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Ask the Experts: Risk for Guillain–Barré syndrome with influenza vaccination

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Experts provide overview of Guillain–Barré syndrome (GBS), review GBS risk among influenza vaccines, and review immunization recommendations for patients’ with GBS.

As beneficial as vaccines are in reducing morbidity and mortality from vaccine-preventable illnesses, they are not without their risks. Most commonly, vaccines may cause local injection site reactions such as pain at the injection site, erythema, and sometimes a low-grade fever.1 These reactions are typically mild and do not involve much intervention. In contrast, Guillain-Barré Syndrome (GBS) is a less common but more severe condition in which the immune system can attack the nerves, potentially leading to peripheral neuropathy and progression to paralysis. With influenza season approaching, many concerns exist regarding the risk of GBS after initial vaccination and its recurrence after subsequent doses. This article provides an overview of GBS, review GBS risk among influenza vaccines, and review immunization recommendations for patients with GBS.

The all-cause incidence of GBS ranges from 0.4 to 4 cases per 100,000 per year, with a median of 1.3 cases annually.2 Further, the incidence of GBS appears to increase with age. In those younger than 30 years, less than 1 case of GBS occurs per 100,000, while in individuals older than 75 years, an estimated 4 cases per 100,000 occur per year.3,4 Studies also have consistently shown that men are 1.5 times more likely to develop GBS than women.4

Pain, numbness, paraesthesia, or weakness in the limbs are typically the first presenting symptoms, usually occurring within 12 days and, in children, pain often predominates.5 Additional signs and symptoms result from dysfunction of the autonomic nervous system and may include urinary retention, ileus, sinus tachycardia, hypertension, dysrhythmia, and postural hypotension. Muscle wasting occurs in more severe cases after approximately 2 weeks while the severity of the disease reaches its plateau by approximately 4 weeks. Full recovery may take weeks to months and begins with a return of proximal strength followed by distal strength.4 Several subtypes of GBS have been identified, including acute inflammatory demyelinating polyradiculoneuropathy, which is the most common form of GBS in the United States and predominantly causes peripheral neuropathy. Less common subtypes of GBS include acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, and Fisher syndrome, which causes ophthalmoplegia, areflexia, and ataxia.3,4 Overall, within 1 year following the development of GBS, up to 20% of patients experience some form of disability following the resolution of GBS and between 4% and 15% of patients die.3,4,6

GBS is hypothesized to be an immune-mediated disorder that results from the generation of autoantibodies that attack peripheral nerves, subsequently leading to demyelination of axons, axonal damage by toxic enzymes and radicals, and/or blockage of signal conduction.4 In turn, a loss of skeletal and cranial nerve–innervated muscle tone develop.3 Autoantibodies may form in response to a bacterial or viral illness, and approximately two-thirds of GBS cases are preceded by either a respiratory or gastrointestinal infection. Campylobacter jejuni is the most frequent cause of gastrointestinal infections that result in GBS; however, the specific infectious agent often is not identified and usually resolves before neurological symptoms develop.2 Other pathogens that have been associated with GBS include cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, Mycoplasma pneumoniae, HIV, influenza virus, and vaccinia virus.2,3

GBS also may result from vaccination, as vaccines stimulate the immune system to produce antigen-specific antibodies through a humoral and/or cellular immune process. Several mechanisms have been theorized to help explain why vaccines may cause GBS. The first is the concept of "molecular mimicry," whereby the vaccine’s antigen is mistaken as a host antigen and an autoimmune process subsequently develops.3 Alternatively, damage to the axon or myelin sheath could be caused directly by the vaccine or by excipients within the vaccine as a result of the dose or degree of antigenicity of the vaccine. A genetic predisposition to the development of an autoimmune process leading to GBS also has been proposed.3,6,7

GBS became a national concern after the 1976 influenza vaccination program. In 1976, there was an H1N1 outbreak in which 40 million doses of vaccine were distributed. Following this vaccination campaign, 532 cases of GBS occurred within 6 weeks. The rate of GBS after vaccination was determined to be 7.2 cases per million recipients worldwide compared with 0.79 cases per million in unvaccinated people.8,9 In the 2003 Immunization Safety Review, the Institute of Medicine concluded that the evidence favored a casual relationship between the 1976 influenza vaccine and GBS in adults.10 Although subsequent studies have confirmed this relationship, a casual link with influenza vaccine formulations from later years has not been found.3,8

