Elsevier

Sleep Medicine Reviews

Volume 38, April 2018, Pages 177-186
Sleep Medicine Reviews

Clinical Review
Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis

https://doi.org/10.1016/j.smrv.2017.06.006Get rights and content

Summary

An increased incidence of narcolepsy was seen in many countries after the pandemic H1N1 influenza vaccination campaign in 2009–2010. The H1N1 vaccine – narcolepsy connection is based on observational studies that are prone to various biases, e.g., confounding by H1N1 infection, and ascertainment, recall and selection biases. A direct pathogenic link has, however, remained elusive. We conducted a systematic review and meta-analysis to analyze the magnitude of H1N1 vaccination related risk and to examine if there was any association with H1N1 infection itself. We searched all articles from PubMed, Web of Science and Scopus, and other relevant sources reporting the incidence and risk of post-vaccine narcolepsy. In our paper, we show that the risk appears to be limited to only one vaccine (Pandemrix®). During the first year after vaccination, the relative risk of narcolepsy was increased 5 to 14-fold in children and adolescents and 2 to 7-fold in adults. The vaccine attributable risk in children and adolescents was around 1 per 18,400 vaccine doses. Studies from Finland and Sweden also appear to demonstrate an extended risk of narcolepsy into the second year following vaccination, but such conclusions should be interpreted with a word of caution due to possible biases. Benefits of immunization outweigh the risk of vaccination-associated narcolepsy, which remains a rare disease.

Introduction

Narcolepsy is a complex chronic hypersomnia syndrome affecting approximately 20–50 per 100,000 persons [1], [2], [3], [4]. The previously reported estimated incidence is approximately 1 per 100,000 persons per year with the peak of onset at the 2nd decade [4], [5], [6]. Two distinct disease categories can be distinguished. Narcolepsy type 1 (NT1) is likely caused by an autoimmune-mediated destruction of hypocretin-producing neurons in the lateral hypothalamus [7], [8]. NT1 is almost always associated with cataplexy. In narcolepsy type 2 (NT2), there is no hypocretin deficiency or cataplexy.

An increased incidence of narcolepsy was observed in six European countries after the pandemic influenza A virus, A(H1N1)pdm09 (“swine flu”), vaccination campaign during the winter 2009–2010. The first signal was observed in Finland and Sweden, followed by France, England, Ireland, and Norway – all the countries where AS03-adjuvanted pandemic vaccine Pandemrix (GlaxoSmithKline Biologicals, Wavre, Belgium) was widely used ∗[9], ∗[10], ∗[11], ∗[12], ∗[13], ∗[14], [15]. In the European Union and European Economic Area (EU/EEA), three centrally and five nationally authorized vaccines were used with coverage of at least 46.2 million people [15]. Five vaccines had no adjuvant, two had MF59-adjuvant and one, Pandemrix, had AS03 adjuvant. Pandemrix was the most used vaccine (over 30.5 million people vaccinated) in Europe. In the United States, over 90 million doses of pandemic H1N1 vaccination were administered in 2009–2010, but no adjuvanted vaccines were used [16].

One particular problem with the observational studies is their proneness to various biases such as confounding by natural H1N1 infection, and ascertainment, recall and selection biases. For instance, a seasonal and temporary increase in the incidence of narcolepsy was also seen in China after the 2009–2010 pandemic influenza A virus without clear relation to any vaccine [17], [18], [19]. This implicates the possibility that the H1N1 virus per se could be a triggering factor for the development of narcolepsy at least in Asian population. Furthermore, it was recently reported that influenza virus is capable of damaging hypocretinergic neurons in immune-depleted mice causing a narcolepsy-resembling phenotype [20].

Narcolepsy has also been a rare, underdiagnosed disease with long delay between onset of symptoms and diagnosis [21]. Therefore, the recognition of the syndrome may have been limited especially among primary health care practitioners before increased media attention after H1N1-related cases. Simply an increase in attention towards this disease could lead to increase in the number of diagnosed cases without an actual rise in incidence. The methods in the observational studies are also somewhat heterogeneous. For example, incorrect case confirmation and inaccurate gathering of information on the symptom onset and vaccination date could cause ascertainment bias [22].

Even if observational studies could prove strong connection between vaccination and narcolepsy, the true causative relationship requires a pathogenic-proven link. However, specific biological mechanisms behind the vaccine-associated narcolepsy are still incompletely understood [8]. Some evidence exists on increased immune response against viral nucleoprotein in Pandemrix in subjects who have genetic predisposition to narcolepsy by HLA DQB1*06:02 allele [23].

Taken into account biological and epidemiological controversies in connection between narcolepsy, H1N1 influenza virus infections and vaccinations, we conducted a systematic review and meta-analysis to clarify the risk of narcolepsy associated with H1N1 vaccines and infections.

