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Cumulative Risk of Guillain–Barre´ Syndrome Among Vaccinated and Unvaccinated Populations During the 2009 H1N1 Influenza Pandemic Claudia Vellozzi, MD, MPH, Shahed Iqbal, PhD, MBBS, MPH, Brock Stewart, PhD, Jerome Tokars, MD, MPH, and Frank DeStefano, MD, MPH
Guillain---Barré syndrome (GBS) is an acute, monophasic, autoimmune neurologic disorder of the peripheral nerves characterized primarily by muscle weakness and loss of reflexes. Estimates of GBS incidence range from 0.8 to 1.9 cases per 100 000 person-years, are higher in males, and increase with age.1,2 Although the exact causes of GBS are unknown, they are thought to be triggered by antigenic stimulation resulting in demyelination and damage to the peripheral nerves.3,4 GBS has been shown to be associated with antecedent gastrointestinal or upper respiratory tract illnesses, including influenza.5---9 Rarely, GBS may follow vaccination.10---12 During the 1976 swine-origin influenza A pandemic, the risk of GBS was found to be increased by nearly 8 fold in the 6 weeks following receipt of the swine-origin influenza vaccine.11 After 1976, several studies have assessed the risk of GBS following seasonal inactivated influenza vaccines demonstrating either no increased risk or a small increased risk of approximately 1 to 2 additional GBS cases per 1 million vaccine doses administered.13,14 However, the 1976 GBS incident influenced the approach to the 2009 H1N1 vaccine safety monitoring efforts, and GBS became a primary focus of surveillance activities. The pandemic (H1N1) 2009 influenza virus began widespread circulation during the first half of the influenza season with illness peaking during October and November 2009.15 At the same time, influenza A (H1N1) 2009 monovalent vaccines (pH1N1 vaccines) became available in early October 200916 and were administered rapidly and broadly throughout the United States. During this time the United States and several countries worldwide implemented enhanced pH1N1 vaccine safety monitoring.17---19 Many programs have subsequently published their surveillance and evaluation findings for the risk of GBS during the
Objectives. We sought to assess risk of Guillain–Barre´ syndrome (GBS) among influenza A (H1N1) 2009 monovalent (pH1N1) vaccinated and unvaccinated populations at the end of the 2009 pandemic. Methods. We applied GBS surveillance data from a US population catchment area of 45 million from October 15, 2009, through May 31, 2010. GBS cases meeting Brighton Collaboration criteria were included. We calculated the incidence density ratio (IDR) among pH1N1 vaccinated and unvaccinated populations. We also estimated cumulative GBS risk using life table analysis. Additionally, we used vaccine coverage data and census population estimates to calculate denominators. Results. There were 392 GBS cases; 64 (16%) occurred after pH1N1vaccination. The vaccinated population had lower average risk (IDR = 0.83, 95% confidence interval = 0.63, 1.08) and lower cumulative risk (6.6 vs 9.2 cases per million persons, P = .012) of GBS. Conclusions. Our findings suggest that at the end of the influenza season cumulative GBS risk was less among the pH1N1vaccinated than the unvaccinated population, suggesting the benefit of vaccination as it relates to GBS. The observed potential protective effect on GBS attributed to vaccination warrants further study. (Am J Public Health. 2014;104:696–701. doi:10.2105/AJPH.2013. 301651)
6 weeks following the pH1N1 vaccine20---25; some but not all of the surveillance systems found a significant but small increased risk of GBS following pH1N1 vaccination. Most, however, were unable to adequately evaluate the potential confounding because of exposure to the pandemic (H1N1) 2009 influenza virus. Influenza and other respiratory illnesses have been associated with GBS,6---8,26,27 and it has been suggested that the absolute increase in risk of GBS is much higher after influenzalike illnesses (ILIs) than a potential increase in risk after vaccination.7,27 We hypothesized that the overall risk of GBS at the end of the 2009 influenza season (October 2009 through May 2010) may have been lower among the pH1N1 vaccinated population than the unvaccinated population. Surveillance for GBS using active-case finding through US Centers for Disease Control and Prevention’s (CDC’s) Emerging Infections Program (EIP) was implemented as part of enhanced pH1N1 vaccine
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safety monitoring activities25,28; we used these data to test our hypothesis. We evaluated the average and cumulative risk of incident GBS among those vaccinated with pH1N1 vaccine and those unvaccinated (did not receive pH1N1 vaccine) during the surveillance period of October 1, 2009, through May 31, 2010.
