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
Influenza vaccination Influenza-coded health-care encounter
Cases of Guillain-Barré syndrome
45 40 35 30 25 20 15 10 5 0
* * * * ** *
2 3 4 5 6 7
* * **
* * ** * * *
* * * **
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Weeks to Guillain-Barré syndrome from influenza vaccination or influenza-coded health-care encounter
Figure: Number of cases of Guillain-Barré syndrome by week after receipt of influenza vaccine and after an influenza-coded health-care encounter *Five or fewer admissions for Guillain-Barré syndrome; because of a contractual agreement with the data provider, numbers of five or fewer cannot be reported.
advisory board for GlaxoSmithKline. The other authors declare that they have no competing interests.
*Jeﬀrey C Kwong, Natasha S Crowcroft, Kumanan Wilson, Allison J McGeer, Shelley L Deeks jeﬀ[email protected]
Institute for Clinical Evaluative Sciences, Toronto, ON M4N 3M5, Canada (JCK, KW); Department of Family and Community Medicine, Toronto, ON, Canada (JCK); Dalla Lana School of Public Health (JCK, NSC, AJM, SLD) and Department of Laboratory Medicine and Pathobiology (NSC, AJM), University of Toronto, Toronto, ON, Canada; Department of Medicine, Ottawa Hospital Research Institute (KW) and Department of Epidemiology & Community Medicine (KW), University of Ottawa, Ottawa, ON, Canada; and Public Health Ontario, Toronto, ON, Canada (JCK, NSC, SLD) 1
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 health-care encounters: a selfcontrolled study. Lancet Infect Dis 2013; 13: 769–76. Poser CM, Behan PO. Late onset of Guillain-Barré syndrome. J Neuroimmunol 1982; 3: 27–41.
Access to antifungal medicines in resource-poor countries We read with great interest the Personal View by Angela Loyse and colleagues1 about improving access to essential antifungal medicines for cryptococcal meningitis in resourcepoor countries. It is an interesting compilation of existing information about the availability of various drugs to treat of systemic fungal infections, especially cryptococcal meningitis in patients with HIV/ AIDS in resource-limited settings. The authors cite our article 2 about lipid-formulation amphotericin B (Fungisome [Lifecare Innovations, India]). We tested doses of 1 mg/kg per day and 3 mg/kg per day (not 5 mg/kg per day as stated in the print article, now corrected online) in patients with HIV/AIDS and cryptococcal meningitis. The dose of 1 mg/kg per
day ultimately was as eﬀective as the dose of 3 mg/kg per day, reducing the cost of treatment compared with other international brands and increasing the affordability of the drug for poor people in developing countries. This formulation has been developed by Delhi University, GS Medical College, and KEM Hospital, Mumbai, with funding from Department of Biotechnology of the Government of India, and has been tested and is in clinical use at a dose of 1mg/kg per day in India. 3,4 The drug has the potential to be widely used and needs consideration for funding from various agencies (eg, WHO, key stakeholders, and other policy makers) for the benefit of the poor. NAK holds a patent from the Government of India Patent Oﬃce for an improved process for manufacturing a stable injectable, sterile synergistic amphotericin B formulation; no personal financial benefits or royalites are received from the patent. MPJ declares that he has no competing interests.
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