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Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A

AbstractObjective To evaluate the risk of narcolepsy in children and adolescents in England targeted for vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine (Pandemrix) from October 2009.Design Retrospective analysis. Clinical information and results of sleep tests were extracted from hospital notes between August 2011 and February 2012 and reviewed by an expert panel to confirm the diagnosis. Vaccination and clinical histories were obtained from general practitioners.Setting Sleep centres and paediatric neurology centres in England.Participants Children and young people aged 4 18 with onset of narcolepsy from January 2008.Main outcome measures The odds of vaccination in those with narcolepsy compared with the age matched English population after adjustment for clinical conditions that were indications for vaccination. The incidence of narcolepsy within six months of vaccination compared with the incidence outside this period measured with the self controlled cases series method.Results Case notes for 245 children and young people were reviewed; 75 had narcolepsy (56 with cataplexy) and onset after 1 January 2008. Eleven had been vaccinated before onset; seven within six months. In those with a diagnosis by July 2011 the odds ratio was 14.4 (95% confidence interval 4.3 to 48.5) for vaccination at any time before onset and 16.2 (3.1 to 84.5) for vaccination within six months before onset. The relative incidence from the self controlled cases series analysis in those with a diagnosis by July 2011 with onset from October 2008 to December 2010 was 9.9 (2.1 to 47.9). The attributable risk was estimated as between 1 in 57500 and 1 in 52000 doses.Conclusion The increased risk of narcolepsy after vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine indicates a causal association, consistent with findings from Finland. Because of variable delay in diagnosis, however, the risk might be overestimated by more rapid referral of vaccinated children.IntroductionNarcolepsy is a chronic disorder presenting with excessive daytime sleepiness, often accompanied by a transient loss of muscle tone triggered by strong emotion (cataplexy). Diagnosis is based on clinical criteria and can be confirmed by polysomnography followed by a multiple sleep latency test.1 Estimates of prevalence generally range between 25 and 50 per 100000, though might be less in some populations, possibly because of differences in genetic susceptibility or exposure to aetiological risk factors.2 Information on incidence is more limited. Onset can occur at any age2 but is commonest in those aged 10 19, in whom an incidence of 3.84 per 100000 person years has been reported.3 The interval between onset and diagnosis can be long, with a median of 10.5 years in one study.4 Diagnostic delay is less in those with cataplexy and in younger patients.5 van cleef gold necklace fake There is a strong association with human leucocyte antigen (HLA) DQB10602 and reported associations with environmental factors such as streptococcal infection,6 seasonal influenza,7 and more recently pandemic A/H1N1 2009 influenza.8In England, a monovalent pandemic strain vaccine containing the oil in water adjuvant AS03 (Pandemrix) was introduced in October 2009 during the second wave of infection, initially for people with high risk clinical conditions9 10 and then in healthy children aged under 5 from mid December 2009.11 By March 2010, around 24% of healthy children aged 12 A second pandemic vaccine was used black van cleef necklace copy (Celvepan) but accounted for less than 1% of the total.In August 2010 concerns were raised in Finland and Sweden about a possible association between narcolepsy and Pandemrix.13 A subsequent cohort study in Finland reported a 13 fold increased risk of narcolepsy after vaccination in children and young people aged 4 19, most of whom had onset within three months after vaccination and almost all within six months.14 To evaluate the risk of narcolepsy after vaccination in England we identified cases in those aged under 19 with onset since 1 January 2008 and compared the proportion vaccinated with that in the age matched English population after adjusting for clinical conditions that were indications for pandemic vaccination.MethodsCase ascertainment and validationCases in children and young people aged 4 18 at onset of narcolepsy from January 2008 were ascertained from sleep centres and paediatric neurology centres in England. With lists supplied by the British Sleep Society and the British Paediatric Neurology Association we identified 23 centres that saw children. In July 2011 we contacted these 23 centres and 16 replied that they had seen affected children in the relevant time period. To provide an alternative means of case ascertainment we identified all the cases in England recorded in the hospital episode statistics database15 with the ICD 10 (international classification of diseases, 10th revision) diagnosis code G47.4 (narcolepsy and cataplexy) in the same age group in the same time period. Clinical