Jeanet M. Kemmeren

Acute cerebellar ataxia in the Netherlands: a study on the association with vaccinations and varicella zoster infection.

AIM Acute cerebellar ataxia (ACA, sudden onset of truncal ataxia and gait disturbances) usually follows a benign illness (25% varicella). It is also described after vaccination, like MMR and varicella zoster virus (VZV). We will establish incidence rates of (varicella related) ACA and assess the attributable risk of vaccination to ACA in the Netherlands. METHOD Data on ACA in children, following infections, like varicella, and vaccinations, obtained from prospective, active pediatric surveillance and passive surveillance on adverse events following immunizations (AEFI) were compared with hospitalization data for ataxia. Capture-recapture (CRC) method was used to estimate the burden of ACA in the Netherlands. RESULTS 45 children with ACA were included (44 and 1 reported by pediatric and AEFI surveillance respectively, 30 were hospitalized). Chickenpox preceded ACA in 15 cases, one case followed MMR. Of the hospitalization reports, 13 fulfilled the criteria for ACA. Using CRC the estimated number of hospitalized ACA cases was 42. For varicella related ACA, this estimate was 10, resulting in an incidence rate of 0.7:100,000 (95%CI 0.52-0.94, all cases) and 0.17:100,000 (95%CI 0.09-0.31, varicella related cases) for children under 15 years of age. CONCLUSION The incidence rates were comparable with other studies. We found no association with MMR, but chickenpox was clearly related to ACA. According to age-specific seroprevalence data the incidence rate of ACA was 5:100,000 VZV infections for children up to 5 years, compared to an ACA-reporting rate of 0.15:100,000 doses VZV-vaccine. Therefore, uptake of VZV-vaccine in the immunization programme will diminish the incidence rate of ACA.

Reported adverse events in girls aged 13–16 years after vaccination with the human papillomavirus (HPV)-16/18 vaccine in the Netherlands

In 2009, human papillomavirus (HPV) vaccination was offered to girls born in 1993-1996 in a catch-up campaign, followed in 2010 by the implementation of the vaccination in the National Immunization Programme (NIP) for girls born in 1997. To monitor the tolerability of the 2009 catch-up campaign, we investigated the occurrence of adverse events within 7 days after vaccination with the bivalent HPV vaccine. A total of 6000 girls were asked to participate, including 1500 from each birth cohort from 1993 to 1996. One week after each of the required three successive doses, the participants received by e-mail a Web-based questionnaire focused on local reactions and systemic events. One or more questionnaires were returned by 4248 girls. Any local reaction was reported by 92.1% of the girls after the first dose, 79.4% after the second dose, and 83.3% after the third dose, and 91.7%, 78.7%, and 78.4% reported any systemic event after the three doses, respectively. Pain in the arm was the most frequently reported local reaction, of which 24.0%, 11.7%, and 14.7% was classified as pronounced. Myalgia was the most often reported systemic event. The proportion of local reactions and most systemic events was significantly lower after the second and third dose compared with the first dose (Odds ratio [OR], 0.33-0.76). Older girls reported a higher proportion of adverse events than younger girls. After vaccination with the bivalent HPV vaccine, girls 13-16 years of age reported a high proportion of short-term adverse events. These are maximum estimates and not necessarily caused by the vaccination itself. Although, girls experienced HPV vaccination as painful, no serious or unexpected adverse events were reported. The results of this survey are being communicated to health care workers and the public.

Incidence of Multiple Sclerosis in the General Population in the Netherlands, 1996–2008

Background: We estimated the multiple sclerosis (MS) incidence in the Netherlands for better active monitoring of potential vaccine safety signals. Methods: A retrospective cohort study (1996–2008) was conducted using a population-based general practice research database containing electronic medical records. Additional information was collected to validate incident probable cases. Results: In the source population (648,656 persons), 146 incident probable MS cases were identified. Overall incidence rate was 6.3/100,000 person years (py; 95% CI, 5.2–7.2). In the subgroup in which MS could be fully validated, the incidence increased from 4/100,000 py (95% CI, 3–5) in 1996–2004 to 9/100,000 py in 2007/8 (95% CI, 6–16). This increase was highest among women, but not statistically significantly different by gender. The median lag time between first recorded symptoms and MS diagnosis decreased from 32 months (<1998) to 2 months (>2005). Conclusions: MS is rare in the Netherlands. In recent years, there was a slight increase in the incidence especially among women during the fertile age. This increase coincided with a decrease in lag time between symptoms and diagnosis, both for men and women. This trend should be taken into account in the interpretation of MS cases occurring in a population where new vaccinations will be introduced shortly.

