Re: Finland - National Health Dept. Suspends A/H1N1 Vaccine Due to Possible Narcolepsy Connection
Re: Finland - National Health Dept. Suspends A/H1N1 Vaccine Due to Possible Narcolepsy Connection
ECDC: Reports of cases of narcolepsy and cataplexy in children and adolescents in Finland, Iceland, and Sweden
02 Mar 2011
In February 2011, ECDC published a report concerning a rise in narcolepsy in children and adolescents in some northern countries. This update provides initial findings on this topic and describes relevant developments for Europe.
Background
Increased numbers of narcolepsy-cataplexy in children and adolescents became apparent in Finland in mid-2010. An increase in cases was also reported in Sweden and, to a lesser degree, in Iceland. Initial reports associated the rise with the 2009 pandemic and the use of pandemic vaccines. In late August 2010, Finnish authorities stopped using the adjuvanted pandemic vaccine (GlaxoSmithKline?s Pandemrix).
The European Commission initiated a formal procedure, and the European Medicines Agency?s Committee on Human Medical Products (EMA CHMP) reviewed the available data. The CHMP noted that no similar aggregation of cases was reported from other countries (Pandemrix was used extensively in at least 19 EU/EEA countries) and hence no clear link with vaccination [1]. In September 2010, EMA stated that further studies were needed, but did not recommend suspending Pandemrix or withdrawing its marketing authorisation.
Analytic studies were initiated in Finland and Sweden. ECDC commissioned a large-scale study through its VAESCO project (Vaccine Adverse Events Surveillance and Communication), attempting to estimate background rates of narcolepsy while simultaneously investigating a possible association between pandemic vaccination, wild-type influenza infection, and other vaccines. Results are expected for June 2011.
Narcolepsy
Narcolepsy is a disabling chronic neurological disorder characterised by recurrent episodes of excessive daytime sleepiness. Cataplexy (episodic muscle weakness), sleep paralysis, and hypnagogic hallucinations often accompany narcolepsy. Symptoms usually develop gradually [2]. A multi-factorial aetiology has been suggested for narcolepsy, involving a genetic predisposition in combination with environmental risk factors. A majority of genetically susceptible individuals have one or more alleles of HLA DQB1*0602 across all ethnic groups [3]. Possible environmental risk factors include streptococcal infections, passive smoking, withdrawal from antidepressants, and obesity [4-6]. Researchers have proposed an autoimmune mechanism as a trigger for the selective loss of hypothalamic orexin/hypocretin-producing neurons involved in REM-sleep regulation [7-9].
The incidence rate has been estimated at around 0.74 to 1.37 cases per 100 000 person-years, depending on the way the condition is defined. Because narcolepsy is an enduring condition, prevalence rates are much higher [5] and since early presentations can be subtle, diagnoses may be brought forward through increased awareness.
Working case definitions for narcolepsy with and without cataplexy, with levels of diagnostic certainty from 1 (lowest) to 3 (highest), were developed by the ECDC-VAESCO consortium in collaboration with the European Narcolepsy Network (Annex). This built upon the prior experience of the Brighton Collaboration.
Finland ? interim THL report
As of 10 February 2011, the Finnish National Institute for Health and Welfare (THL) had received 62 notifications of suspicion of narcolepsy or narcolepsy/cataplexy following vaccination with Pandemrix [10]. Of these, 59 occurred in children and adolescents (4?19 years of age). The majority showed narcoleptic/cataplectic symptoms compatible with ICD-10 code G47.4. Vaccination coverage in this age group was around 65%. The average time from vaccination to the onset of excessive day time sleepiness or cataplexy was 52 days. An interim report of a nationwide, register-based retrospective cohort study by a National Narcolepsy Task Force suggested that the risk of developing narcolepsy/cataplexy in the 4?19 age group was increased by 9.2% if vaccinated with Pandemrix (95% CI: 4.5?21.4). The Task Force concluded that it is probable that the vaccination contributed to the observed increase in narcolepsy/cataplexy, but most likely in association with a still unknown genetic and/or environmental factor. However, the strength of the observed association is of such magnitude that it is unlikely to be explained by confounding factors. A final report is expected for August 2011 [10].
Sweden
As of 27 January 2011, 61 cases of narcolepsy following vaccination with Pandemrix have been received by the Swedish Medical Product Agency and forwarded to the EMA EudraVigilance database for spontaneous adverse drug reports [11]. Fifty-three cases were in people younger than 20. Most of the cases reported the onset of disease before the end of February 2010, the remainder before the summer of 2010. An earlier ECDC-VENICE survey* reported vaccination coverage for Sweden at 59% [12]. Sweden is currently involved in three activities:
* Registry studies of narcolepsy/cataplexy cases in vaccinated versus unvaccinated people.
* Case ascertainment of cases appearing in healthcare information systems during 2009?2010.
* Identifying and investigating cases being included in the ECDC-VAESCO case-control study.