METHODS The EIP active surveillance for GBS started on October 1, 2009. However, because pH1N1 vaccines were not widely available during the first part of October, we restricted our analysis to October 15, 2009, through May 31, 2010. The data source and methodologies used are briefly described here. More detailed descriptions have been published previously.24,25
Data Source In 1995, CDC established the EIP in 10 sites (California [3 counties], Colorado [5 counties],
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Connecticut, Georgia [8 counties], Maryland, Minnesota, New Mexico, New York [excluding New York City], Oregon [3 counties], and Tennessee) for surveillance, prevention, and control of emerging infectious diseases. The EIP catchment area included nearly 45 million people who are representative of the US population in terms of age, gender, race, urban residence, population density, and percentage below poverty level. The EIP network is collaboration between local health departments, academic institutions, health care providers, public health and clinical laboratories, and federal agencies.29
Case Finding and Classification During the pH1N1 vaccination program, GBS cases were actively sought in the EIP catchment area during October 1, 2009, to May 31, 2010, primarily using a network of neurologists and other health care providers specifically established for this project. Hospital discharge data using International Statistical Classification of Diseases, Ninth Edition,30 code 357.0, were also reviewed periodically throughout and at the end of the surveillance period to capture cases possibly missed using the provider network. Trained surveillance officers reviewed medical records and used a standard form to abstract information on patient characteristics, onset date of symptoms, clinical presentation, and laboratory findings for suspected cases of GBS. A telephone questionnaire was also administered to persons with suspected GBS for additional clinical information and vaccination history. Surveillance officers classified cases according to Brighton Collaboration criteria,31 an international organization dedicated to vaccine safety and the development of adverse event case definitions.32 CDC subject matter experts reviewed complex cases; any unresolved case classification underwent further adjudication by a panel of 4 neurologists to make the final determination. Only confirmed (Brighton levels 1 and 2) and probable (Brighton level 3) GBS cases were included in the analysis.
Vaccination Records, Coverage, and Person-Time Calculation Dates of receipt of pH1N1 vaccine for the GBS cases were recorded from vaccination cards, vaccine registries, or providers
administering the vaccine, or via self-report (as recorded in the medical record or telephone interview) if a documented source was not available. We estimated the monthly pH1N1 vaccine coverage in the EIP catchment area by using survey data from the Behavioral Risk Factor Surveillance System (BRFSS) and the National 2009 H1N1 Flu Survey (NHFS). Previously published methods were used to combine monthly estimates from the 2 surveys.25,33 To calculate daily doses of pH1N1vaccine administered, monthly vaccine coverage data were multiplied by proportions of doses administered each day; we obtained daily vaccine data from a sample of private outpatient primary care provider offices in the EIP population compiled by SDI Health LLC (Plymouth Meeting, PA).25 SDI Health LLC obtains claims data from approximately 60% of outpatient primary care providers throughout the United States. We multiplied the total number of vaccine doses on a given date by the difference between that date and the end of the study period (i.e., May 31, 2010) to calculate person-time for those vaccinated with pH1N1 vaccine. Individuals contributed person-time to the unvaccinated group until they received vaccination, at which time they contributed to the vaccinated group.
