher IgG responses compared to a low antigen dose containing vaccine (Triaxis). Avidities of Pt- and Prn-antibodies before and after booster vaccination were significantly higher in aP than in wP primed children. This study shows that a booster vaccine with high pertussis antigen concentrations induces higher antibody levels than a low antigen containing vaccine. In children primed with the Dutch DTwP-IPV-Hib vaccine we suggest to administer a booster vaccine containing high pertussis antigens to optimize IgG responses. The pertussis vaccination history has to be taken into account in decisions on changes in pertussis vaccination policy.

Background: The Streptococcus pneumoniae polysaccharide capsule may be related to invasive pneumococcal disease (IPD) course., Methods: We performed a retrospective cohort study with nationally representative surveillance data from 1075 hospitalized patients with IPD from the Netherlands from 1 June 2004 through 31 May 2006 in the prevaccination era. Serotypes were grouped according to invasive disease potential, rate of the most serious clinical syndromes of meningitis and bacteremia without focus, and case-fatality rates. Multivariable logistic regression analysis was performed to obtain odds ratios adjusted for baseline confounders for the association of serotypes and these outcomes, using the serotypes with the lowest rates as reference., Results: IPD caused by serogroups with low invasive disease potential concerned meningitis or bacteremia without focus in 22% of cases, and 74% of patients had an underlying comorbidity. For highly invasive serogroups these figures were 10% (P < .01) and 56% (P < .01). Individual serotypes varied in the relative rate by which they caused meningitis or bacteremia without focus. Compared with the reference group composed of serotypes 1, 5, 7F, 15B, 20, and 33F, the group of serotypes 3, 19F, 23A, 16F, 6B, 9N, and 18C was associated with increased case-fatality rates (group adjusted odds ratio, 2.6; 95% confidence interval, 1.5-4.7)., Conclusions: The serotype appeared to be independently associated with IPD severity in adults, which indicates that careful monitoring of IPD after implementation of conjugate vaccines is necessary.

With a retrospective study of invasive pneumococcal disease (IPD) surveillance data representative for approximately 25% of the Dutch population (1275 hospitalized cases) over the period June 2004-June 2006 prior to the implementation of the 7-valent pneumococcal conjugate vaccine (PCV7), the aim was to provide baseline data on IPD for the interpretation of changes after implementation of conjugate vaccines. The IPD incidence peaked in 3-5-mnth-olds (63 cases per 100,000 persons yearly) and increased in adulthood, particularly after the age of 60yrs, from 26 cases in 60-64-yr-olds to 97 cases per 100,000 in persons > or =90yrs. Beyond the age of 4yrs, 19% of IPD patients were immunocompromised, and this considerable percentage may have implications for vaccine efficacy.

Objective: To evaluate the effects of influenza vaccination with or without heptavalent pneumococcal conjugate vaccination on respiratory tract infections (RTIs) in children., Study Design: This was a randomized, double-blind, placebo-controlled trial comprising 579 children age 18 to 72 months with a previous history of physician-diagnosed RTI, recruited between 2003 and 2005. The children were assigned to 2 doses of parenteral inactivated trivalent subunit influenza plus heptavalent pneumococcal conjugate vaccination (TIV+PCV7), influenza plus placebo vaccination (TIV+plac), or control hepatitis B virus vaccination plus placebo (HBV+plac). Main outcome measures were febrile RTI and related polymerase chain reaction (PCR)-confirmed influenza, primary care visits, antibiotic prescriptions, and acute otitis media (AOM) episodes., Results: During influenza seasons, febrile RTI were reduced by 24% (95% confidence interval [CI] = 1% to 42%) in the TIV+PCV7 group and by 13% (95% CI = -12% to 32%) in the TIV+plac group compared with the control group. The occurrence of PCR-confirmed influenza was reduced by 52% (95% CI = 7% to 75%) in the TIV+PCV7 group and by 51% (95% CI = 3% to 75%) in the TIV+plac group. Episodes of AOM were reduced by 57% (95% CI = 6% to 80%) in the TIV+PCV7 group and by 71% (95% CI = 30% to 88%) in the TIV+plac group. Outside of the influenza seasons, no significant effects of vaccinations were demonstrated on the studied outcomes., Conclusions: During influenza seasons, influenza vaccination with or without pneumococcal conjugate vaccination substantially reduced cases of confirmed influenza and AOM episodes.