Safety of vaccination against influenza A (H1N1) during pregnancy in the Netherlands: results on pregnancy outcomes and infant's health: cross- sectional linkage study

This study aims to assess the safety of Influenza A(H1N1), vaccination administered during the second and third trimester and containing MF59 and thiomersal (Focetria®), measured by pregnancy outcomes and infants health.

Effect of vaccinations on seizure risk and disease course in Dravet syndrome

Objective: To study the effect of vaccination-associated seizure onset on disease course and estimate the risk of subsequent seizures after infant pertussis combination and measles, mumps, and rubella (MMR) vaccinations in Dravet syndrome (DS). Methods: We retrospectively analyzed data from hospital medical files, child health clinics, and the vaccination register for children with DS and pathogenic SCN1A mutations. Seizures within 24 hours after infant whole-cell, acellular, or nonpertussis combination vaccination or within 5 to 12 days after MMR vaccination were defined as “vaccination-associated.” Risks of vaccination-associated seizures for the different vaccines were analyzed in univariable and in multivariable logistic regression for pertussis combination vaccines and by a self-controlled case series analysis using parental seizure registries for MMR vaccines. Disease courses of children with and without vaccination-associated seizure onset were compared. Results: Children who had DS (n = 77) with and without vaccination-associated seizure onset (21% and 79%, respectively) differed in age at first seizure (median 3.7 vs 6.1 months, p < 0.001) but not in age at first nonvaccination-associated seizure, age at first report of developmental delay, or cognitive outcome. The risk of subsequent vaccination-associated seizures was significantly lower for acellular pertussis (9%; odds ratio 0.18, 95% confidence interval [CI] 0.05–0.71) and nonpertussis (8%; odds ratio 0.11, 95% CI 0.02–0.59) than whole-cell pertussis (37%; reference) vaccines. Self-controlled case series analysis showed an increased incidence rate ratio of seizures of 2.3 (95% CI 1.5–3.4) within the risk period of 5 to 12 days following MMR vaccination. Conclusions: Our results suggest that vaccination-associated earlier seizure onset does not alter disease course in DS, while the risk of subsequent vaccination-associated seizures is probably vaccine-specific.

Guillain-Barré syndrome: background incidence rates in The Netherlands.

Guillain‐Barré syndrome (GBS) is a (sub)acute polyradiculoneuropathy, which may occur following immunization. To interpret the occurrence of GBS after introduction of large‐scale immunization programmes, it is important to define recent background incidence rates (IRs) of GBS. We used a general practitioner electronic medical record database to assess age‐specific GBS IRs between 1996 and 2008 in The Netherlands. All possible GBS cases were manually reviewed. Validated incident cases were reviewed by a neurologist (B. J.) for diagnostic certainty using the GBS case definition of the Brighton Collaboration (BC). In a population of 638,891 persons, we identified 23 validated incident GBS cases (mean age 46 years). IR was 1.14 per 100,000 person years (95% confidence interval [CI] 0.67–1.61) and was lower for people under 50 years (0.76; 95%CI 0.41–1.32) compared with elderly of 50 years or older (1.80; 95%CI 0.98–3.05). Only six cases fulfilled level 1 or 2 of diagnostic certainty of the BC case definition. IR of GBS increases with age. As vaccinations are often targeted at specific age groups, age‐specific rates should be used to monitor GBS observed versus expected rates after introduction of large‐scale vaccination programmes.

Discolored leg syndrome after vaccination-descriptive epidemiology

Discoloration of the leg following vaccination is a relatively unknown entity. We carried out a study of discolored leg syndrome (DLS) during a 10-year consecutive period with the objective of characterizing DLS in infants following vaccination received in the Dutch National Vaccination Program as well as its occurrence and association with different vaccines. Discolored leg syndrome was defined as an even or patchy red, blue or purple discoloration of the leg(s) and/or leg petechiae with or without swelling. All reports of adverse events following immunization that were made to the passive surveillance system between 1994 and 2003 were included—a total of 1162 identified cases. Red, blue, purple discoloration and isolated petechiae were reported in 39, 19, 27 and 14% of these cases, respectively. Of these 1162 cases, 1105 were considered to be related to the vaccination, based on a predefined risk window with symptom onset after vaccination (48 h for discolorations and 2 weeks for petechiae). Of the 1105 cases, about 50% occurred after DTP-IPV+Hib1 vaccinations, and 30% occurred after DTP-IPV+Hib2 vaccinations. Discolored leg syndrome was frequently accompanied by fierce crying (78%). The median time interval between vaccination and the occurrence of DLS was 3.8 ± 46.7 h, and the median duration was short (2 ± 61.7 h). Advancing the vaccination schedule from 3 to 2 months of age caused a small increase in DLS. Discolored leg syndrome manifested mainly after the first and/or second vaccination. In addition to dose, the occurrence of DLS may be slightly age-dependent and self-limiting. The pathophysiology is unknown but may be the result of a vasomotor reaction. Future studies should elucidate the recurrence rate, identify risk factors and assess late outcomes.