Statistical Methods We first used incidence density methods to calculate the rates of GBS among the pH1N1 vaccinated and unvaccinated populations and estimate the incidence density ratios (IDR) overall and by different age groups (< 25 years, 25---64 years, ‡ 65 years); We used direct standardization method to calculate overall age adjusted rates for the vaccinated and unvaccinated groups. Exact binomial method was used to calculate 95% confidence intervals for the IDRs. The incidence density method measures the average rate of disease occurrence during a defined observation period. We also used life table analysis to calculate the cumulative probability of GBS risk for each day in the study period for the vaccinated versus unvaccinated groups. We then calculated the difference in the daily cumulative risks between the pH1N1 vaccinated and unvaccinated groups overall and by age groups (< 25 years, 25---64 years, ‡ 65 years). The life
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table analysis accounted for individuals being vaccinated and entering the vaccinated cohort at different times throughout the observation period to reconstruct cumulative risk measures according to vaccination status from the beginning to the end of the study period; the primary measure of interest was the difference in the cumulative proportion of GBS cases between the vaccinated and unvaccinated cohorts at the end of the observation period (i.e., May 31, 2010). We used bootstrapping methods to calculate 95% confidence intervals around the cumulative risks and to test the level of significance at .05 level.34 In addition, we used population estimates from US Census Bureau and vaccine coverage data to calculate the number of people in the vaccinated and unvaccinated groups. SAS version 9.3 (SAS Institute, Cary, NC) and R version 3.0.1 (Foundation for Statistical Computing, Vienna, Austria)34 were used for all analyses.
RESULTS A total of 707 suspected GBS cases were identified during the surveillance period between October 1, 2009, and May 31, 2010. After removing cases that did not meet Brighton case classification criteria (levels 1---3; n = 282; 40%) and cases with onset dates prior to October 15, 2009 (n = 33; 5%), 392 cases were included for this analysis; 84% met level 1 and 2 Brighton criteria. Sixty-four (16%) cases occurred at any time after pH1N1 vaccination. Most cases occurred among persons aged 25 to 64 years (Table 1). Slightly more than half of the cases (n = 34; 53%) following pH1N1 vaccination were among men. The incidence density rate of GBS for the entire period of surveillance among those vaccinated was found to be lower than among those who were not vaccinated (overall age-adjusted IDR = 0.83); this was consistent across all age categories; however, these associations were not statistically significant (Table 1). Figure 1 demonstrates the cumulative risk for the vaccinated and unvaccinated groups by date and for all ages combined using the life table analysis. The cumulative risk point estimates of GBS among the pH1N1vaccinated group were lower throughout the study period, however during a brief period (January through February) the risk was similar (but still
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TABLE 1—Frequency and Incidence Density Ratio of Guillain–Barre´ Syndrome Cases Among pH1N1 Vaccinated and Unvaccinated Population by Age Group: Emerging Infections Program Catchment Area, October 15, 2009—May 31, 2010 pH1N1 Vaccinated
Unvaccinated
Age, Years
Total Cases, No. (%)
No. Cases
No. PersonYearsa
Ratea
No. Cases
No. PersonYearsa
Ratea
IDR (95% CI)
< 25 25–64
60 (15.3) 232 (59.2)
14 35
25.75 26.74
0.54 1.31
46 197
68.47 126.73
0.67 1.55
0.81 (0.41, 1.50) 0.84 (0.57, 1.21)
‡ 65
100 (25.5)
15
6.27
2.39
85
28.70
2.96
0.81 (0.43, 1.41)
Overall
392 (100.0)
64
58.76
1.19b
328
223.90
1.43b
0.83 (0.63, 1.08)b
Note. CI = confidence interval; IDR = incidence density ratio; pH1N1 = influenza A (H1N1) 2009. The Emerging Infections Program includes 10 sites: California (3 counties), Colorado (5 counties), Connecticut, Georgia (8 counties), Maryland, Minnesota, New Mexico, New York (excluding New York City), Oregon (3 counties), and Tennessee. The sample size was n = 392. a 100 000 person-years. b Age-adjusted.
lower) to that of the unvaccinated group. The cumulative risk on the last day of the study period among the vaccinated group was significantly lower than that of the unvaccinated group (6.6 vs 9.2 cases per million persons, respectively; P = .012) for all ages, but not significantly different when stratified by the 3 age groups (< 25 years: P = .665; 25---64 years: P = .227; ‡ 65 years: P = .191; Table 2).