Few studies have examined the relationship between viral activity and bacterial invasive disease, considering both influenza virus and respiratory syncytial virus (RSV). This study aimed to assess the potential relationship between invasive pneumococcal disease (IPD), meningococcal disease (MD), and influenza virus and RSV activity in The Netherlands. Correlations were determined between population-based data on IPD and MD during 1997-2003 and influenza virus and RSV surveillance data. Incidence rate ratios of disease during periods of high influenza virus and RSV activity over the peri-seasonal and summer baseline periods were calculated. The analyses comprised 7266 and 3072 cases of IPD and MD. When data from all seasons were included, the occurrence of pneumococcal bacteraemia and MD correlated significantly with influenza virus and RSV activity both in children and adults. Periods of increased influenza virus and RSV activity showed higher rates of pneumococcal bacteraemia in older children and adults than the peri-season period. Rates of MD in children were also higher during periods of increased influenza virus activity; the same appeared true for MD in older children during periods of increased RSV activity. Although no causal relationship may be inferred from these data, they support a role for influenza virus and RSV in the pathogenesis of IPD and MD.

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.

Objective: To compare different methods to estimate the disease burden of influenza, using influenza and respiratory syncytial virus-(RSV) associated primary care data as an example., Study Design and Setting: In a retrospective study in the Netherlands over 1997-2003, primary care attended respiratory episodes and national viral surveillance data were used to compare the rate-difference method to other, more complex methods., Results: The influenza-associated excess estimated by the different methods varied. The estimates provided by the rate-difference model lay well within this range. According to the rate-difference method, influenza-associated primary care consultations were present for all ages, including low-risk adults. The highest influenza-associated burden was demonstrated for children below the age of 5 years. The RSV-associated primary care burden was highest in the youngest age category and well above that associated with influenza. Significant RSV-associated excess was also recorded among adults, particularly in high-risk adults and the elderly., Conclusion: The straightforward rate-difference model seemed satisfactory to estimate the influenza-associated burden. Significant influenza-associated excess was demonstrated among persons not yet recommended for influenza vaccination in The Netherlands. The RSV-associated burden was highest for the youngest children, but also significant for adults.

In 2007, the Dutch Health Council recommended influenza vaccination of all institutional healthcare workers (HCWs). In this questionnaire study largely based on the health belief model we assessed the attitude and intentions of hospital personnel towards such vaccination. We sent out 220 questionnaires to medical personnel and nurses of departments of the University Medical Center Utrecht, The Netherlands. Only one-third of the 112 responders (response rate of 51%) reported a positive intention to comply with the national recommendation. Factors associated with a positive intention were the awareness of a HCW's responsibility not to harm patients, the belief to have a high risk of influenza infection and confidence in vaccine efficacy. Physicians were more likely than nurses and other staff to have a positive intention. Education is needed to convince hospital personnel about influenza vaccination.

The aim of the current study was to estimate influenza- and respiratory syncytial virus (RSV)-associated mortality and hospitalisations, especially the influenza-associated burden among low-risk individuals < or =65 yrs old, not yet recommended for influenza vaccination in many European countries. Retrospectively during 1997-2003, Dutch national all-cause mortality and hospital discharge figures and virus surveillance data were used to estimate annual average influenza- and RSV-associated excess mortality and hospitalisation using rate difference methods. Influenza virus active periods were significantly associated with excess mortality among 50-64-yr-olds and the elderly, but not in younger age categories. Influenza-associated hospitalisation was highest and about equal for 0-1-yr-olds and the elderly, and also significant for low-risk adults. Hospitalisation among children was mostly due to respiratory conditions, and among adults cardiovascular complications were frequent. RSV-active periods were associated with excess mortality and hospitalisation among the elderly. The highest RSV-related excess hospitalisation was found in 0-1-yr-olds. Influenza-associated mortality was demonstrated in 50-64-yr-olds. Among low-risk individuals < or =65 yrs of age, influenza-associated hospitalisation rates were highest for 0-4-yr-olds, but also significant for 5-64-yr-olds. These data may further support extension of recommendations for influenza vaccination to include younger low-risk persons. The respiratory syncytial virus-associated burden was highest for young children but also substantial for the elderly.

