EDITORIAL
Influenza vaccines and Guillain-Barré syndrome The continuing question
James J. Sejvar, MD
Correspondence to Dr. Sejvar: [email protected] Neurology® 2013;81:1562–1563
Influenza is a global public health problem, with complications of seasonal influenza resulting in thousands of deaths and substantial morbidity worldwide. Periodically, particularly virulent viral strains emerge, resulting in more infections and fatalities (e.g., influenza A [H1N1] virus and influenza A/H5N1, “bird flu”). Influenza infection may be prevented or mitigated by vaccination; seasonal vaccine is highly effective in reducing clinical illness and limiting viral spread through respiratory droplets. Various vaccines are occasionally associated with adverse events (AEs), but AEs following influenza vaccine may raise particular concern among health care providers and patients. In 1976, the emergence of a swineorigin influenza A/H1N1 virus, antigenically similar to the virus responsible for the catastrophic 1918 “swine flu” pandemic, prompted concerns about a similar pandemic. A national immunization program was immediately initiated in the United States to mitigate the possibility, and over an 11-week period more than 45 million people received the vaccine. The feared pandemic never materialized; however, vaccine safety surveillance suggested a higher than expected incidence of Guillain-Barré syndrome (GBS) among vaccinees. A subsequent thorough investigation demonstrated that recipients of the swine influenza vaccine were over 7 times more likely to develop GBS within the first 6 weeks following vaccination than non-vaccinees1; overall, slightly less than 1 excess case of GBS per 100,000 vaccines. Although numerous epidemiologic studies suggested causality, the underlying reason for this association remains unknown. The association of the 1976 influenza vaccine with GBS led to concern about the potential risk of subsequent seasonal influenza vaccines. Seasonal influenza vaccines are reformulated each year to cover the most predominant circulating strains of virus. Between 1977 and 2011, at least 10 published assessments of the risk of GBS following influenza vaccines were conducted.2 The study methodologies were sound but differed; each had varying limitations. Of 10 studies, 4 suggested a small increase in risk of GBS following administration of various formulations of influenza
vaccine, with relative risks ranging from 1.45 to 2.35 (or estimated attributable risks of between 0.06 and 0.16 per 100,000 vaccinations), a magnitude lower than with the 1976 influenza vaccine.3 By contrast, several studies have suggested an increased risk of GBS following natural influenza virus infection, particularly influenza A, a risk greater than that seen following seasonal influenza vaccination.4–6 Another study suggested that influenza vaccination might in fact be protective against development of GBS, presumably on the basis of reduction of risk of illness.7 Given the limitations of all these assessments, one could argue that the absolute magnitude of risk of GBS following either influenza virus infection or influenza vaccine has yet to be quantified in a robust manner. However, the preponderance of data suggests that the risk of developing GBS following influenza vaccination is low, particularly in comparison to the morbidity and mortality caused by influenza itself, particularly in high-risk groups such as children, the elderly, and immunocompromised persons. A related question that often arises is that of the risk of GBS recurrence following influenza vaccination in someone who has already experienced an episode of GBS. Data on recurrence risk are extremely limited, but the risk appears to be low. A survey conducted among members of a GBS patient organization in the United Kingdom contacted 927 patients with GBS and asked them to complete a questionnaire about their initial illness, subsequent immunizations, and recurrence of symptoms suggestive of GBS in the 6 weeks following immunizations.8 Of these 927 patients with GBS, 311 reported vaccinations subsequent to their initial illness; 11 (3.5%) reported recurrence of symptoms such as weakness and fatigue. Of the 29 patients with GBS who received a vaccination within 6 weeks of their initial GBS illness, 2 (6.9%, 95% confidence interval 0.85–22.8) reported a recurrence of symptoms following receipt of a vaccine different from that associated with their first episode of GBS. The authors acknowledge the limitations of study selection bias (patients experiencing symptoms may be more likely to participate in the survey) and drawing conclusions from