DISCUSSION
Rate/Million Persons
Using data from an active GBS case-finding surveillance program established during the 2009---2010 influenza season,25 our findings show that by the end of the surveillance period,
May 31, 2010, which coincided with the end of the influenza season, the cumulative risk of GBS ranked lower among the pH1N1 vaccinated population in the EIP catchment area compared with the unvaccinated population. This finding was consistent among all age groups. These differences may represent a protective effect of receipt of pH1N1 against pandemic (H1N1) 2009 influenza and the subsequent risk of GBS, contributing to an overall favorable benefit---risk profile of the vaccine. These findings are consistent with previous studies suggesting a protective effect of influenza vaccination on GBS, most likely attributed to the protection against influenza. In a case-control study from the United Kingdom
10 pH1N1 vaccinated Unvaccinated
8 6 4 2 0 Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Month Note. pH1N1 = influenza A (H1N1) 2009. The Emerging Infections Program includes 10 sites: California (3 counties), Colorado (5 counties), Connecticut, Georgia (8 counties), Maryland, Minnesota, New Mexico, New York (excluding New York City), Oregon (3 counties), and Tennessee.
FIGURE 1—Cumulative risk of Guillain–Barre´ among the pH1N1 vaccinated and unvaccinated groups by date and all ages combined: Emerging Infections Program catchment area, October 15, 2009—May 31, 2010.
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during 1991 to 2001, Tam et al. found a possible protective effect of influenza vaccination and GBS onset within 60 days of vaccination (odds ratio [OR] = 0.16; 95% confidence interval [CI] = 0.02, 1.25), yet the odds ratio for ILI was 18.64 (95% CI = 7.49, 46.37).7 In another study from the United Kingdom, Stowe et al. also demonstrated a similar protective association between influenza vaccine and GBS incidence within 30 days following vaccination (relative incidence [RI] = 0.58; 95% CI = 0.18, 1.86) and similar magnitude of association of GBS with ILI (RI = 16.6; 95% CI = 9.4, 29.5) using a self-controlled study design and data from 1990 to 2005.6 Our findings may have been more robust if the timing of vaccinations and influenza infections had been different during the H1N1 2009 pandemic. In the United States, vaccination coincided with peak influenza activity. Data from the World Health Organization and US surveillance systems showed the proportion of individuals testing positive for influenza A H1N1 peaked at 38.2% during the week ending October 24, 2009,15 and live attenuated and inactivated pH1N1 vaccines first became available October 5 and October 12, 2009, respectively.35 We found a similar pattern among the EIP catchment area for the timing of ILI and vaccine administration (Figure 2). Therefore much of the ILI was prior to or at the same time the pH1N1 vaccines became available and widely distributed. Furthermore, the pH1N1 vaccine likely provided good protection against pandemic (H1N1) 2009 virus, having been estimated to be 62% effective.36,37 With this effectiveness, if high vaccination coverage had been achieved prior to widespread influenza activity, more infections may have been prevented and consequently we may have observed a greater reduction in the cumulative incidence of GBS in the vaccinated population. The slightly higher cumulative GBS risk in the unvaccinated group demonstrated in this study may have been because of the high influenza activity of the pandemic with continued circulation of virus, albeit low, through May 2010 (Figure 2). A study in France during 1996 to 2004 evaluated the correlation of GBS with influenza-like illnesses and analyzed antiinfluenza antibodies; they found that GBS cases that were definitively linked to influenza were
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TABLE 2—Cumulative Risk of Guillain–Barre´ Syndrome on Last Day of Surveillance Among Unvaccinated and Vaccinated Groups, by Age Group: Emerging Infections Program Catchment Area, October 15, 2009—May 31, 2010 Differenceb Unvaccinated, Riska (95% CI)
pH1N1 Vaccinated, Riska (95% CI)
Riska (95% CI)
P
< 25
4.22 (3.07, 5.39)
3.69 (1.83, 5.91)
0.53 (–2.03, 2.85)
.655
25–64
9.73 (8.74, 10.71)
7.81 (5.28, 10.48)
1.92 (–1.19, 4.88)
.227
‡ 65 Overall
18.36 (14.92, 21.89) 9.16 (8.70, 9.61)
12.97 (6.55, 20.24) 6.58 (5.05, 8.24)
5.39 (–2.95, 12.82) 2.59 (0.56, 4.48)
.191 .012
Age, Years
Note. CI = confidence interval; pH1N1 = influenza A (H1N1) 2009. The Emerging Infections Program includes 10 sites: California (3 counties), Colorado (5 counties), Connecticut, Georgia (8 counties), Maryland, Minnesota, New Mexico, New York (excluding New York City), Oregon (3 counties), and Tennessee. a Per 1 000 000 persons. b Unvaccinated – vaccinated groups.
