77 Incidence Peaks and the Role of Influenza In our study, we observed a notably adverse relationship between NT1 incidence and preceding H3N2 influenza season severity. Influenza strains are recognized for their competitive circulation in each influenza season, a process mediated by the speed of genetic recombination of individual strains, the lingering antibody titres from the last circulation of a specific influenza strain. Partial or cross-immunity between influenza type A (H1N1 and H3N2) and type B (Victoria and Yamagata) also contributes to these effects [170172]. This interplay of factors typically results in the dominance of one or two influenza strains during each season [173]. Within this competitive environment it seems logical that there is less space for influenza strains that could trigger NT1 when non-triggering influenza strains are dominant in a particular year. Therefore, we hypothesize that the negative correlation with H3N2 influenza season severity could be a protective phenomenon for other (possibly NT1inducing) influenza strains. NT1 incidence fluctuations so far seemed more pronounced in children. Using complete incidence data from seven European countries we have now also uncovered that there has been a significant peak in adult-onset NT1 in 2010 following the pH1N1. This suggests that Pandemrix vaccination and/or type A H1N1 influenza infection could also trigger NT1 in genetically susceptible adults. Similar findings have been reported by Dauvilliers et al. [134]. The 2010 adult-onset NT1 peak was not identified in most earlier studies which could be related to the relatively smaller magnitude of the 2010-peak in adults, and the increased awareness that primarily focused on child-onset NT1 following the pH1N1 [135, 174]. Pandemrix was also mainly used in younger age groups and a relationship with type A H1N1 influenza infection was only suggested later [135, 175]. We are the first to identify incidence fluctuations in NT2 and IH with peaks in 2010 in children and in 2013 in adults. The 2010 peak in children remained present in our sensitivity analyses (excluding HLA DQB1*06:02 positive individuals and during permutation test), suggesting this peak is not due to misdiagnosis of people with NT1 or dependent on statistical methods. Our results suggest an influence of annually fluctuating external factors similar to NT1. Using the same sample from the Netherlands, we have recently uncovered that individuals with NT2 and IH also regularly report respiratory infections close to onset of their excessive daytime sleepiness [163]. Together with the significantly positive relationship with preceding type A H1N1 influenza season severity, this suggests that a trigger-related immunological basis underlying NT2 and IH pathophysiology should be seriously considered, and warrants future investigations [163]. Media attention for EDS after Pandemrix-associated 3
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