Iceland
Iceland reported increased narcolepsy diagnoses in the age group 0?18 years for 2010. No cases of narcolepsy have been diagnosed in those 19 years or older. Of the five cases diagnosed in 2010, three were vaccinated. 40,875 individuals were vaccinated with Pandemrix in the 0?18 years age group (total age group: 85,318). 109,414 individuals received Pandemrix in the age group above 19 years of age (total age group: 232,312). All cases have been confirmed by neurologists.
Reports to EudraVigilance
As of 27 January 2011, 162 reports suggestive of narcolepsy and mentioning Pandemrix have been recorded in the EU EudraVigilance database of suspected adverse reactions to medicinal products maintained by the European Medicines Agency. Of these, 55 reports had been received from Finland, 20 from France, 8 from Germany, 2 from Ireland, 1 from the Netherlands, 10 from Norway, 1 from Portugal, 61 from Sweden, and 4 from Switzerland. There were no reports from other EU/EEA countries.
Canada
Canada uses large amounts of Arepanrix, a product very similar to Pandemrix, which is produced locally by GlaxoSmithKline in Canada. As of 26 January 2011, two cases of narcolepsy have been reported per around 2 million vaccinated among those 0?17 years of age (0.1 cases/100,000 vaccinated).
2010/2011 influenza season and use of Pandemrix in the European Union
The vaccine used in Finland and Sweden (Pandemrix) was used in 2009/10 by at least 30.8 million Europeans in 19 EU/EEA countries. In February 2010, WHO recommended that the 2010/2011 seasonal influenza vaccines for the northern hemisphere be based on influenza antigens for A(H1N1)2009, A(H3N2), and B viruses [13], and most manufacturers produced these vaccines as unadjuvanted products. ECDC supported the WHO guidance that seasonal vaccines should be used to prevent seasonal influenza. Vaccines reached EU countries in the summer/autumn of 2010 [14]. At the same time, Pandemrix remained authorised for use preventing A(H1N1)2009. Those viruses predominated the season and accounted for most of the severe cases [15]. However, B viruses have been detected throughout the season in steadily increasing proportions. They have caused deaths and latterly have predominated over A(H1N1)2009 in some countries (see ECDC?s Weekly Influenza Surveillance Overviews). In early February 2011, the European Commission?s DG SANCO undertook a rapid survey of the current use of Pandemrix in EU/EEA Member States, when only a few EU countries were still using Pandemrix: in Sweden, Pandemrix was used for a small number of immunodeficient individuals who benefited from an adjuvanted preparation. Ireland reported using the vaccine but not in children and adolescents (under the age of 20). Portugal was using the vaccine in children and adolescents, although numbers were diminishing. The same was the case for the UK. Six countries known to have used Pandemrix during the 2009/10 season did not respond to the enquiry.
Authorisation and effectiveness of pandemic and seasonal vaccines in Europe
Assessing the benefit-risk profile of centrally-authorised vaccines is the responsibility of EMA?s Committee for Human Medicinal Products, and granting a marketing authorisation for these vaccines in the European Union is the responsibility of the European Commission. Both the 2009 pandemic vaccines and the new seasonal vaccines have been shown to be effective in the field in 2009 and 2010 [16-18].
ECDC -VAESCO study ? initial report on background rates
As of 15 February 2011, the VAESCO network has estimated preliminary background incidence rates of narcolepsy in six European countries (Denmark, Finland, Netherlands, Italy, Sweden, UK). The data were gathered from population-based healthcare databases (GPs and hospitals). Background incidence rates of narcolepsy were presented to EMA, WHO, and the ECDC Advisory Forum in mid-February. Updated background rates for a total of over 40 million persons are now available.
Observed narcolepsy incidence rates were around 1 per 100,000 person years and varied only slightly over time. In Finland, a statistically significant increase in the incidence rate has been observed after September 2009 only in the age group of 5?19 years of age (as in the THL study). The rates in the age groups 20?59 and 60+ years of age have been unchanged since 2006. In the Netherlands, an increase in the incidence rate of narcolepsy based on yet unvalidated diagnoses was observed in the 20?59 years age group, an age group that generally was not offered pandemic vaccine. No age-specific increases could be observed in other countries.
The VAESCO network is conducting its case-control study in nine European countries, estimating the relative risk of narcolepsy in vaccinated-versus-unvaccinated individuals. Other possible risk factors that will be assessed include natural influenza infection, other vaccines administered before/after pandemic vaccination, and, sufficient funds provided, genetic predisposition. Results from the ongoing case-control study are expected in June 2011.
Assessment of EMA/CHMP
On 18 February 2011, EMA?s Committee on Human Medical Products published a review of data on narcolepsy and possible association with Pandemrix. The Committee concluded that the new evidence added to the concern arising from the case reports in Finland and Sweden, but data were insufficient to establish a causal relationship between Pandemrix and narcolepsy and no change to the product information was warranted. The Committee indicated that it is important to gather more data from other studies, including the ECDC-VAESCO network, and the manufacturer has now also announced details of their own investigations.