From the Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the author, if any, are provided at the end of the editorial. 1562
© 2013 American Academy of Neurology
ª"NFSJDBO"DBEFNZPG/FVSPMPHZ6OBVUIPSJ[FESFQSPEVDUJPOPGUIJTBSUJDMFJTQSPIJCJUFE
self-assessments, both possibly overestimating the frequency of relapse. A more recent assessment of risk of GBS relapse following any vaccination, using data from a large hospital database, similarly concluded that risk of recurrence of GBS following influenza vaccination is low; among 107 persons with a history of GBS, no recurrences were noted following receipt of 405 doses of trivalent seasonal influenza vaccine.9 However, since the vaccine-related risk of GBS with the 1976 formulation or subsequent seasonal influenza vaccine formulations is so low, the small sample sizes preclude a definitive risk assessment. The current guidelines from the US Centers for Disease Control and Prevention regarding influenza vaccines list a history of GBS within 6 weeks of previous influenza vaccine as a “precaution” for receipt of subsequent influenza vaccine (http://www.cdc.gov/vaccines/recs/provisional/ downloads/influenza-feb-2009-508.pdf). So, what is the clinician to do? Overall, the preponderance of evidence suggests that, with the exception of the 1976 vaccine, the risk of developing GBS following seasonal influenza vaccine is extremely low; indeed, even in 1976, had an influenza pandemic actually occurred, it is likely that the comparative risk of morbidity from vaccine-associated GBS would have been exceedingly small in comparison to the morbidity and mortality associated with influenza itself. The decision to vaccinate may warrant a discussion between health care provider and patient, and particularly among persons who have had GBS, as the fear of a relapse is real and understandable. However, the benefits of influenza vaccination, based on current evidence, are apparent, and important to consider as we approach the upcoming influenza season. Morbidity and mortality from influenza illness far outweigh the risk of developing GBS following vaccination, particularly among groups at high risk for complications from influenza.
STUDY FUNDING No targeted funding reported.
DISCLOSURE J. Sejvar is an employee of the US Government. The material reported in this manuscript does not necessarily reflect the opinions of the US Centers for Disease Control and Prevention or the US Department of Health and Human Services. The author reports no disclosures. Go to Neurology.org for full disclosures.
REFERENCES 1. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976–1977. Am J Epidemiol 1979;110:105–123. 2. Sejvar JJ, Pfeifer D, Schonberger LB. Guillain-barre syndrome following influenza vaccination: causal or coincidental? Curr Infect Dis Rep 2011;13:387–398. 3. Salmon DA, Proschan M, Forshee R, et al. Association between Guillain-Barre syndrome and influenza A(H1N1) 2009 monovalent inactivated vaccines in the USA: a metaanalysis. Lancet 2013;381:1461–1468. 4. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. GuillainBarre syndrome and influenza virus infection. Clin Infect Dis 2009;48:48–56. 5. Greene SK, Rett MD, Vellozzi C, et al. Guillain-Barre syndrome, Influenza Vaccination, and Antecedent Respiratory and Gastrointestinal Infections: A Case-Centered Analysis in the Vaccine Safety Datalink, 2009–2011. PloS One 2013;8(6):e67815. 6. Verity C, Stellitano L, Winstone AM, et al. Guillain-Barre syndrome and H1N1 influenza vaccine in UK children. Lancet 2011;378:1545–1546. 7. Tam CC, O’Brien SJ, Rodrigues LC. Influenza, Campylobacter and Mycoplasma infections, and hospital admissions for Guillain-Barre syndrome, England Emerg Infect Dis 2006;12:1880–1887. 8. Pritchard J, Mukherjee R, Hughes RA. Risk of relapse of Guillain-Barre syndrome or chronic inflammatory demyelinating polyradiculoneuropathy following immunisation. J Neurol Neurosurg Psychiatry 2002;73:348–349. 9. Baxter R, Lewis N, Bakshi N, et al. Recurrent GuillainBarre syndrome following vaccination. Clin Infect Dis 2012;54:800–804.