In an analysis of the Vaccine Adverse Event Reporting System (VAERS) database from 1991 to 1999, 382 cases of GBS were reported following influenza vaccination with a median onset of 12 days postvaccination. Compared with the tetanus–diphtheria vaccine, the mean incidence of GBS was statistically greater following influenza vaccination (9.5 vs. 2.2 cases/10 million). For each year examined by the study, the percentage of association between influenza vaccination and GBS remained above 67% while the relative and attributable risks remained above 2 and 1, respectively.5 Another study analyzing VAERS data from 1990 to 2005 found that the incidence of GBS following influenza vaccination in those 18 years or older was 0.7 per 1 million individuals (range of influenza vaccine administered: 24–71 million doses).11 VAERS, however, has several limitations because, by design, it is a passive surveillance system. Therefore, underreporting, differential reporting, stimulated reporting, reporting of coincidental events, and variability in report quality and completeness may occur for practitioners using the VAERS. VAERS also does not collect data on how many doses of vaccine are administered, so determining the actual rate of an adverse event such as GBS is difficult.12

Despite the limitations of VAERS data, an evaluation of influenza vaccination in the Medicare program also showed no association between the vaccine and GBS during the 2000–01 influenza season.13 Surveillance of the 2009 H1N1 monovalent vaccine revealed an excess of 0.8 cases of GBS per 1 million individuals compared with unvaccinated persons; however, this rate of GBS is similar to that found with other seasonal influenza vaccines. Further, of the 326 cases of GBS identified in this study between October and May 2009, only 27 had documentation of having received the 2009 H1N1 vaccine, 16 of which had antecedent illness in the 42 days preceeding GBS onset.14

The Guillain-Barré Syndrome Support Group determined that the highest risk for the recurrence of GBS for patients who had already developed and recovered from GBS were in those who received influenza, tetanus, or typhoid vaccines (Table 1).15 Overall, the risk of recurrence requiring treatment or hospitalization was reported to be 1.18%.15 A similar study conducted by the Dutch Society of Neuromuscular Disorders found that 9 of 245 individuals (3.7%) who reported having GBS previously had recurrent GBS post–influenza vaccination.16

Table 1. Frequency of relapse of GBS following various immunizationsa
Vaccine No. patients with GBS No. (%) relapse
Influenza 211 8 (3.8)
Tetanus 105 6 (5.7)
Typhoid 50 3 (60)
Polio 42 4 (9.5)
Hepatitis A 37 3 (8.1)
Hepatitis B 20 1 (5.0)
Rabies 1 0
Pneumococcal 15 0
Bacillus Calmette-Guerin 8 2 (25.0)
Yellow fever 12 2 (16.7)
Meningococcal 16 1 (6.2)
Cholera 5 0
Rubella 5 0
Diptheria 5 2 (40.0)
Measles 2 0
Smallpox 2 0
Mumps 1 0

Legend: aSome patients received more than one vaccine.  |  Modified from Table 1 in reference 15.

Although GBS has been reported after influenza immunization in a variety of studies (Table 2), some ambiguity remains regarding its association with this outcome. For patients who have a past history of GBS, their risk for vaccine-associated GBS is higher than that for patients without such history; however, their risk of recurrence remains very low. The Advisory Committee on Immunization Practices recommends against influenza vaccination for all patients with a history of GBS within 6 weeks.17 For all other patient with history of GBS beyond this time frame, the decision to vaccinate must be preceded by a benefit–risk assessment. In most cases, the benefits that vaccination confers far outweigh any risks; however, these decisions need to be made on a case-by-case basis and may change depending on the particular patient. In the case of GBS, the immunizing pharmacist should refer to their vaccination protocol for guidance, as some protocols may suggest administering the influenza vaccine under strong precaution, while others may stipulate that the patient be referred to their physician for evaluation prior to vaccination.
 

