Risk of Narcolepsy Associated with Inactivated Adjuvanted (AS03) A/H1N1 (2009) Pandemic Influenza Vaccine in Quebec

<div><p>Context</p><p>An association between an adjuvanted (AS03) A/H1N1 pandemic vaccine and narcolepsy has been reported in Europe.</p><p>Objective</p><p>To assess narcolepsy risk following administration of a similar vaccine in Quebec.</p><p>Design</p><p>Retrospective population-based study.</p><p>Setting</p><p>Neurologists and lung specialists in the province were invited to report narcolepsy cases to a single reference centre.</p><p>Population</p><p>Patients were interviewed by two sleep experts and standard diagnostic tests were performed. Immunization status was verified in the provincial pandemic influenza vaccination registry.</p><p>Main Outcome Measures</p><p>Confirmed narcolepsy with or without cataplexy with onset of excessive daytime sleepiness between January 1^st, 2009, and December 31^st, 2010. Relative risks (RRs) were calculated using a Poisson model in a cohort analysis, by a self-controlled case series (SCCS) and a case-control method.</p><p>Results</p><p>A total of 24 cases were included and overall incidence rate was 1.5 per million person-years. A cluster of 7 cases was observed among vaccinated persons in the winter 2009–2010. In the primary cohort analysis, 16-week post-vaccination RR was 4.32 (95% CI: 1.50–11.12). RR was 2.07 (0.70–6.17) in the SCCS, and 1.48 (0.37–7.03) using the case-control method. Estimates were lower when observation was restricted to the period of pandemic influenza circulation, and tended to be higher in persons <20 years old and for cataplexy cases.</p><p>Conclusions</p><p>Results are compatible with an excess risk of approximately one case per million vaccine doses, mainly in persons less than 20 years of age. However, a confounding effect of the influenza infection cannot be ruled out.</p></div

Risk of narcolepsy ± narcolepsy associated with A/H1N1 (2009) vaccination using the cohort method according to observation period and post-vaccination risk period, in Quebec, 2009–2010.

<p><i>+: Cases with onset after vaccination during risk period; E−: Cases not vaccinated or with onset before vaccination or after end of risk period.</i></p><p><i>*Primary analysis defined a priori.</i></p><p>Risk of narcolepsy ± narcolepsy associated with A/H1N1 (2009) vaccination using the cohort method according to observation period and post-vaccination risk period, in Quebec, 2009–2010.</p

Risk of narcolepsy ± narcolepsy associated with A/H1N1 (2009) vaccination using the ‘self-controlled case-series method’ according to age and diagnostic classification, in the province of Quebec, 2009–2010.

<p>Risk of narcolepsy ± narcolepsy associated with A/H1N1 (2009) vaccination using the ‘self-controlled case-series method’ according to age and diagnostic classification, in the province of Quebec, 2009–2010.</p

Additional file 2: of Evolution of severe sleep-wake cycle disturbances following traumatic brain injury: a case study in both acute and subacute phases post-injury

Raw actigraphy data of the second hospital stay, comprising activity counts and sleep/wake scoring per one-min epoch. (XLSX 348 kb

Distribution of 24 narcolepsy cases according to exposure status and patients’ characteristics.

<p>*Fisher exact test for proportions and Wilcoxon rank test for medians.</p><p>Distribution of 24 narcolepsy cases according to exposure status and patients’ characteristics.</p

Sample collections.

*<p>Numbers of samples by country of origin are listed in the <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003270#s3" target="_blank">Methods</a> section.</p><p>Case cohort names represent location of genotyping, and do not reflect country of origin of samples.</p

Association signal at the mapping intervals flanking rs34593439 and rs7553711.

<p>Association scores at 15q25.1 (panel A) and 1q25.1 (panel B). Genotyped (diamonds) and imputed (circles) SNPs are indicated and the top genotyped SNP in the interval is outlined in orange. A SNP in 15q25.1 previously associated with Diabetes is outlined in blue. The degree of red color in each diamond or circle indicates the strength of LD with the top SNP (on a scale shown in the legend at the upper left hand corner of the plot). The X-axis shows the chromosome and physical distance (kb) from the human genome reference sequence (hg19), the left Y-axis shows the negative base ten logarithm of the p-value and the right Y-axis shows recombination rate (cM/Mb) as a navy line. The genome-wide significance threshold (P<5×10⁻⁸) is given by the dashed grey line. Genes in the regions are annotated at the bottom as green arrows. Also indicated in 1q25.1 is a ∼130 kb region with no SNPs on the ImmunoChip.</p

Non-HLA narcolepsy risk variant loci reaching genome-wide significance.

<p>Chr.: Chromosome; BP: position according to NCBI build 36 (Hg18) coordinates; MAF_N: minor allele frequency in narcolepsy (_N) and controls (_C); P: P value according to variance component model (EMMAX). EMMAX does not provide OR (Odds Ratio) or adjusted allele frequencies, therefore MAF, OR, and 95% confidence intervals (CI) were calculated with Plink on subset of 8,474 samples with the greatest PCA homogeneity (see Figure S2; EV 11.21<0.004, EV 4.12<0.01).</p

Manhattan Plot of association statistics.

<p>The significance threshold used (blue line) was P = 5×10⁻⁸; The insets depict plots of 1) association results in a broad region encompassing the HLA locus (chr 6:24,067–35,474 kb) that were excluded from the present analysis (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003270#s3" target="_blank">Methods</a>) and 2) QQ plot of results for 109,777 markers after excluding a 1 Mb window surrounding the associated loci (λ = 1.004). The inflation statistic for all 111,240 tested markers is 1.04.</p