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Vol. 292 No. 20, November 24, 2004
Guillain-Barr? Syndrome Following Influenza Vaccination
Penina Haber, MPH; Frank DeStefano, MD, MPH; Fredrick J. Angulo, DVM, PhD; John Iskander, MD, MPH; Sean V. Shadomy, DVM, MPH; Eric Weintraub, MPH; Robert T. Chen, MD, MA
JAMA. 2004;292:2478-2481.
ABSTRACT
Context An unexplained increase in the risk of Guillain-Barr? syndrome (GBS) occurred among recipients of the swine influenza vaccine in 1976-1977. Guillain-Barr? syndrome remains the most frequent neurological condition reported after influenza vaccination to the Vaccine Adverse Events Reporting System (VAERS) since its inception in 1990.
Objective To evaluate trends of reports to VAERS of GBS following influenza vaccination in adults.
Design, Setting, and Participants VAERS is the US national spontaneous reporting system for adverse events following vaccination. Reports of GBS in persons 18 years or older following influenza vaccination were evaluated for each influenza season from July 1, 1990, through June 30, 2003. The number of people vaccinated was estimated from the National Health Interview Survey and US census data. Beginning in 1994, active follow-up was conducted to verify GBS diagnosis and obtain other clinical details.
Main Outcome Measure Reporting rates of GBS following influenza vaccination over time.
Results From July 1990 through June 2003, VAERS received 501 reports of GBS following influenza vaccination in adults. The median onset interval (13 days) was longer than that of non-GBS reports of adverse events after influenza vaccine (1 day) (P<.001). The annual reporting rate decreased 4-fold from a high of 0.17 per 100 000 vaccinees in 1993-1994 to 0.04 in 2002-2003 (P<.001). A GBS diagnosis was confirmed in 82% of reports. Preceding illness within 4 weeks of vaccination was identified in 24% of reported cases.
Conclusions From 1990 to 2003, VAERS reporting rates of GBS after influenza vaccination decreased. The long onset interval and low prevalence of other preexisting illnesses are consistent with a possible causal association between GBS and influenza vaccine. These findings require additional research, which can lead to a fuller understanding of the causes of GBS and its possible relationship with influenza vaccine.
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COMMENT
Since the inception of VAERS in 1990, we have observed extensive variability in reporting rates of GBS after influenza vaccination but most notably a marked decline since the 1996-1997 season. This pattern was not observed with non-GBS reports. Possible explanations for these findings include changes in vaccine coverage, reporting artifacts, general decline in GBS overall, or changes in the influenza vaccine that could be causally related to GBS.
Influenza vaccination coverage in adults increased 2-fold from 1988-1989 to 1999-2000 among healthy adults and high-risk persons older than 18 years.21 If younger people who are at decreased risk for GBS were being vaccinated, it could have resulted in decreased reporting rates of GBS after influenza vaccination. This is not a likely explanation for our findings, however, since we found decreases in GBS reporting rates in all age groups and we adjusted the annual rates for age.
Like all passive surveillance systems, VAERS is subject to underreporting, differential reporting, and variability in report quality and completeness.22 Reporting to VAERS is more likely when the adverse event is severe or occurs shortly after vaccination, the vaccine is newly introduced, and when there has been publicity about a vaccine adverse event.16-17,23-24 We tried to address concerns about the quality of the VAERS data by performing a follow-up study in which we were able to confirm a diagnosis of GBS in 82% of the reports, and analyses restricted to confirmed reports did not alter our findings. We also found similar results in a subanalysis restricted to cases with onset less than 6 weeks following vaccination and thus more likely to have been causally related to vaccination. We do not think that diminishing awareness of GBS following influenza vaccination is a likely explanation of our findings because a major study that found an increased risk of GBS following influenza vaccination was published in 1998.13 Moreover, reporting of non-GBS adverse events after influenza vaccination did not decrease over time.
At least 2 of our findings suggest that many of the reports to VAERS of GBS following influenza vaccination were not entirely coincidental. First, the reported onset interval differed for GBS reports compared with other influenza vaccine VAERS reports (Figure 3). Second, the relatively low prevalence of antecedent illness in our study (24%) was similar to the findings of the swine flu investigations (33% in vaccinated cases compared with 62% in unvaccinated cases). During the swine flu investigations, the markedly lower proportion of vaccinated compared with unvaccinated cases with a history of a recent illness provided strong evidence for a causal relationship between influenza vaccination and GBS, suggesting that vaccine replaced acute illness as a trigger of GBS.2
The significant decrease in GBS hospital discharges in the general population from 1997 through 2001 in the Nationwide Inpatient Sample suggests that the decrease in GBS reports to VAERS may be due at least in part to a general decline in the background rate of GBS. This is unlikely to be the only explanation since the decline in GBS reports to VAERS following influenza vaccination after 1996 (60%) was much steeper than the corresponding decline in Nationwide Inpatient Sample GBS hospital discharge rates (20%). However, both of these decreases may be related.
Influenza vaccines have traditionally been made in chicken eggs, and Campylobacter is an endemic infection among chickens and a known cause of GBS.25-26 The Food-borne Diseases Active Surveillance Network (FoodNet) has found that from 1996 to 2003, laboratory-confirmed Campylobacter infections in humans decreased 28% in the United States due to enhanced food safety interventions.27 Interestingly, 1996-1997 is also when both the decline in GBS reports to VAERS and GBS hospitalizations in the Nationwide Inpatient Sample began. These data raise intriguing questions about whether GBS among influenza vaccinees may be related to Campylobacter infection. Additional research to unravel this possibility may lead to a fuller understanding of the causes of GBS and its possible relationship with influenza vaccine.
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