Daniel Weibel

The incidence of narcolepsy in Europe: Before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns

BACKGROUND In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification. METHODS We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom. RESULTS Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time. CONCLUSIONS The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.

Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccine: multinational case-control study in Europe

Objective To assess the association between pandemic influenza A (H1N1) 2009 vaccine and Guillain-Barré syndrome. Design Case-control study. Setting Five European countries. Participants 104 patients with Guillain-Barré syndrome and its variant Miller-Fisher syndrome matched to one or more controls. Case status was classified according to the Brighton Collaboration definition. Controls were matched to cases on age, sex, index date, and country. Main outcome measures Relative risk estimate for Guillain-Barré syndrome after pandemic influenza vaccine. Results Case recruitment and vaccine coverage varied considerably between countries; the most common vaccines used were adjuvanted (Pandemrix and Focetria). The unadjusted pooled risk estimate for all countries was 2.8 (95% confidence interval 1.3 to 6.0). After adjustment for influenza-like illness/upper respiratory tract infection and seasonal influenza vaccination, receipt of pandemic influenza vaccine was not associated with an increased risk of Guillain-Barré syndrome (adjusted odds ratio 1.0, 0.3 to 2.7). The 95% confidence interval shows that the absolute effect of vaccination could range from one avoided case of Guillain-Barré syndrome up to three excess cases within six weeks after vaccination in one million people. Conclusions The risk of occurrence of Guillain-Barré syndrome is not increased after pandemic influenza vaccine, although the upper limit does not exclude a potential increase in risk up to 2.7-fold or three excess cases per one million vaccinated people. When assessing the association between pandemic influenza vaccines and Guillain-Barré syndrome it is important to account for the effects of influenza-like illness/upper respiratory tract infection, seasonal influenza vaccination, and calendar time.

Prospective nationwide surveillance of hospitalizations due to pertussis in children, 2006-2010.

Background: Frequency of pertussis is highly variable from country to country and it depends on multiple factors including case definitions and type of surveillance systems used. Many countries recently reported an increase of pertussis cases especially in infants and adolescents. Methods: From April 2006 to March 2011, 15-year-old patients hospitalized with suspected or proven pertussis were reported to the Swiss Pediatric Surveillance Unit. Patients with ≥14 days of cough plus paroxysms, whooping or post-tussive vomiting fulfilled the clinical case definition of pertussis. For laboratory confirmation, Bordetella pertussis polymerase chain reaction was offered free of charge. Results: Data were available from 159 of 173 reported cases and 130 (90% of them <12 months old) were eligible including 125 laboratory-confirmed B. pertussis infections. Rates per 100,000 population were 2.6 (<16 years) and 38.8 (<12 months), respectively. Most frequent complications were cyanosis (63%) and sleep disturbance (60%); 35 (27%) patients received intensive care and 1 patient died. Source of infection was known in 79 (61%) patients and was mainly a sibling, parent or both. Most patients were unimmunized (65%) or incompletely immunized (30%). Conclusions: The high rate of pertussis hospitalization in young infants established in this surveillance project and the incomplete pertussis immunization status in almost all hospitalized patients require further efforts for improvement. In addition, introduction of pertussis immunizations for all adolescents (in 2013), young adults (in 2012) and pregnant women (in 2013) in Switzerland should increase indirect protection of vulnerable newborns and infants too young to be fully immunized.

Prospective study on central venous line associated bloodstream infections

Objective To prospectively assess the incidence rates and characteristics of central venous line associated bloodstream infections (CLABSI) in one institution. Methods All patients with indwelling central venous catheters (CVC) between 1 April 2008 and 31 March 2009 were enrolled. The medical records of patients were reviewed and information on relevant characteristics entered into a standardised questionnaire. Central laboratory records were regularly checked for positive blood cultures in study patients. Results There were 209 CVC for a total of 14752 CVC days in 152 patients (88 males, 58%) including neonates and patients with surgical conditions and haemato-oncological and other underlying diseases. Median age at CVC insertion was 3 months (IQR 0–56 months). Fourteen CLABSI occurred in 13 patients. Overall CLABSI incidence (per 1000 CVC days) was 0.95 (9.71 for silastic percutaneous CVC, 7.65 for other CVC, 1.97 for Broviac, 0.18 for Port-a-cath). CVC remained in place for ≤14 days in 109 (52%) instances, 15–90 days in 45 (22%) instances and >90 days in 55 (26%) instances. The incidence of CLABSI in these three categories was 3.36, 4.36 and 0.47, respectively. Predominating cultured organisms were coagulase-negative staphylococci (N=3), S. aureus (N=3), and Enterococcus spp. (N=3). Conclusions CLABSI incidence varied by type of catheter and type of patient, with the highest risk in neonates (with silastic percutaneous CVC) and by far the lowest risk for Port-a-cath CVC. Prophylactic measures to reduce CLABSI should be tailored to individual types of catheters and patient characteristics.