Elevated Immune Response Among Children 4 Years of Age With Pronounced Local Adverse Events After the Fifth Diphtheria, Tetanus, Acellular Pertussis Vaccination.

Background: In the Netherlands, acellular pertussis vaccines replaced the more reactogenic whole-cell pertussis vaccines. This replacement in the primary immunization schedule of infants coincided with a significant increase in pronounced local adverse events (AEs) in 4 years old children shortly after the administration of a fifth diphtheria, tetanus, acellular pertussis and inactivated polio (DTaP-IPV) vaccine. The objective of this study was to investigate possible differences in vaccine antigen-specific immune responses between children with and without a pronounced local AE after the fifth DTaP-IPV vaccination. Methods: Blood was sampled in 2 groups of 4-year-olds: a case group reporting pronounced local swelling and/or erythema up to extensive limb swelling at the injection site (n = 30) and a control group (n = 30). Peripheral blood mononuclear cells were stimulated with individual vaccine antigens. Plasma antigen-specific IgG, IgG subclass and total IgE concentrations and T-cell cytokine [interferon-gamma, interleukin (IL)-13, IL-17 and IL-10] production by stimulated peripheral blood mononuclear cells were determined by multiplex bead-based fluorescent multiplex immunoassays. Results: In children with AEs, significantly higher total IgE and vaccine antigen-specific IgG and IgG4 responses as well as levels of the T-helper 2 (Th2) cytokine IL-13 were found after pertussis, tetanus and diphtheria stimulation compared with controls. Conclusions: Children with pronounced local reactions show higher humoral and cellular immune responses. Acellular vaccines are known to skew toward more Th2 responses. The pronounced local AEs may be associated with more Th2 skewing after the fifth DTaP-IPV vaccination, but other biologic factors may also impact the occurrence of these pronounced local reactions.

Baseline incidence of intussusception in early childhood before rotavirus vaccine introduction, the Netherlands, January 2008 to December 2012

Intussusception is a rare, potentially life-threatening condition in early childhood. It gained attention due to an unexpected association with the first rotavirus vaccine, RotaShield, which was subsequently withdrawn from the market. Across Europe, broad variations in intussusception incidence rates have been reported. This study provides a first estimate of intussusception incidence in young children in the Netherlands from 1 January 2008 to 31 December 2012, which could be used for future rotavirus safety monitoring. Our estimates are based on two different sources: electronic medical records from the primary healthcare database (IPCI), as well as administrative data from the Dutch hospital register (LBZ). The results from our study indicate a low rate of intussusception. Overall incidence rate in children < 36 months of age was 21.2 per 100,000 person-years (95% confidence interval (CI): 12.5–34.3) based on primary healthcare data and 22.6 per 100,000 person-years (95% CI: 20.9–24.4) based on hospital administrative data. The estimates suggest the upper and lower bound of the expected number of cases.

Comparison of the tolerability of an acellular pertussis-containing vaccine given as the fifth booster dose in differently primed children.

BACKGROUND In 2005, an acellular pertussis-containing DTP-IPV-Hib vaccine for infants replaced the whole-cell combination vaccine in the National Immunisation Programme of the Netherlands. From 2008 onwards, an increase in local reactions to boosters was seen in an enhanced passive reporting system of adverse events following immunisation. METHOD A cross-sectional study was conducted to assess the difference in tolerability of a DTaP-IPV booster in four-year-old children primed in infancy with either three doses DTaP-IPV-Hib (aP-primed) or three doses of DTwP-IPV-Hib (wP-primed). Parents were asked to report in a questionnaire the local reactions and systemic adverse events that developed within one week after booster administration. RESULTS Children in the aP-primed group experienced significantly more local reactions (36.1% versus 58.5%; OR 2.7; 95% CI 2.2-3.3) and also more systemic events (11.0% versus 20.6%; OR 2.2; 95% CI 1.6-3.0) after the DTaP-IPV booster than wP-primed children. Besides, aP-primed children more often used acetaminophen (13.1% versus 6.7%); were more frequently absent from school, preschool, crèche or other activities (4.2% versus 1.5%), and more often had contact with the healthcare system (4.5% versus 1.6%) within one week after the booster than wP-primed children. CONCLUSION The frequency of adverse events after DTaP-IPV booster immunisation in four year old children is higher in children primed with DTaP-IPV-Hib than in children primed with DTwP-IPV-Hib. However, for primary and booster vaccinations together, immunisation with acellular pertussis combination vaccines results in fewer adverse events than vaccination of whole cell combination vaccines. So, both the effectiveness and adverse events needs consideration in the discussion with regard to optimal timing of booster dose of DTaP-IPV.