Objective: Cytokines and other inflammatory mediators are involved in the pathogenesis of otitis media. We hypothesized that polymorphisms in inflammatory response genes contribute to the increased susceptibility to acute otitis media in otitis-prone children., Patients and Methods: DNA samples from 348 children with > or = 2 acute otitis media episodes, who were participating in a randomized, controlled vaccination trial, and 463 healthy adult controls were included. Polymorphisms in TNFA, IL1B, IL4, IL6, IL10, IL8, NOS2A, C1INH, PARP, TLR2, and TLR4 were genotyped. Genotype distributions in children with recurrent acute otitis media were compared with those in controls. Within the patient group, the number of acute otitis media episodes before vaccination and the clinical and immunologic response to pneumococcal conjugate vaccinations were analyzed., Results: The IL6-174 G/G genotype was overrepresented in children with acute otitis media when compared with controls. In the patient group, TNFA promoter genotypes -238 G/G and -376 G/G and the TLR4 299 A/A genotype were associated with an otitis-prone condition. Furthermore, lower specific anticapsular antibody production after complete vaccination was observed in patients with the TNFA-238 G/G genotype or TNFA-863 A allele carriage. Finally, the IL10-1082 A/A genotype contributed to protection from the recurrence of acute otitis media after pneumococcal vaccination., Conclusions: Variation in innate immunoresponse genes such as TNFA-863A, TNFA-376G, TNFA-238G, IL10-1082 A, and IL6-174G alleles in the promoter sequences may result in altered cytokine production that leads to altered inflammatory responses and, hence, contributes to an otitis-prone condition.

Despite the availability of antibiotics and the care offered by intensive-care units, invasive pneumococcal disease still causes serious illness with high morbidity and mortality. Currently, two vaccines are available in the Netherlands that offer protection against invasive pneumococcal disease: a 7-valent conjugated vaccine and a 23-valent polysaccharide vaccine. Case reports and pharmaceutical use as registered by the Foundation for Pharmaceutical Statistics (SFK) show that general practitioners and pharmacists are not always aware of the appropriate use of both vaccines. For vaccination against pneumococci in children aged 0-5 years, general practitioners should prescribe only the conjugated vaccine. The non-conjugated polysaccharide vaccine is intended especially for the elderly and specific groups at risk. Pharmacists should verify that the pneumococcal vaccines they hand out on prescription are recommended for the age-group of the individuals to whom the vaccine will be administered.

Objective: To determine whether vaccinations aggravate the course of autoimmune diseases such as juvenile idiopathic arthritis (JIA) and whether the immune response to vaccinations may be hampered by immunosuppressive therapy for the underlying disease., Methods: In this multicenter cohort study, 234 patients with JIA (ages 1-19 years) were vaccinated with meningococcal serogroup C (MenC) conjugate to protect against serogroup C disease (caused by Neisseria meningitidis). Patients were followed up for disease activity for 1 year, from 6 months before until 6 months after vaccination. IgG antibody titers against MenC polysaccharide and the tetanus carrier protein were determined by enzyme-linked immunosorbent assay and toxin binding inhibition assay, respectively. A serum bactericidal assay was performed to determine the function of the anti-MenC antibodies., Results: No change in values for any of the 6 components of the core set criteria for juvenile arthritis disease activity was seen after MenC vaccination. Moreover, no increase in the frequency of disease relapse was detected. Mean anti-MenC IgG concentrations in JIA patients rose significantly within 6-12 weeks after vaccination. Of 157 patients tested, 153 were able to mount anti-MenC IgG serum levels >2 micro g/ml, including patients receiving highly immunosuppressive medication. The 4 patients with a lower anti-MenC antibody response displayed sufficient bactericidal activity despite receiving highly immunosuppressive medication., Conclusion: The MenC conjugate vaccine does not aggravate JIA disease activity or increase relapse frequency and results in adequate antibody levels, even in patients receiving highly immunosuppressive medication. Therefore, patients with JIA can be vaccinated safely and effectively with the MenC conjugate.