Section snippets

Literature search and selection criteria

We searched PubMed, Web of Science, and Scopus for all articles reporting incidence and risk of Pandemrix H1N1-vaccination-associated narcolepsy in November 2016 without a language restriction. The full search string was (narcolepsy[MeSH] or narcolepsy) AND (vaccines[MeSH] OR vaccination[MeSH] OR influenza[MeSH] or Pandemrix OR vaccines OR vaccination).

We also checked the references of all relevant studies and review articles to identify additional sources. Webpages of National Institute for

Included studies

Literature search resulted in 310 articles (Fig. 1) after removal of duplicate papers. Additional ten articles were included outside of the search as explained in the methods section ∗[12], [15], [25], [26], [27], [28], [29], [30], ∗[31], [32]. Seventy-five reviews were excluded, but their reference lists were examined to include any appropriate articles not retrieved in the literature search. After screening for the titles and abstracts, full texts of 78 articles were read. Forty-nine studies

Discussion

In this meta-analysis we found a 5- to 14-fold increase in incidence of narcolepsy in children and adolescents and a 3- to 7-fold increase in adults in the countries where Pandemrix vaccine was widely used in 2009–2010 (Finland, France, Ireland, the Netherlands, Norway, Sweden and the UK). The risk in the observational studies is dependent on the used index date. Use of onset of symptoms as index date produced the highest risk followed by date of healthcare contact, referral to sleep studies,

Conflicts of interest

Dr. Dauvilliers reports personal fees from UCB, Bioprojet, Jazz, Theranexus, and Actelion, outside of the submitted work. Dr. Partinen reports grants from Academy of Finland and personal fees from UCB, GSK, Leiras-Pharma, MSD, and Orion, outside of the submitted work. Dr. Alakuijala reports no disclosures.

Acknowledgements

We thank Eric Burns for language editing. Dr. Sarkanen reports grants from the Finnish Medical Foundation during conduct of the study.

References (65)

  • N.A. Halsey et al.

    The safety of influenza vaccines in children: an Institute for Vaccine Safety white paper

    Vaccine

    (2015)
  • W.J. Kim et al.

    Incidence of narcolepsy before and after MF59-adjuvanted influenza A(H1N1)pdm09 vaccination in South Korean soldiers

    Vaccine

    (2015)
  • N.L. McCarthy et al.

    Evaluating the safety of influenza vaccine using a claims-based health system

    Vaccine

    (2013)
  • T. Sarkanen et al.

    Clinical course of H1N1-vaccine-related narcolepsy

    Sleep Med

    (2016)
  • F.S. Dawood et al.

    Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study

    Lancet Inf Dis

    (2012)
  • C. Hublin et al.

    The prevalence of narcolepsy: an epidemiological study of the Finnish twin cohort

    Ann Neurol

    (1994)
  • W.T. Longstreth et al.

    The epidemiology of narcolepsy

    Sleep

    (2007)
  • M.H. Silber et al.

    The epidemiology of narcolepsy in Olmsted county, Minnesota: a population-based study

    Sleep

    (2002)
  • C. Peyron et al.

    A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains

    Nat Med

    (2000)
  • H. Nohynek et al.

    AS03 adjuvanted H1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland

    PLoS One

    (2012)
  • E. Miller et al.

    Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis

    BMJ

    (2013)
  • Medical Products Agency. Occurrence of narcolepsy with cataplexy among children and adolescents in relation to the H1N1...
  • Y. Dauvilliers et al.

    Post-H1N1 narcolepsy-cataplexy

    Sleep

    (2010)
  • D. O'Flanagan et al.

    Investigation of an association between onset of narcolepsy and vaccination with pandemic influenza vaccine, Ireland April 2009-December 2010

    Euro Surveill

    (2014)
  • European Centre for Disease Prevention and Control. Narcolepsy in association with pandemic influenza vaccination (a...
  • Centers for Disease Control and Prevention. Final estimates for 2009–10 seasonal influenza and influenza A (H1N1) 2009...
  • F. Han et al.

    Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China

    Ann Neurol

    (2011)
  • F. Han et al.

    Decreased incidence of childhood narcolepsy 2 years after the 2009 H1N1 winter flu pandemic

    Ann Neurol

    (2013)
  • C. Tesoriero et al.

    H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep-wake regulatory neurons in mice

    Proc Natl Acad Sci U S A

    (2016)
  • G. Luca et al.

    Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study

    J Sleep Res

    (2013)
  • O. Vaarala et al.

    Antigenic differences between AS03 adjuvanted influenza A(H1N1) pandemic vaccines: implications for Pandemrix-associated narcolepsy risk

    PLoS One

    (2014)
  • Investigation of an increase in the incidence of narcolepsy in children and adolescents in 2009 and 2010-final report...
  • Cited by (0)

    The most important references are denoted by an asterisk.

    View full text