more likely to occur during seasons with high influenza activity.27 Previous studies using the EIP 2009---2010 GBS surveillance data reported an increased risk of GBS within 6 weeks following pH1N1 vaccination.24,25 This observed increased risk of GBS would also correspond to the peak of influenza activity during the 2009---2010 season (Figure 2) which was not assessed in the previous reports.24,25 In fact, most of the studies that reported an increase risk in GBS within a short interval (usually 6---8 weeks)
following pH1N1 vaccination could not adequately adjust for the potential confounding effects by ILI.23---25,38 Greene et al. found an association of GBS with pH1N1 vaccine (relative risk = 4.4; 95% CI = 1.3, 14.2); however, in a secondary analysis using a case-centered design, which controls for seasonality, the relative risk fell to 2.0 (95% CI = 0.5, 8.1).23 Although an association with influenza illness was not assessed, the effect of seasonality (and indirectly influenza as it is seasonal) does suggest that influenza illness 1.6 a
A/pH1N1
Percentage
10
b
ILI a Other (A/H1N1, A/H3N2, A−Unknown, B)
8
1.2
Weekly pH1N1 doses administered
6
0.8
4 0.4 2 0
0 3
17
Oct
31
14
Nov
28
12
Dec
26
9
23
Jan
6
20
Feb
6
20
Mar
3
17
Apr
1
15
May
Million Doses Administered
12
29
Weeks Ending in Corresponding Dates Note. ILI = influenza-like illness; pH1N1 = influenza A (H1N1) 2009. The Emerging Infections Program includes 10 sites: California (3 counties), Colorado (5 counties), Connecticut, Georgia (8 counties), Maryland, Minnesota, New Mexico, New York (excluding New York City), Oregon (3 counties), and Tennessee. a Laboratory confirmed cases from laboratories participating in the Centers for Disease Control and Prevention Viral Surveillance System (US and World Health Organization Collaborating Laboratories and National Respiratory and Enteric Virus Surveillance System). b The weekly percentage of outpatient visits for ILI among ILINet sentinel physicians in the Emerging Infections Program catchment area.
FIGURE 2—Proportion of ILI and laboratory confirmed influenza by virus strain type, and pH1N1 vaccinations by week: Emerging Infections Program catchment area, October 2009— May 2010.
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may be confounding the estimated association with pH1N1 vaccinations. The European consortium, Vaccine Adverse Events Surveillance and Communication (VAESCO), had similar findings detecting an association of GBS with pH1N1 vaccines (primarily adjuvanted; OR = 2.8; 95% CI = 1.3, 6.0); however, after controlling for ILI and receipt of seasonal influenza vaccines there was no longer an association (OR = 1.0; 95% CI = 0.3, 2.7).22 In any case, the attributable risk of GBS following pH1N1 vaccines reported by previous studies (estimated to be 1---5 per 1000 000 doses) is much lower than the estimated risk because of ILI (4---7 per 100 000 cases of influenza),13,14,23,25,27,38 suggesting that the risk of GBS following influenza vaccinations is outweighed substantially by the risks of GBS after influenza illness at the population level. A short period of risk after vaccination, such as the 6 weeks that was used in many of these studies, helps to determine if there is a causal association between GBS and vaccination. It may be important to identify an independent (not confounded) increased risk to help counsel patients, inform vaccination decisions and potentially provide valuable information for vaccine injury compensation. The cumulative risk assessment for the entire influenza season can elucidate the public health impact of vaccination and help inform influenza vaccination policy. Our analysis is bound by some limitations, many of which have been described in previous publications using these data.24,25 There may have been misclassification of GBS cases particularly among younger people where the diagnosis can be more difficult. However the surveillance officers were trained to use a standardized data collection abstraction form and neurologists adjudicated complex cases. The vaccinated population was calculated using survey coverage data from the BRFSS and NHFS that may have been impacted by nonresponse or self-reporting biases, including incorrect recall or confusion as to which influenza vaccine was received. It has been reported that survey data from BRFSS may have overestimated the 2009---2010 influenza vaccine coverage.25 Wise et al. performed a sensitivity analysis in their assessment of the incidence rate ratios for GBS 6 weeks following pH1N1 vaccines using the same data sources as this report and found that the estimates were