Objective: To develop an easily applicable prediction rule for asthma in young adulthood using childhood characteristics., Methods: A total of 1,055 out of 1,328 members of a Dutch birth cohort were followed from 2 to 21 years of age. Univariate and multivariate logistic regression analyses were used to evaluate the predictive value of childhood characteristics on asthma at 21 years of age. A prognostic function was developed, and the area under the receiving operating characteristic (ROC) curve was used to estimate the predictive ability of the prognostic models., Results: Of the 693 responding subjects, 86 (12%) were diagnosed with asthma. Independent prognostic factors at ages 2 and 4 years were female gender (odds ratios (OR) 1.9 and 2.1; 95% confidence intervals (CI) 1.2-3.2 and 1.3-2.5), smoking mother (OR 1.6 and 1.6; CI 1.0-2.7 and 1.0-2.6), lower respiratory tract illness (OR 1.9 and 2.4; CI 1.0-3.6 and 1.4-4.0), and atopic parents (OR 2.1 and 1.9; CI 1.3-3.4 and 1.2-3.1). The predictive power of both models was poor; area under ROC curve was 0.66 and 0.68, respectively., Conclusion: Asthma in young adulthood could not be predicted satisfactorily based on childhood characteristics. Nevertheless, we propose that this method is further tested as a tool to predict development of asthma.

Objective: To assess (1) prevalences of recurrent URTIs (rURTIs) and relapsing/persistent rURTIs and associated medical consumption between 0 and 21 years of age and (2) whether rURTIs experienced in early life predispose to upper airway disease later in life., Methods: A cohort of all children born in Nijmegen, The Netherlands, between September 1982 and September 1983, was assessed repeatedly from 2 to 21 years of age with questionnaires regarding infections of the upper respiratory tract (URTIs), use of antibiotics, ENT operations and known risk factors for URTIs., Results: One hundred and sixty-one of the 693 cohort member (23%) suffered from relapsing rURTIs between 0 and 21 years of age, whereas only 7 (1%) suffered from persistent rURTIs throughout this period. Two hundred and six (30%) had used antibiotics more than once; and 220 (32%) had undergone at least one ENT operation. Of the 166 participants with rURTI between 8 and 21 years, 140 (84%) had had rURTI before., Conclusions: rURTIs are highly prevalent throughout early life and associated medical consumption is substantial. The challenge therefore is to develop therapeutic/preventive strategies that will prevent rURTIs in the first years of life.

Objective: To assess the quality of life of 384 Dutch children aged 1-7 years with recurrent acute otitis media (AOM), and compare it with that of children from four reference populations: (i) children from a general population; (ii) children with mild-to-moderate asthma, (iii) children with mild-to-moderately severe chronic illness, and (iv) US children with persistent or recurrent otitis media., Design: Survey., Setting: A general and an academic hospital (study population of children with recurrent AOM, n = 384); general population (n = 225 and 117); primary care (children with asthma, n = 64); community care (children with chronic illness, n = 82); and a general hospital (children with persistent or recurrent otitis media, n = 169)., Participants: A total of 384 children aged 1-7 years who had experienced at least two episodes of AOM in the preceding year and their caregivers., Main Outcome Measures: Generic and disease-specific quality of life as judged by the children's caregivers. Age-adjusted total and subscale scores were compared with those of the reference populations., Results: For all generic questionnaires, children with recurrent AOM had poorer scores than children from the general population. Quality of life of children with four or more episodes of AOM in the preceding year was poorer than that of children with two to three episodes. Children with recurrent AOM scored lower on the health-related questionnaire than children with mild-to-moderately severe chronic illness. Quality of life of the present study population was similar to those of children with asthma and US children with chronic otitis media with effusion or recurrent AOM., Conclusion: Recurrent AOM has a considerable negative impact on the quality of life of children and causes concern to their caregivers. These effects are proportional to the severity of the condition. Professionals involved in the care of children with OM should be aware that OM not only affects physical functioning but also general well-being of the child and its family. These outcomes should therefore be included in the evaluation of the child with otitis media both in the clinical and research setting.

