76 Chapter 3 severity. This effect was most pronounced in the Netherlands, where influenza type B Victoria was even more strongly correlated with NT1 incidence in children. Paediatric NT2 and IH incidence was significantly positively related to preceding type A H1N1 influenza season and negatively related to type A H3N2 influenza severity. Besides the significant relationship with type A H1N1 influenza, we identified a strong correlation between NT1 and influenza type B Victoria incidence rates. It is plausible that other infections have been responsible for triggering NT1 before the reintroduction of the type A H1N1 influenza virus in 2009. Streptococcal infections have previously been proposed but supporting evidence remains inconclusive [63-65, 67, 158]. Other flu strains are likely candidates for triggering NT1 and we here provide first epidemiological evidence that infection with influenza type B Victoria could be an important new suspect [61, 159]. Influenza type B Victoria has consistently circulated in the past century and is known to more frequently and heavily affect children compared to adults [161, 168]. This matches the typical adolescent onset of NT1 [54]. The 2013 NT1 incidence peak is more pronounced in children compared to the peak in 2010. When reviewing preceding flu season severity and influenza strain dominance, it is a possibility that the peak in 2010 was more frequently triggered by the type A H1N1 influenza virus, and the 2013 peak mainly by influenza type B Victoria. External testing of this hypothesis is possible when comparing recently published Chinese NT1 annual onset rates with preceding Chinese flu season severity from the WHO Global Influenza Programme [162, 165]. In China, there were relative NT1 child-onset incidence peaks in 2010, 2012 and 2014 and type B Victoria was notably among the dominant influenza strains in all three preceding flu seasons (compared to type A H1N1 that was not dominant in the 2011-2012 influenza season). Similar comparisons could not be performed for the United States where type B influenza is generally not subtyped [165]. Growing bodies of evidence indicate links between influenza infection and the onset of various other neurological disorders with a typical later disease onset, including Parkinson’s Disease, dementia, and multiple sclerosis [169]. Our findings fit the hypothesis that there is a limited pool of genetically susceptible individuals (that are HLA-DQB1*06:02 positive) who might develop NT1 after an immunological trigger (such as different flu strains, streptococcal infections, and Pandemrix vaccination). After an NT1 incidence peak, this pool of remaining susceptible individuals shrinks, and the NT1 incidence rate in the following year drops. A nuanced perspective is essential in approaching these hypotheses and further research is needed to establish any causal connections between NT1, immunological triggers, and type B Victoria influenza in particular.
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