Neurology 81
October 29, 2013
1563
ª"NFSJDBO"DBEFNZPG/FVSPMPHZ6OBVUIPSJ[FESFQSPEVDUJPOPGUIJTBSUJDMFJTQSPIJCJUFE
Influenza vaccines and Guillain-Barré syndrome The continuing question
James J. Sejvar, MD
Correspondence to Dr. Sejvar: [email protected] Neurology® 2013;81:1562–1563
Influenza is a global public health problem, with complications of seasonal influenza resulting in thousands of deaths and substantial morbidity worldwide. Periodically, particularly virulent viral strains emerge, resulting in more infections and fatalities (e.g., influenza A [H1N1] virus and influenza A/H5N1, “bird flu”). Influenza infection may be prevented or mitigated by vaccination; seasonal vaccine is highly effective in reducing clinical illness and limiting viral spread through respiratory droplets. Various vaccines are occasionally associated with adverse events (AEs), but AEs following influenza vaccine may raise particular concern among health care providers and patients. In 1976, the emergence of a swineorigin influenza A/H1N1 virus, antigenically similar to the virus responsible for the catastrophic 1918 “swine flu” pandemic, prompted concerns about a similar pandemic. A national immunization program was immediately initiated in the United States to mitigate the possibility, and over an 11-week period more than 45 million people received the vaccine. The feared pandemic never materialized; however, vaccine safety surveillance suggested a higher than expected incidence of Guillain-Barré syndrome (GBS) among vaccinees. A subsequent thorough investigation demonstrated that recipients of the swine influenza vaccine were over 7 times more likely to develop GBS within the first 6 weeks following vaccination than non-vaccinees1; overall, slightly less than 1 excess case of GBS per 100,000 vaccines. Although numerous epidemiologic studies suggested causality, the underlying reason for this association remains unknown. The association of the 1976 influenza vaccine with GBS led to concern about the potential risk of subsequent seasonal influenza vaccines. Seasonal influenza vaccines are reformulated each year to cover the most predominant circulating strains of virus. Between 1977 and 2011, at least 10 published assessments of the risk of GBS following influenza vaccines were conducted.2 The study methodologies were sound but differed; each had varying limitations. Of 10 studies, 4 suggested a small increase in risk of GBS following administration of various formulations of influenza
vaccine, with relative risks ranging from 1.45 to 2.35 (or estimated attributable risks of between 0.06 and 0.16 per 100,000 vaccinations), a magnitude lower than with the 1976 influenza vaccine.3 By contrast, several studies have suggested an increased risk of GBS following natural influenza virus infection, particularly influenza A, a risk greater than that seen following seasonal influenza vaccination.4–6 Another study suggested that influenza vaccination might in fact be protective against development of GBS, presumably on the basis of reduction of risk of illness.7 Given the limitations of all these assessments, one could argue that the absolute magnitude of risk of GBS following either influenza virus infection or influenza vaccine has yet to be quantified in a robust manner. However, the preponderance of data suggests that the risk of developing GBS following influenza vaccination is low, particularly in comparison to the morbidity and mortality caused by influenza itself, particularly in high-risk groups such as children, the elderly, and immunocompromised persons. A related question that often arises is that of the risk of GBS recurrence following influenza vaccination in someone who has already experienced an episode of GBS. Data on recurrence risk are extremely limited, but the risk appears to be low. A survey conducted among members of a GBS patient organization in the United Kingdom contacted 927 patients with GBS and asked them to complete a questionnaire about their initial illness, subsequent immunizations, and recurrence of symptoms suggestive of GBS in the 6 weeks following immunizations.8 Of these 927 patients with GBS, 311 reported vaccinations subsequent to their initial illness; 11 (3.5%) reported recurrence of symptoms such as weakness and fatigue. Of the 29 patients with GBS who received a vaccination within 6 weeks of their initial GBS illness, 2 (6.9%, 95% confidence interval 0.85–22.8) reported a recurrence of symptoms following receipt of a vaccine different from that associated with their first episode of GBS. The authors acknowledge the limitations of study selection bias (patients experiencing symptoms may be more likely to participate in the survey) and drawing conclusions from