information including the presence of cataplexy and results of relevant tests including polysomnography, multiple sleep latency test, HLA type, and hypocretin concentrations were extracted from case notes during visits to the 16 study centres from August 2011 to February 2012. Details of the clinical features and test results of cases will be reported elsewhere. Patients' general practitioners were sent a questionnaire to ascertain history of pandemic and seasonal influenza vaccination, date of onset of symptoms, date of first healthcare consultation for a sleep problem, and any underlying clinical condition for which pandemic vaccine was indicated. Information on infections preceding narcolepsy was also sought. These data were reviewed by three narcolepsy experts (blinded to vaccination status) who confirmed the cases in which the diagnosis was definite that is, narcolepsy with cataplexy or narcolepsy without cataplexy according to international classification of sleep disorders criteria.1 Cases not meeting these criteria but with a convincing clinical history were classified as probable narcolepsy. The remainder were excluded because of insufficient information and were not included in the analysis.Index dates definitionsThe date of symptom onset was the earliest date of excessive daytime sleepiness or cataplexy as given by the general practitioner or recorded in the centre notes. When the exact date was not available we used the mid point of the month.The date of first known healthcare contact was the earliest recorded consultation for a sleep related problem as reported by the general practitioner or in the centre notes.The key centre visit was when all cases known at the centre were systematically ascertained; cases identified on an ad hoc basis after this were not included.The date of diagnosis was the earliest date that identified an affected patient at the key centre visit, either on the basis of a clinical history and sleep study confirming narcolepsy or because there was sufficient clinical information to diagnose probable narcolepsy.Statistical analysisWe assessed the association between vaccination and narcolepsy using the case coverage method16: for each patient with narcolepsy in the study the population coverage was ascertained for children of the same age (in months on 30 September 2009) at the relevant index date (that is, date of symptom onset) and with the same risk group status (in a group or not). The association was calculated as the odds ratio for vaccination in the cases compared with the matched population. This was done with logistic regression with the outcome as vaccinated (yes/no) in the cases and with an offset for the log odds of the matched coverage. As the outcome is rare, odds ratios approximate to relative risks. Vaccine coverage by age in years and risk group status came from weekly electronic reports to the Birmingham research unit of the Royal College of General Practitioners by a representative sample of 98 general practices in England for the period September 2009 to August 2010.17 We analysed patient level electronic records extracted from the practices to derive coverage data for specific age and risk groups. To obtain coverage within 12 weeks or six months before an index date we matched the coverage at the index date and at the date 12 weeks or six months earlier and calculated the difference in coverage. Cases categorised by the experts as definite and probable narcolepsy were combined for all analyses. The primary analysis used first symptoms as the index date and was restricted to diagnoses by 31 July 2011. We carried out sensitivity analyses including all patients with a diagnosis by the key centre visit, using first healthcare contact or diagnosis as the index date, not matching on risk group status, or increasing population coverage by a relative 20% (for example, 10% increasing to 12%). Analyses were performed based on vaccination within 12 weeks, within six months, and at any time before the index date.We carried out a separate analysis using the self controlled case series method18 to estimate the incidence of symptom onset within three and six months after vaccination relative to the incidence outside this period (the baseline). Because pandemic influenza vaccination started in October 2009 the observation period for each individual started on 1 October 2009 and ended on 31 December 2010. In a second analysis we used a start date of October 2008 to allow inclusion of additional unexposed person time in the baseline. Analyses were performed with all those with a diagnosis by the key visit date and also restricted to those with a diagnosis by July 2011. Adjustment for time period was made with calendar month of onset. Adjustment by age was not necessary as this was relatively stable within the study period.ResultsVaccine coverageWe extracted information on 160400 individuals aged 2 18 from the Royal College of General Practitioners database. Of these, 14400 (9.0%) were in a clinical risk group, mainly because of asthma. Table 1 gives the uptake of pandemic vaccine by August 2010 by age and risk group status and the estimated