Review
Guillain-Barré syndrome after exposure to influenza virus

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Summary

Guillain-Barré syndrome (GBS) is an acute, acquired, monophasic autoimmune disorder of peripheral nerves that develops in susceptible individuals after infection and, in rare cases, after immunisation. Exposure to influenza via infection or vaccination has been associated with GBS. We review the relation between GBS and these routes of exposure. Epidemiological studies have shown that, except for the 1976 US national immunisation programme against swine-origin influenza A H1N1 subtype A/NJ/76, influenza vaccine has probably not caused GBS or, if it has, rates have been extremely low (less than one case per million vaccine recipients). By contrast, influenza-like illnesses seem to be relevant triggering events for GBS. The concerns about the risk of inducing GBS in mass immunisation programmes against H1N1 2009 do not, therefore, seem justified by the available epidemiological data. However, the experiences from the 1976 swine flu vaccination programme emphasise the importance for active and passive surveillance to monitor vaccine safety.

Introduction

Infection with influenza virus affects a substantial proportion of the worldwide population each year.1, 2, 3 In 2009, the perceived global threat of influenza reached an exceptional level after the emergence of a novel swine-origin influenza A H1N1 (so-called swine flu, subtype H1N1 2009), which was first isolated in local outbreaks in Mexico, Canada, and the USA.4 The subsequent rapid global spread of this strain and concerns about its possible virulence led national and global health authorities to initiate countermeasures in early 2009, by means of mass immunisation programmes in several countries, including the USA and countries of the European Union. These vaccination campaigns were the cornerstone of public health measures to prevent the undesired consequences of a pandemic. They also served as a reminder (at least to the neurological community) of the 1976 national influenza immunisation programme against swine flu subtype A/NJ/76 in the USA, which was stopped because of the emergence of Guillain-Barré syndrome (GBS) in vaccine recipients.5 GBS after vaccination is rare, and most studies have concluded that it is a chance event except in the 1976 programme. However, the small size of vaccine safety trials before licensing, the testing and licensing of vaccines for potential pandemic diseases before the start of the pandemic (so-called mock-up licensing), and the very low incidence of GBS mean that data could be insufficient to assess the risk reliably.6 Conventional vaccine safety monitoring after licensing does not entirely eradicate this concern.

By contrast with vaccination, evidence is increasing that influenza infection and influenza-like illnesses can act as triggers for GBS. This important fact, which has been highlighted in epidemiological studies,7, 8 seems to be underappreciated in public and professional advisory interpretations of influenza vaccine adverse event data and subsequent risk–benefit assessments. The establishment of background rates for GBS will be very useful in this regard; this information has already been provided for several countries.1

We believe that, in addition to the prevention of multiple non-neurological diseases by influenza vaccination, awareness and correct interpretation of all available data about the relation of GBS, influenza infection, and influenza vaccination are a prerequisite for an objective risk–benefit analysis of current and future influenza vaccination campaigns. We review the existing data derived from studies about GBS after influenza infection and GBS after exposure to influenza vaccine. We also summarise the current information about the plausibility of influenza immunisation as a biological cause of GBS.

Section snippets

GBS

GBS is an acute, acquired, monophasic peripheral neuropathy.9, 10 It is now one of the most common acute paralytic neuromuscular disorders and is associated with substantial mortality and morbidity.11 GBS has various subtypes that can be distinguished by electrophysiological and pathological criteria. The most common form (90–95% of cases) in Europe and North America is acute inflammatory demyelinating polyradiculoneuropathy, which is characterised by demyelinating changes that involve cellular

Virology and vaccination of influenza

Influenza viruses are RNA viruses that belong to the family Orthomyxoviridae. Three types of influenza viruses are known (A, B, and C) of which A and B cause seasonal epidemics.3 Influenza A is classified into different serotypes on the basis of epitope differences in two main types of envelope glycoproteins: haemagglutinin and neuraminidase. 15 haemagglutinin subtypes (H1–H15) and nine neuraminidase subtypes (N1–N9) are known. Influenza A strains that established stable lineage in humans

Polyneuritis during the influenza pandemic of 1918–20

The influenza pandemic of 1918–20 (so-called Spanish influenza) was the most devastating in recorded history, affecting 25–40% of the worldwide population and causing between 15 million and 40 million deaths.63, 64, 65 The pandemic was caused by an abnormally virulent strain of H1N1 influenza A virus and spread in several waves from the USA to Europe and other regions of the world. Data from old serum banks have shown that the influenza outbreaks were caused by an antigenic shift and subsequent

1976 US national influenza immunisation programme

In 1976, US health authorities initiated a mass immunisation programme against H1N1 influenza strain A/NJ/76 to prevent an anticipated epidemic after an outbreak among US Army recruits in Fort Dix, NJ, USA.2, 90 The programme was launched to immunise the entire adult population in the USA, but was suspended prematurely after reports of GBS among vaccine recipients.2, 5, 91 Between Oct 1 and Dec 16, 1976, 40 million doses of the vaccine were distributed. In the same period a total of 532 cases

Conclusion

Although mass immunisation programmes against H1N1 2009 have finished in many countries, vaccine safety remains a concern for patients, carers, health authorities, and the public. The relation between GBS, influenza vaccine, and influenza infection is of special interest, owing to the negative experiences that were gained more than 30 years ago during the mass immunisation for swine influenza in the USA and informal media reports from the USA and France of suspected GBS after H1N1 2009

Search strategy and selection criteria

References for this review were identified through searches of PubMed for articles published from January, 1971, to June, 2010, by use of the terms “Guillain-Barré syndrome”, “influenza”, “H1N1”, “immunization”, and “vaccination”. Relevant articles published between 1918 and 1920 were identified through searches in the authors' personal files, in Google Scholar, and Springer Online Archives Collection. Articles resulting from these searches and relevant references cited in those articles

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