Roadmap for the international collaborative epidemiologic monitoring of safety and effectiveness of new high priority vaccines

With the advent of new vaccines targeted to highly endemic diseases in low- and middle-income countries (LMIC) and with the expansion of vaccine manufacturing globally, there is an urgent need to establish an infrastructure to evaluate the benefit-risk profiles of vaccines in LMIC. Fortunately the usual decade(s)-long time gap between introduction of new vaccines in high and low income countries is being significantly reduced or eliminated due to initiatives such as the Global Alliance for Vaccines and Immunizations (GAVI) and the Decade of Vaccines for the implementation of the Global Vaccine Action Plan. While hoping for more rapid disease control, this time shift may potentially add risk, unless appropriate capacity for reliable and timely evaluation of vaccine benefit-risk profiles in some LMICs are developed with external assistance from regional or global level. An ideal vaccine safety and effectiveness monitoring system should be flexible and sustainable, able to quickly detect possible vaccine-associated events, distinguish them from programmatic errors, reliably and quickly evaluate the suspected event and its association with vaccination and, if associated, determine the benefit-risk of vaccines to inform appropriate action. Based upon the demonstrated feasibility of active surveillance in LMIC as shown by the Burkina Faso assessment of meningococcal A conjugate vaccine or that of rotavirus vaccine in Mexico and Brazil, and upon the proof of concept international GBS study, we suggest a sustainable, flexible, affordable and timely international collaborative vaccine safety monitoring approach for vaccines being newly introduced. While this paper discusses only the vaccine component, the same system could also be eventually used for monitoring drug effectiveness (including the use of substandard drugs) and drug safety.

Pharmacoepidemiological safety studies in children: a systematic review.

In order to identify challenges in pediatric pharmacoepidemiological safety studies, we assessed the characteristics of such (published) studies.

Pandemic influenza vaccine & narcolepsy: simulations on the potential impact of bias

ABSTRACT Several studies have identified an association between PandemrixTM, an AS03 adjuvanted pandemic influenza A(H1N1) vaccine, and narcolepsy, a rare and under-diagnosed sleep disorder with a median onset-to-diagnosis interval of ten years. This paper reviews potential sources of bias in published studies and aims to provide, through simulation, methodological recommendations for assessment of vaccine safety signals. Our simulation study showed that in the absence of an association between the vaccine and the outcome, presence of detection bias and differential exposure misclassification could account for elevated risk estimates. These may play a major role, particularly in alert situations when observation times are limited and the disease has a long latency period. Estimates from the case-control design were less inflated than those from the cohort design when these biases were present. Overall, these simulations provide useful insights for the design and interpretation of future studies.

Pediatric Drug Safety Signal Detection: A New Drug–Event Reference Set for Performance Testing of Data-Mining Methods and Systems

BackgroundBetter evidence regarding drug safety in the pediatric population might be generated from existing data sources such as spontaneous reporting systems and electronic healthcare records. The Global Research in Paediatrics (GRiP)–Network of Excellence aims to develop pediatric-specific methods that can be applied to these data sources. A reference set of positive and negative drug–event associations is required.ObjectiveThe aim of this study was to develop a pediatric-specific reference set of positive and negative drug–event associations.MethodsConsidering user patterns and expert opinion, 16 drugs that are used in individuals aged 0–18 years were selected and evaluated against 16 events, regarded as important safety outcomes. A cross-table of unique drug–event pairs was created. Each pair was classified as potential positive or negative control based on information from the drug’s Summary of Product Characteristics and Micromedex. If both information sources consistently listed the event as an adverse event, the combination was reviewed as potential positive control. If both did not, the combination was evaluated as potential negative control. Further evaluation was based on published literature.ResultsSelected drugs include ibuprofen, flucloxacillin, domperidone, methylphenidate, montelukast, quinine, and cyproterone/ethinylestradiol. Selected events include bullous eruption, aplastic anemia, ventricular arrhythmia, sudden death, acute kidney injury, psychosis, and seizure. Altogether, 256 unique combinations were reviewed, yielding 37 positive (17 with evidence from the pediatric population and 20 with evidence from adults only) and 90 negative control pairs, with the remainder being unclassifiable.ConclusionWe propose a drug–event reference set that can be used to compare different signal detection methods in the pediatric population.

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.

Patterns of spontaneous reports on narcolepsy following administration of pandemic influenza vaccine; a case series of individual case safety reports in Eudravigilance.

OBJECTIVE This study aims to describe the frequency and quality of spontaneous narcolepsy case reports following administration of pandemic influenza vaccine as captured in the Eudravigilance database. METHODS We conducted a retrospective descriptive study of spontaneous Individual Case Safety Reports (ICSRs), reporting narcolepsy following administration of pandemic influenza vaccine as received by Eudravigilance until July 2014. De-duplication was carried out by Eudravigilance. Frequency of reporting is described as number of ICSRs received per month over time. The quality of the ICSRs was evaluated by completeness of information and diagnostic certainty using the Automated Brighton Collaboration case definition tool (ABC-tool) for narcolepsy. RESULTS After de-duplication, a total of 1333 ICSRs of narcolepsy and/or cataplexy following pandemic influenza vaccine were identified, originating from 18 countries worldwide. Most of the ICSRs (61.9%) originated from the signaling countries, Sweden and Finland. Although de-duplication of case reports was carried out, it is suspected that many duplicates exist, in particular from Sweden. The majority of the ICSRs (95.3%), reported exposure to Pandemrix®. Only few reports were received for Arepanrix® (1.6%) or Focetria® (0.5%), and Celvapan® (0.1%). Of those ICSRs reporting age, 73.1% concerned persons below age of 20years. When using the ABC-tool, all ICSRs were classified as having insufficient information to meet the Brighton Collaboration case definition of narcolepsy. CONCLUSION An increase in reporting of narcolepsy appeared in Eudravigilance only after awareness was raised by the national authorities. Most narcolepsy reports were received from countries where the signal initially occurred, and were related to Pandemrix® in children/adolescents. Basic information about the patient and the exposure was present in most of the ICSRs. The ICSRs captured by Eudravigilance however, do not collect enough information to assess the diagnostic certainty according to the Brighton Collaboration case definition.