Table 2. Incidence of GBS among influenza vaccines
Reference number Year(s) of influenza vaccine Incidence of GBS
9 H1N1 1976 7.2 cases per 1 million vaccinated recipients compared with 0.79 cases per million in unvaccinated people
5 1991–99 9.5 per 10 million influenza vaccination compared with 2.2 per 10 million tetanus–diphtheria vaccination
11 1990–2005 0.7 per million influenza vaccination
13 2000–01 Incident risk ratio for combined years was 1.04, 0.86 among people vaccinated in 2000, and 1.21 among people vaccinated in 2001.
14 H1N1 2009 An excess of 0.8 cases per 1 million individuals compared with unvaccinated person; however, this rate of GBS is similar to that found with seasonal influenza vaccine

Legend: Modified from Table 1 in article reference 15.

Karl Hess, PharmD, FCPhA
Assistant Professor of Pharmacy Practice and Administration

Christal Pham, PharmD
Community Pharmacy Practice Resident

College of Pharmacy
Western University of Health Sciences
Pomona, CA

References

  1. CDC. Basic and common questions: possible sideseffects from vaccines. Accessed at www.cdc.gov/vaccines/vac-gen/side-effects.htm, December 14, 2010.
  2. Hughes R, Rees J. Clinical and epidemiologic features of Guillain-Barré syndrome. J Infect Dis. 1997;176(suppl 2):S92–8.
  3. Haber P, Sejvar J, Mikaeloff Y, DeStefano F. Vaccines and Guillain-Barré syndrome. Drug Saf. 2009;32:309–23.
  4. Hughes R, Cornblath D. Guillain-Barré syndrome. Lancet. 2005;366:1653–66.
  5. Geier M, Geier D, Zahalsky A. Influenza vaccine and Guillain-Barré syndrome. Clin Immunol. 2003;107:116–21.
  6. Souayah N, Nasar A, Suri MF, Qureshi AI. Guillain-Barré syndrome after vaccination in United States: data from the Centers for Disease Control and Prevention/Food and Drug Administration Vaccine Adverse Event Reporting System (1990-2005). J Clin Neuromuscul Dis. 2009;11(1):1–6.
  7. Shoenfeld Y, Aron-Maor A. Vaccination and autoimmunity: "vaccinosis": a dangerous liaison? J Autoimmun. 2000;14(1):1–10.
  8. Lehmann HC, Hartung HP, Kieseier BC, Hughes RA. Guillain–Barré syndrome after exposure to influenza virus. Lancet Infect Dis. 2010;10:643–51.
  9. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barré syndrome following vaccination in the National Influenza Immunization Program, United States, 1976–1977. Am J Epidemiol. 1979;110:105–23.
  10. Institute of Medicine. Immunization safety review: influenza vaccines and neurological complications. Accessed at www.iom.edu/Reports/2003/Immunization-Safety-Review-Influenza-Vaccines-and-Neurological-Complications.aspx, August 17, 2011.
  11. Vellozzi C, Burwen DR, Dobardzic, et al. Safety of trivalent inactivated influenza vaccines in adults: background for pandemic infleunza vaccine safety monitoring. Vaccine. 2009;27:2114–20.
  12. Department of Health & Human Services. About the VAERS program. Accessed at http://vaers.hhs.gov/about/index, August 18, 2011.
  13. Burwen DR, Ball R, Bryan WW, et al. Evaluation of Guillain–Barré syndrome among recipients of influenza vaccine in 2000 and 2001. Am J Prev Med. 2010;39:296–304.
  14. CDC. Preliminary results: surveillence for Guillain-Barré syndrome after receipt of influenza A (H1N1) 2009 monovalent vaccine: United States, 2009-2010. MMWR Morb Mortal Wkly Rep. 2010;59:657–61.
  15. Pritchard J, Mukherjee R, Hughes RA. Risk of relapse of Guillain-Barré syndrome or chronic inflamatory demyelinating polyradiculoneuropathy following immunisation. J Neurol Neurosurg Psychiatry. 2002;73:348–9.
  16. Kuitwaard K, Bos-Eyseen ME, Blomkwist-Markens P, Van Doorn PA. Recurrences, vaccinations and long-term symptoms in GBS and CIDP. J Peripher Nerv Syst. 2009;14:310–5.
  17. Fiore AE, Uyeki TM, Broder K, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep. 2010;59(RR-8):1–62.

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