Jan Bonhoeffer

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.

The Brighton Collaboration: addressing the need for standardized case definitions of adverse events following immunization (AEFI)

UNLABELLED To further scientific progress of immunization safety, comparability of data from clinical trials and surveillance systems is essential. Comparability requires the availability of standardized case definitions for adverse events following immunization (AEFI) and guidelines for case determination, recording and data presentation. METHOD International collaborative working groups, consisting of professional volunteers from developed and developing countries, conduct systematic literature reviews to develop 50-100 AEFI definitions. Case definitions are finalized after a comment period by a reference group consisting of organizations concerned with immunization safety, and will be disseminated via the world-wide-web and other means for free world-wide use. RESULTS Literature reviews yielded substantial diversity in data collection and presentation. We have developed standardized case definitions together with guidelines for use in clinical trials and surveillance systems. CONCLUSIONS Diversity in safety methods leads to considerable loss of scientific information. We have built the necessary international network of currently about 300 participants from patient care, public health, scientific, pharmaceutical, regulatory and professional organizations to develop and assess standardized AEFI case definitions and guidelines. Evaluation studies, global implementation, ongoing definition development and a continuously growing network will be essential for the success of the collaboration.

Three-Year Surveillance of Intussusception in Children in Switzerland

OBJECTIVE. We attempted to obtain baseline data on the incidence of intussusception and its association with gastroenteritis in a cross-sectional observational study in children. METHODS. Admissions to all 38 pediatric units in Switzerland because of intussusception were reported to the Swiss Pediatric Surveillance Unit from April 2003 to March 2006. Patient and disease characteristics were assessed prospectively with the use of a standardized questionnaire based on the case definition for intussusception developed by the Brighton Collaboration. Completeness of reporting was verified through capture-recapture analysis. RESULTS. There were 294 patients with reported intussusception; 35 cases were excluded for various reasons, and 29 additional patients were identified through International Classification of Diseases, 10th Revision, codes. After capture-recapture analysis, we estimated underreporting to the Swiss Pediatric Surveillance Unit to be 32% and we calculated a true number of 381 intussusception episodes. The highest level of diagnostic certainty was reached by 248 patients, and 20 fulfilled level 2 criteria; for the remaining 20 patients, available information was insufficient. The mean age of the patients was 2.7 years. The yearly mean incidence of intussusception was 38, 31, and 26 cases per 100000 live births in the first, second, and third year of life, respectively, with no apparent seasonality. Seventy patients had a history of coinciding gastroenteritis, and 5 of 61 tested positive for rotavirus. Spontaneous devagination was observed for 38 patients; enemas reduced intussusception successfully in 183 cases, whereas surgical treatment was required in 67. All patients recovered without sequelae. CONCLUSIONS. This is the first prospective nationwide surveillance of intussusception in childhood using a standardized case definition. Most cases occurred beyond infancy, and association with rotavirus gastroenteritis was rare.

Prospective surveillance of hospitalisations associated with varicella-zoster virus infections in children and adolescents

Our goal was to determine the epidemiology of severe varicella-zoster virus (VZV) infections in hospitalised paediatric patients. Admissions associated with VZV infection of patients aged 0–16 years were reported by all 38 paediatric units in Switzerland to the Swiss Paediatric Surveillance Unit (SPSU) during 3 consecutive years (4/2000–3/2003). We verified completeness of reporting by capture-recapture analysis with patient records identified by ICD-10 codes. Outcome of illness was assessed 6 months after hospitalisation. A total of 335 cases (235 identified by SPSU reports, 100 by ICD-10 code) were included in this study. Mean age of patients was 4.1 years (median 3.5 years, range 0–16 years); 54% were male. Some 293 (87%) patients presented with chickenpox, 42 (13%) with herpes zoster and 291 (87%) patients were not immunocompromised. A total of 319 complications occurred in 237 (71%) patients: secondary bacterial infections (n =109); central nervous system involvement (n =76); VZV pneumonitis (n =7); others (n =127). Eleven (3%) patients required intensive care and three died. On follow-up, 303 (96%) of 315 patients had completely recovered; sequelae were present in 12 (4%) patients. The calculated hospitalisation rate was 13 per 104 cases. Conclusion:This study describes a sizeable hospitalisation and complication rate of varicella-zoster virus infections and provides a solid basis for future immunisation recommendations in Switzerland.

Narcolepsy as an adverse event following immunization: case definition and guidelines for data collection, analysis and presentation.

rancesca Poli a,2, Sebastiaan Overeemb,∗,2, Gert Jan Lammersc,2, Giuseppe Plazzia,2, ichel Lecendreuxd,2, Claudio L. Bassetti e,1,2, Yves Dauvilliers f,1,2, Daniel Keeneg,1,2, amin Khatamih,1,2, Yulin Li i,j,1,2, Geert Mayerk,1,2, Hanna Nohynekl,1,2, Barbara Pahudm,1,2, eresa Paivan,1,2, Markku Partineno,1,2, Thomas E. Scammellp,1,2, Tom Shimabukuroq,1,2, iriam Sturkenboomr,1,2, Kristy van Dinthers,1,2, Max Wiznitzer t,1,2, Jan Bonhoeffer i,j,2

International collaboration to assess the risk of Guillain Barre Syndrome following Influenza A (H1N1) 2009 monovalent vaccines