From the Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the author, if any, are provided at the end of the editorial. 1562
© 2013 American Academy of Neurology
ª"NFSJDBO"DBEFNZPG/FVSPMPHZ6OBVUIPSJ[FESFQSPEVDUJPOPGUIJTBSUJDMFJTQSPIJCJUFE
self-assessments, both possibly overestimating the frequency of relapse. A more recent assessment of risk of GBS relapse following any vaccination, using data from a large hospital database, similarly concluded that risk of recurrence of GBS following influenza vaccination is low; among 107 persons with a history of GBS, no recurrences were noted following receipt of 405 doses of trivalent seasonal influenza vaccine.9 However, since the vaccine-related risk of GBS with the 1976 formulation or subsequent seasonal influenza vaccine formulations is so low, the small sample sizes preclude a definitive risk assessment. The current guidelines from the US Centers for Disease Control and Prevention regarding influenza vaccines list a history of GBS within 6 weeks of previous influenza vaccine as a “precaution” for receipt of subsequent influenza vaccine (http://www.cdc.gov/vaccines/recs/provisional/ downloads/influenza-feb-2009-508.pdf). So, what is the clinician to do? Overall, the preponderance of evidence suggests that, with the exception of the 1976 vaccine, the risk of developing GBS following seasonal influenza vaccine is extremely low; indeed, even in 1976, had an influenza pandemic actually occurred, it is likely that the comparative risk of morbidity from vaccine-associated GBS would have been exceedingly small in comparison to the morbidity and mortality associated with influenza itself. The decision to vaccinate may warrant a discussion between health care provider and patient, and particularly among persons who have had GBS, as the fear of a relapse is real and understandable. However, the benefits of influenza vaccination, based on current evidence, are apparent, and important to consider as we approach the upcoming influenza season. Morbidity and mortality from influenza illness far outweigh the risk of developing GBS following vaccination, particularly among groups at high risk for complications from influenza.
STUDY FUNDING No targeted funding reported.
DISCLOSURE J. Sejvar is an employee of the US Government. The material reported in this manuscript does not necessarily reflect the opinions of the US Centers for Disease Control and Prevention or the US Department of Health and Human Services. The author reports no disclosures. Go to Neurology.org for full disclosures.
REFERENCES 1. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976–1977. Am J Epidemiol 1979;110:105–123. 2. Sejvar JJ, Pfeifer D, Schonberger LB. Guillain-barre syndrome following influenza vaccination: causal or coincidental? Curr Infect Dis Rep 2011;13:387–398. 3. Salmon DA, Proschan M, Forshee R, et al. Association between Guillain-Barre syndrome and influenza A(H1N1) 2009 monovalent inactivated vaccines in the USA: a metaanalysis. Lancet 2013;381:1461–1468. 4. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. GuillainBarre syndrome and influenza virus infection. Clin Infect Dis 2009;48:48–56. 5. Greene SK, Rett MD, Vellozzi C, et al. Guillain-Barre syndrome, Influenza Vaccination, and Antecedent Respiratory and Gastrointestinal Infections: A Case-Centered Analysis in the Vaccine Safety Datalink, 2009–2011. PloS One 2013;8(6):e67815. 6. Verity C, Stellitano L, Winstone AM, et al. Guillain-Barre syndrome and H1N1 influenza vaccine in UK children. Lancet 2011;378:1545–1546. 7. Tam CC, O’Brien SJ, Rodrigues LC. Influenza, Campylobacter and Mycoplasma infections, and hospital admissions for Guillain-Barre syndrome, England Emerg Infect Dis 2006;12:1880–1887. 8. Pritchard J, Mukherjee R, Hughes RA. Risk of relapse of Guillain-Barre syndrome or chronic inflammatory demyelinating polyradiculoneuropathy following immunisation. J Neurol Neurosurg Psychiatry 2002;73:348–349. 9. Baxter R, Lewis N, Bakshi N, et al. Recurrent GuillainBarre syndrome following vaccination. Clin Infect Dis 2012;54:800–804.
Neurology 81
October 29, 2013
1563
ª"NFSJDBO"DBEFNZPG/FVSPMPHZ6OBVUIPSJ[FESFQSPEVDUJPOPGUIJTBSUJDMFJTQSPIJCJUFE
