Influenza vaccination and Guillain-Barré syndrome In their Comment, Lucija Tomljenovic and Yehuda Shoenfeld1 raise doubts about the results presented by Jeﬀrey Kwong and colleagues2 about the risk of Guillain-Barré syndrome after seasonal influenza vaccination. They claim that a risk interval of 6 weeks after immunisation could introduce a type II error bias in the analysis of a possible association between vaccination and Guillain-Barré syndrome. The authors cite two studies in support of their claim: a case-control study3 and a case report.4 The casecontrol study focused on the risk of CNS demyelination in childhood after hepatitis B immunisation; the investigators reported an increased risk associated with exposure to one brand of the hepatitis B vaccine more than 3 years before the onset of the disease.3 However, according to the Global Advisory Committee on Vaccine Safety,5 some methodological limitations affected the results of the study, which therefore did not provide convincing evidence that hepatitis B vaccination, or any brand of the vaccine, is associated with CNS demyelination. The patient described in the case report 4 received the A/New Jersey/1976/H1N1 vaccine on Nov 17, 1976. From mid-December, 1976, he had a range of neurological symptoms (eg, paraesthesia of the hands and feet) and difficulty in performing some common tasks (eg, climbing stairs, walking, and running). On Aug 19, 1977, he had an enteric infection and 3 days later developed a polyneuropathy. According to the investigators, 1 month after vaccination the patient had a progressive but unrecognised Guillain-Barré syndrome, which was subsequently exacerbated by an enteric infection. Although interesting, this observation does not 368
constitute conclusive evidence that the commonly accepted 6 weeks’ risk interval could be inadequate. About two-thirds of patients with Guillain-Barré syndrome have had an infection within 6 weeks before syndrome onset. Campylobacter jejuni, Mycoplasma pneumoniae, and several viral infections (including influenza, cytomegalovirus, and Epstein-Barr virus) have been identified as possible triggers of the disease.6 During an extended period an individual can acquire several infections, some of which might be undetected; therefore, expanding the risk interval might bias the results. A long latency between immunisation and onset of GuillainBarré syndrome makes it impossible to rule out other causes. The Brighton Collaboration GBS Working Group highlighted that the biological plausibility of an association of Guillain-Barré syndrome with an infection or a vaccination inevitably decreases beyond 6 weeks. 6 The Comment by Tomljenovic and Shoenfeld is insuﬃciently supported by evidence and could therefore be misleading. I have received travel grants from Pfizer, Novartis, Sanofi Pasteur, and GlaxoSmithKline for scientific meetings.
Franco Giovanetti [email protected]
Azienda Sanitaria Locale CN2 Alba Bra, Dipartimento di Prevenzione, via Vida 10, 12051 Alba, Italy 1 2
Tomljenovic L, Shoenfeld Y. Association between vaccination and Guillain-Barré syndrome. Lancet Infect Dis 2013; 13: 730–31. Kwong JC, Vasa PP, Campitelli, MA, et al. Risk of Guillain-Barré syndrome after seasonal influenza vaccination and influenza healthcare encounters: a self-controlled study. Lancet Infect Dis 2013; 13: 769–76. Mikaeloﬀ Y, Caridade G, Suissa S, Tardieu M. Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood. Neurology 2009; 72: 873–80. Poser CM, Behan PO. Late onset of Guillain-Barré syndrome. J Neuroimmunol 1982; 3: 27–41. Global Advisory Committee on Vaccine Safety: response to the paper (in press) by Y. Mikaeloﬀ and colleagues in Neurology entitled “Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood”, October 2008. http://www.who. int/vaccine_safety/committee/topics/ hepatitisb/multiple_sclerosis/oct_2008/en/ (accessed Sept 27, 2013).
Sejvar JJ, Kohl KS, Gidudu J et al. Guillain-Barré syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine 2011; 29: 599–612.
In their Comment, Lucija Tomljenovic and Yehuda Shoenfeld1 propose a lengthening of the latency period between vaccine exposure and onset of Guillain-Barré syndrome from the epidemiologically proven time interval of about 6 weeks to an interval of months or years. However, their references do not support their conclusions. In a referenced article, Mikaeloff and colleagues2 discussed hepatitis B vaccination and CNS demyelination. The 3 year study period seems to be based on another study, and not on a specific biological model. Furthermore, this study did not involve the influenza vaccine or peripheral nervous system. In another publication, Mikaeloff 3 identified the interval between infection and Guillain-Barré syndrome onset as days to weeks, not months to years. In a 31-year-old article, Poser and Behan4 hypothesised that GuillainBarré syndrome might have a late onset weeks to months after a trigger. They proposed an initial subclinical course or smouldering, mild clinical evolution with so-called bridging symptoms of pain, paraesthesia, and weakness followed by an acute exacerbation after a secondary infection. However, this clinical scenario and the case described are consistent with a diﬀerent diagnosis, chronic inflammatory demyelinating polyneuropathy, not Guillain-Barré syndrome. Guillain-Barré syndrome is a monophasic illness with a clinical nadir within 4 weeks of onset and gradual improvement, whereas chronic inflammatory demyelinating polyneuropathy has an onset phase of more than 8 weeks and a waxing and waning course.5 The article also needs to be interpreted with the knowledge that the Institute of Medicine stated that case reports about influenza www.thelancet.com/infection Vol 14 May 2014
vaccine and Guillain-Barré syndrome, including this one, are “uninformative with respect to causality”6 and that it was published when the first author was an expert witness in lawsuits about Guillain-Barré syndrome and vaccines.7 Tomljenovic and Shoenfeld identify acute disseminated encephalomyelitis as a demyelinating neuropathy. In fact, it is a monophasic demyelinating syndrome affecting the brain and spinal cord, not the peripheral nerves, with onset days to weeks after an immunological challenge.8 Furthermore, they use the term “advanced Guillain-Barré syndrome”, which has no neurological relevance in the context of the paragraph and appears to be a poor rephrasing of Poser and Behan’s term “acute, clinical Guillain-Barré syndrome”. With the absence of support from and an apparent misinterpretation of their cited medical literature, Tomljenovic and Shoenfeld should reconsider their conclusions. They hypothesise about the timing of the immunological event preceding Guillain-Barré syndrome. They must be careful not to give their speculation any credibility until there is proven and reproducible research to support it. I have received money for expert testimony from the US Department of Health and Human Services Vaccine Injury Compensation Program.