number of first doses given in England by this date, based on 2009 population estimates.19 The cumulative vaccine uptake by day, age, and risk status is consistent with the initial targeted vaccination of risk groups followed by all children aged under 5 (fig 1).Fig 1 Cumulative population uptake by day of pandemic A/H1N1 2009 influenza vaccine by age at September 2009 and risk group statusStudy casesReview of clinical recordsWe reviewed the clinical records in 245 cases identified by clinicians and/or from the hospital episode statistics database search at the 16 study centres. Although in all cases the diagnoses or hospital admission dates were after January 2008, we excluded 130 because onset of symptoms was before January 2008 and 23 because the diagnosis had not been confirmed by the sleep centre. This left 92 cases for independent review by the narcolepsy expert panel: in 10 there was insufficient information knock off turquoise van cleef necklace to assign a diagnosis, in three the date of diagnosis was after the key visit, three patients were outside the 4 18 age range, and in one the onset was before January 2008. Of the 75 remaining cases, 66 were definite according to the international classification of sleep disorders criteria (56 had narcolepsy with cataplexy and 10 had narcolepsy without cataplexy). The nine remaining were considered probable narcolepsy. Table 2 shows the demographic and clinical features in these 75 cases; in 55 cases the patients has received a diagnosis by July 2011.Table 2 Demographic and clinical features of 75 patients with narcolepsy in cases included in analysis according to ASO3 adjuvanted pandemic A/H1N1 2009 vaccinationView this table:View popupView inlineCases identified from hospital episode statisticsOf the 162 cases identified via this database in England, 130 were identified from the 16 study centres. Only 35 fitted our case definition and were included in the analysis. In the 95 excluded cases, 62 patients had onset before January 2008, and in 25 the diagnosis in the hospital episode statistics database was not confirmed by the study centre (case notes in eight such cases were not available for review). The remaining 32 cases identified from hospital episode statistics were in centres that had not reported cases or were cases at non centre hospitals; these 32 cases were distributed as follows: two hospitals had four cases each, two had three cases each, and 18 had single cases.Vaccination historyWe obtained vaccination history and risk group status in all 75 study cases; none of the patients with a diagnosis of probable narcolepsy was vaccinated (table 2). Of the 11 definite cases in which the patient had previously received pandemic vaccine, six had onset within three months, one within three to six months, and four between seven and 14 months after vaccination; all had received Pandemrix and age at vaccination ranged between 3 and 16. Figure 2 shows the 75 cases by month of symptom onset and whether they had previously receieved vaccine, together with vaccine uptake. The vaccinated patient with onset in 2011 received Pandemrix in 2011, when residual stocks were used instead of seasonal vaccine.20 Two were reported to have an influenza like illness in the six months before first symptoms, neither of whom was vaccinated.Case coverage analysisTable 3 shows the results of the case coverage analysis for patients who had received a diagnosis by July 2011 and by the key study visit with and without adjustment for risk group status. Odds ratios were significantly increased in all analyses; odds ratios without matching on risk group status were generally higher as were those based on date of onset of symptoms. The odds ratio with symptom onset as the index date and with the assumption that all vaccinated patients were in a risk group was 5.0 (1.3 to 19.3) for vaccination within six months and 3.3 (1.2 to 8.7) for "vaccinated at any time," while increasing coverage by a relative 20% gave a risk group adjusted odds ratio of 13.0 (2.5 to 68.3) for vaccination within six months and 11.5 (3.4 to 39.2) for "vaccinated at any time."Table 3 Case coverage analysis in patients with narcolepsy showing odds ratios for receipt of ASO3 adjuvanted pandemic A/H1N1 2009 vaccine before narcolepsy using different index dates, follow up periods, and risk intervalsView this table:View popupView inlineSelf controlled case series analysisOnly 18 cases diagnosed by the key visit had onset of symptoms between October 2009 and December 2010, of whom seven were unvaccinated, one was vaccinated after onset, and 10 were vaccinated before onset (five within 84 days, six within 182 days, four more than 182 days before). Restriction of cases to those diagnosed by July 2011 excluded four unvaccinated cases and one case vaccinated more than 182 days before onset. Starting the observation period from October 2008 added another 22 unvaccinated cases and two more cases vaccinated after onset. Relative incidence estimates were only significantly raised when we included the period from October 2008 in the baseline (table 4).

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