BACKGROUND The global spread of the 2009 novel pandemic influenza A (H1N1) virus led to the accelerated production and distribution of monovalent 2009 Influenza A (H1N1) vaccines (pH1N1). This pandemic provided the opportunity to evaluate the risk of Guillain-Barré syndrome (GBS), which has been an influenza vaccine safety concern since the swine flu pandemic of 1976, using a common protocol among high and middle-income countries. The primary objective of this project was to demonstrate the feasibility and utility of global collaboration in the assessment of vaccine safety, including countries both with and without an established infrastructure for vaccine active safety surveillance. A second objective, included a priori, was to assess the risk of GBS following pH1N1 vaccination. METHODS The primary analysis used the self-controlled case series (SCCS) design to estimate the relative incidence (RI) of GBS in the 42 days following vaccination with pH1N1 vaccine in a pooled analysis across databases and in analysis using a meta-analytic approach. RESULTS We found a relative incidence of GBS of 2.42 (95% CI 1.58-3.72) in the 42 days following exposure to pH1N1 vaccine in analysis of pooled data and 2.09 (95% CI 1.28-3.42) using the meta-analytic approach. CONCLUSIONS This study demonstrates that international collaboration to evaluate serious outcomes using a common protocol is feasible. The significance and consistency of our findings support a conclusion of an association between 2009 H1N1 vaccination and GBS. Given the rarity of the event the relative incidence found does not provide evidence in contradiction to international recommendations for the continued use of influenza vaccines.

Prevalence of nosocomial infections in Swiss children's hospitals

OBJECTIVE To acquire data on pediatric nosocomial infections (NIs), which are associated with substantial morbidity and mortality and for which data are scarce. DESIGN Prevalence survey and evaluation of a new comorbidity index. SETTING Seven Swiss pediatric hospitals. PATIENTS Those hospitalized for at least 24 hours in a medical, surgical, intensive care, or intermediate care ward. RESULTS Thirty-five NIs were observed among 520 patients (6.7%; range per hospital, 1.4% to 11.8%). Bacteremia was most frequent (2.5 per 100 patients), followed by urinary tract infection (1.3 per 100 patients) and surgical-site infection (1.1 per 100 patients; 3.2 per 100 patients undergoing surgery). The median duration until the onset of infection was 19 days. Independent risk factors for NI were age between 1 and 12 months, a comorbidity score of 2 or greater, and a urinary catheter. Among surgical patients, an American Society of Anesthesiologists (ASA) score of 2 or greater was associated with any type of NI (P = .03). Enterobacteriaceae were the most frequent cause of NI, followed by coagulase-negative staphylococci; viruses were rarely the cause. CONCLUSIONS This national prevalence survey yielded valuable information about the rate and risk factors of pediatric NI. A new comorbidity score showed promising performance. ASA score may be a predictor of NI. The season in which a prevalence survey is conducted must be considered, as this determines whether seasonal viral infections are observed. Periodic prevalence surveys are a simple and cost-effective method for assessing NI and comparing rates among pediatric hospitals.

Procalcitonin guidance to reduce antibiotic treatment of lower respiratory tract infection in children and adolescents (ProPAED): a randomized controlled trial.

Background Antibiotics are overused in children and adolescents with lower respiratory tract infection (LRTI). Serum-procalcitonin (PCT) can be used to guide treatment when bacterial infection is suspected. Its role in pediatric LRTI is unclear. Methods Between 01/2009 and 02/2010 we randomized previously healthy patients 1 month to 18 years old presenting with LRTI to the emergency departments of two pediatric hospitals in Switzerland to receive antibiotics either according to a PCT guidance algorithm established for adult LRTI or standard care clinical guidelines. In intention-to-treat analyses, antibiotic prescribing rate, duration of antibiotic treatment, and number of days with impairment of daily activities within 14 days of randomization were compared between the two groups. Results In total 337 children, mean age 3.8 years (range 0.1–18), were included. Antibiotic prescribing rates were not significantly different in PCT guided patients compared to controls (OR 1.26; 95% CI 0.81, 1.95). Mean duration of antibiotic exposure was reduced from 6.3 to 4.5 days under PCT guidance (−1.8 days; 95% CI −3.1, −0.5; P = 0.039) for all LRTI and from 9.1 to 5.7 days for pneumonia (−3.4 days 95% CI −4.9, −1.7; P<0.001). There was no apparent difference in impairment of daily activities between PCT guided and control patients. Conclusion PCT guidance reduced antibiotic exposure by reducing the duration of antibiotic treatment, while not affecting the antibiotic prescribing rate. The latter may be explained by the low baseline prescribing rate in Switzerland for pediatric LRTI and the choice of an inappropriately low PCT cut-off level for this population. Trial Registration Controlled-Trials.com ISRCTN17057980 ISRCTN17057980

Adverse events following immunization: perception and evidence.

Purpose of review The aim of this article is to highlight the evidence on new and ongoing vaccine safety concerns in the light of several vaccines recently licensed and others made available and recommended more widely. Recent findings There is increasingly convincing epidemiologic and laboratory evidence against a causal relation of several alleged adverse events following immunization. The scientific framework to detect and investigate adverse events following immunization is increasingly robust. Summary Currently available vaccines are safe in immunocompetent individuals and there is no evidence to deviate from current immunization schedules.