Max Wiznitzer [email protected]
Rainbow Babies & Childrens Hospital, Case Western Reserve University School of Medicine, Cleveland, OH, USA 1 2
3 4 5
Tomljenovic L, Shoenfeld Y. Association between vaccination and Guillain-Barré syndrome. Lancet Infect Dis 2013; 13: 730–31. Mikaeloﬀ Y, Caridade G, Suissa S, Tardieu M. Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood. Neurology 2009; 72: 873–80. Haber P, Sejvar J, Mikaeloﬀ Y, DeStefano F. Vaccines and Guillain-Barré syndrome. Drug Saf 2009; 32: 309–23. Poser CM, Behan PO. Late onset of Guillain-Barré syndrome. J Neuroimmunol 1982; 3: 27–41. Sejvar JJ, Kohl KS, Gidudu J, et al. Guillain-Barré syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine 2011; 29: 599–612.
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National Research Council. Immunization safety review: influenza vaccines and neurological complications. Washington, DC: The National Academies Press, 2004: 44. United States Court of Federal Claims. Catherine Irene Corder vs Secretary of the Department of Health and Human Services. Oﬃce of Special Masters No 08-228V; May 31, 2011: 47. http://www.uscfc.uscourts.gov/sites/ default/files/opinions/MILLMAN. CORDER053111.pdf (accessed April 3, 2014). Sonneville R, Klein IF, Wolﬀ M. Update on investigation and management of postinfectious encephalitis. Curr Opin Neurol 2010; 23: 300–04.
In their Comment, Lucija Tomljenovic and Yehuda Shoenfeld1 question the results of our self-controlled study,2 which demonstrated that the risk of Guillain-Barré syndrome is higher after influenza infection than after seasonal influenza vaccination. The first concern they raise is that the 6 week risk window could miss cases with longer latency periods. Citing a review article 3 from more than three decades ago that described a few cases of Guillain-Barré syndrome diagnosed 4–10 months after a suspected exposure—during which time other infections associated with Guillain-Barré syndrome could have occurred—they suggest that we might have underestimated the association between influenza vaccination and Guillain-Barré syndrome by using a 6 week interval. Although our study cannot exclude the possibility of delayed-onset Guillain-Barré syndrome, one would expect that such a phenomenon would occur among both individuals who received influenza vaccination and those who had influenza illness. However, no appreciable evidence of late-onset Guillain-Barré syndrome between 16 weeks and 40 weeks (roughly 4–10 months) after influenza is evident in our data (figure). Furthermore, their suggestion that “vaccination could be more detrimental to the recipient than the infections” would require a very complex model involving lower risk from vaccination in the immediate period and higher risk in the later period, which is inconsistent
with both our reported data and the observation in the cited article3 that late-onset Guillain-Barré syndrome is generally milder. Although we agree with the need to keep an open mind about the timing of adverse events after vaccination, we believe that a 6 week risk window for GuillainBarré syndrome after exposure is an evidence-based choice. Their second concern is the identification of three times more cases of Guillain-Barré syndrome in the influenza vaccine group than in the influenza illness group in our study. Tomljenovic and Shoenfeld imply that this diﬀerence means that Guillain-Barré syndrome is more likely after vaccination than after illness. They have not understood the self-controlled methodology. In fact, comparing the frequency of events between two exposure groups is inappropriate in a selfcontrolled design. In our study, the larger number of cases in the vaccine group was merely a reflection that many more people receive influenza vaccines than have laboratoryconfirmed influenza. The purpose of a self-controlled analysis is not to compare the numbers of events between two populations, but rather to assess temporal clustering of events after an exposure. Our study compared the rates of temporal clustering between two different exposures and found it to be much greater after influenza illness than after influenza vaccination. Concerns about safety are often cited as reasons to avoid vaccination, especially for influenza vaccines. Our study used sound methods to compare the risk of Guillain-Barré syndrome after influenza vaccine and influenza illness and facilitates decision making about these competing risks. AJM reports receiving an investigator-initiated research grant from, and participating in a sponsored clinical trial of a Clostridium diﬃcile vaccine developed by, Sanofi Pasteur, and participating in a sponsored clinical trial of an antiviral medication and participating in an