WHO position on related influenza immunisation policy
WHO?s Global Advisory Committee on Vaccine Safety reviewed the data in early February without changing its position on pandemic or seasonal influenza vaccines [13]. WHO specifically stated that countries could continue using monovalent vaccines, including Pandemrix, in order to immunise persons at risk of severe disease from A(H1N1)2009 if trivalent seasonal vaccine was unavailable.
ECDC comment (2 March 2011)
The Finnish Task Force concluded that it was probable that Pandemrix contributed to the observed increase in narcolepsy/cataplexy, but most likely in association with a still unknown genetic and/or environmental factor, and Finland suspended the use of Pandemrix in August 2010. Sweden reports contemporaneous increases in diagnoses of narcolepsy-cataplexy, and awaits the results of a detailed national investigation. Numbers of cases are small in Iceland, and no such signals have been noted elsewhere in Europe despite large-scale use of the same vaccine. All in all, the signal is concerning but lacks the consistency needed to come to a conclusion on a causative relationship [1].
EMA?s Committee on Medical Products for Humans concluded that the results from Finland added to the concern arising from earlier case reports in Finland and Sweden while at the same time the data remained insufficient to establish a causal relationship between Pandemrix and narcolepsy.
WHO?s northern hemisphere influenza vaccination guidance (February 2010) recommended the usual trivalent seasonal vaccines for the 2010/11 season, and ECDC supported this in its guidance for Member States [13,14]. WHO has stated that the triple seasonal vaccine would be preferred over Pandemrix. At the time of writing, Pandemrix is limited in use throughout Europe. Exceptions following local or individual risk-benefit analysis are made for small special groups (e.g. immunodeficient individuals) and in situations that carry a risk of A(H1N1)2009 infection but no seasonal vaccine is available. Such risk-benefit analyses would take into account the Finnish and subsequent findings.
In ECDC?s view it is essential to pursue independent scientific investigations in order to test various hypotheses [1,10,11]. This is happening through the independent national and ECDC-VAESCO studies, which will deliver results in June/July 2011. There is no need for policy decisions ahead of these findings since Pandemrix is essentially no longer in use in any EU/EEA country.
ECDC?s position remains unchanged from that in December 2010 and January 2011, namely that immunisation against seasonal influenza is important and prevents many severe influenza cases and fatalities. Of course personal hygiene measures and medical treatments are also important. When it comes to the choice of vaccines, seasonal vaccines are what should be used to prevent seasonal influenza as they will cover the different viruses involved. [13,14].
Assuring the highest standards of vaccine safety requires constant monitoring and systematic epidemiological assessments. This is an essential component of safe and effective vaccination programmes. It is also important in retaining the confidence of the public and professionals in the safety and effectiveness of vaccines [1]. ECDC?s role as an EU scientific agency is to support EMA and national regulatory and public health authorities. This includes designing, financing, and coordinating rigorous and independent scientific studies on vaccines and vaccine-preventable diseases. The ECDC-VASECO studies will elucidate the epidemiology of narcolepsy/cataplexy after the detection of a signal for vaccine side effects in three countries This is to evaluate the potential risk factors for the observation which may include infections and other factors not just vaccination [1]. Results of such studies will facilitate policy decisions by EU and national authorities.
Further information will be made available by ECDC through its website.
Contact:
influenza@ecdc.europa.eu
Annex. Narcolepsy-cataplexy working ECDC-VAESCO case definition criteria
General note
In rare cases, a suspected narcolepsy case may not be classifiable according to the levels below (e.g. when there is cataplexy, no sleepiness, and hypocretin-1 levels are unavailable). In these instances, the case definition committee will examine the clinical data and decide whether or not the patient can be classified as having narcolepsy, and if yes, at which level.
Level 1
In the presence of:
criterion 1: Excessive daytime sleepinessa and/or suspected cataplexy AND
criterion 2: CSF hypocretin-1 deficiency
Level 2
In the presence of:
criterion 1: Excessive daytime sleepinessa AND
criterion 2: Definite cataplexy AND
criterion 3: Level 1 or 2 MSLT abnormalities
Note: criterion 3 has only been added to add some form of ?objectivity? (without sacrificing sensitivity)
Level 3
In the presence of:
criterion 1: Excessive daytime sleepinessa AND
criterion 2: Level 1 MSLT abnormalities
aExcessive daytime sleepiness
Definition in adults (>= 16 years): An acquired condition, characterised by:
* involuntary sleep episodes during the day
* present almost daily for at least one month
Definition in children (< 16 years):
An acquired condition, characterised by:
* clear increase in daytime sleep episodes
* usually in combination with feelings of subjective sleepiness and impaired concentration
* present almost daily for at least one month
References
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* ECDC and the national collaborators of the VENICE-II Programme (Vaccine European New Integrated Collaboration Effort) produce annual surveys of vaccination policies and performance in EU/EEA countries.
http://www.ecdc.europa.eu/en/activi...=512ff74f-77d4-4ad8-b6d6-bf0f23083f30&ID=1028