Background: It is unknown whether further expansion of the Dutch childhood vaccination program with other vaccines will be accepted and whom should be targeted in educational strategies., Aim: To determine attitudes of parents towards possible future vaccinations for their children and the behavioural determinants associated with a negative attitude., Design: Questionnaire study., Methods: Parents of children aged between 3 months and 5 years of day-care centres were asked to fill out a questionnaire. Determinants of a negative attitude to comply with possible future vaccinations against example diseases such as pneumonia or influenza, hepatitis B, TBC, smallpox and SARS were assessed using polytomous logistic regression analysis., Results: Of the 283 respondents, 123 (43%) reported a positive attitude towards all vaccinations, 129 (46%) reported to have a positive attitude to have their child vaccinated against some diseases and 31 (11%) had no intention to comply with any new vaccination. Determinants of a fully negative attitude were a high education of the parent (odds ratio [OR] 3.3, 95% confidence interval [95% CI]: 1.3-8.6), being a health care worker (OR 4.2, 95% CI: 1.4-12.6), absence of religion (OR 2.6, 95% CI: 1.0-6.7), perception of vaccine ineffectiveness (OR 6.9, 95% CI: 2.5-18.9) and the perception that vaccinations cause asthma or allergies (OR 82.4, 95% CI: 8.9-766.8)., Conclusion: Modifiable determinants for a negative attitude to comply with new vaccinations are mainly based on lack of specific knowledge. These barriers to vaccinations might be overcome by improving health education in the vaccination program, especially when targeted at educated parents and health care workers.

A randomized double-blind trial with a 7-valent pneumococcal conjugate vaccine was conducted in The Netherlands among 383 children, aged 1 to 7 years, with a history of recurrent acute otitis media. No effect of vaccination on the pneumococcal colonization rate was found. However, a shift in serotype distribution was clearly observed (R. Veenhoven et al., Lancet 361:2189-2195, 2003). We investigated the molecular epidemiology of 921 pneumococcal isolates retrieved from both the pneumococcal vaccine (PV) and control vaccine (CV) groups during the vaccination study. Within individuals a high turnover rate of pneumococcal restriction fragment end labeling genotypes, which was unaffected by vaccination, was observed. Comparison of the genetic structures before and after completion of the vaccination scheme revealed that, despite a shift in serotypes, there was clustering of 70% of the pneumococcal populations. The remaining isolates (30%) were equally observed in the PV and CV groups. In addition, the degree of genetic clustering was unaffected by vaccination. However, within the population genetic structure, nonvaccine serotype clusters with the serotypes 11, 15, and 23B became predominant over vaccine-type clusters after vaccination. Finally, overall pneumococcal resistance was low (14%), and, albeit not significant, a reduction in pneumococcal resistance as a result of pneumococcal vaccination was observed. Molecular surveillance of colonization in Dutch children shows no effect of pneumococcal conjugate vaccination on the degree of genetic clustering and the genetic structure of the pneumococcal population. However, within the genetic pneumococcal population structure, a clear shift toward nonvaccine serotype clusters was observed.

In three children with fever, two girls aged 8 and almost 10 months and one boy aged 5 months, invasive pneumococcal disease was present. The youngest girl presented with pneumococcal sepsis which was complicated by haemolytic uraemic syndrome--she recovered--and the boy developed fulminant fatal pneumococcal sepsis/meningitis. The oldest girl was admitted for pneumococcal cellulitis and recovered. More than 80% of the cases of childhood invasive pneumococcal disease occur in children less than 2 years of age. However, the long available 23-valent pneumococcal polysaccharide vaccine is not effective in this age group. Recently, a 7-valent pneumococcal conjugate vaccine was registered in the Netherlands. This conjugate vaccine is effective in protecting infants and children from invasive pneumococcal disease. The Health Council of the Netherlands has recommended inclusion of the conjugate vaccine in the standard vaccine schedule. In the absence of a universal vaccination, the 7-valent pneumococcal conjugate vaccine is recommended for children at high risk of invasive disease.

Acute otitis media (AOM) is the most frequent bacterial infection in childhood. Because of the high morbidity, the costs of AOM and growing concern about increasing resistance of pneumococci, the most common bacterial cause of AOM, prevention of AOM is important. Vaccination with the recently developed pneumococcal conjugate vaccines leads to a reduction in the number of AOM cases caused by the serotypes present in the vaccine, but the reduction in overall AOM incidence is below 10%. In particular the children with recurrent episodes of AOM may benefit more from these pneumococcal conjugate vaccines.