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insensitive to moderate errors in vaccine coverage data.25 Vaccination status for the GBS cases was not always from a documented source and we sometimes relied on patient history, but approximately three quarters of the vaccine histories were documented from vaccine registries or outpatient medical records. Case ascertainment and reporting biases may have also occurred. Physicians may have been more likely to suspect, diagnose or report GBS in persons recently vaccinated during a time of heightened surveillance and concern that the pH1N1 vaccine might be associated with GBS. Furthermore, toward the end of the influenza season and also when pH1N1 vaccination had declined there may have been surveillance fatigue and GBS cases may have been incompletely identified. This may have been particularly true for cases for which there was no vaccine exposure, hence underestimating the probability of incident GBS among the unvaccinated population. It is possible that some of the observed differences in GBS risks among pH1N1 vaccinated and unvaccinated population might be explained by differences in the underlying risk of GBS in these 2 groups such as different comorbidities or demographic characteristics. The “healthy vaccine effect” (when vaccination is deferred at the time of illness or for anyone with a history of GBS) may also contribute to the observed differences as well as any differences in underlying behaviors (i.e., hand washing, avoiding crowds) that may protect against influenza. Finally, we did not include assessments for seasonal influenza vaccines or seasonal influenza illnesses in our analyses or discussions, primarily because most epidemiological studies did not report an association between 2009---2010 seasonal influenza vaccines and GBS,20,23,24,26 and there was very little circulating seasonal influenza virus during the 2009---2010 season (Figure 2) to have any major impact on the findings. Confounding because of administration of seasonal influenza vaccine is unlikely because it would not have prevented a substantial proportion of influenza. In summary, we assert that our approach for assessing GBS risk over the entire study period rather than a stipulated short risk period (6---8 weeks) provides a broader public health perspective of the risk for GBS during a time when high influenza activity was intertwined
with simultaneous exposure to vaccination; however, the potential protective effect on GBS because of vaccination that we observed for the 2009 pandemic may warrant further study during seasonal influenza outbreaks. Contrary to analyses of risk shortly following vaccination, our findings suggest the cumulative risk of GBS was less among the vaccinated population during the pandemic and supports the benefit of influenza vaccination as it relates to GBS.
3. Hardy TA, Blum S, McCombe PA, Reddel SW. Guillain-Barr syndrome: modern theories of etiology. Curr Allergy Asthma Rep. 2011;11(3):197---204.
About the Authors
7. Tam CC, O’Brien SJ, Petersen I, Islam A, Hayward A, Rodrigues LC. Guillain---Barre syndrome and preceding infection with Campylobacter, influenza and Epstein---Barr virus in the General Practice Research Database. PLoS ONE. 2007;2(4).
Claudia Vellozzi, Shahed Iqbal, Brock Stewart, and Frank DeStefano are with the Immunization Safety Office, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA. Jerome Tokars is with the Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention. Correspondence should be sent to Claudia Vellozzi, MD, MPH, Immunization Safety Office, Centers for Disease Control and Prevention, 1600 Clifton Rd NE; MS d-26, Atlanta, GA 30333 (email: [email protected]). Reprints can be ordered at http://www.ajph.org by clicking the “Reprints” link. This article was accepted September 4, 2013. Note. The findings and conclusions are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
Contributors Claudia Vellozzi contributed to the conceptualization, design, interpretation of data, and drafting and revisions of the article. Shahed Iqbal contributed to the design, analysis, interpretation of data, and drafting of the article. Brock Stewart contributed to the analysis and revisions of the article. Jerome Tokars contributed to the interpretation of data and revisions of the article. Frank DeStefano contributed to the conceptualization, design, interpretation of data, and revisions of the article. All authors approved the final version to be published.
Acknowledgments
4. Yuki N, Hartung HP. Guillain---Barre syndrome. N Engl J Med. 2012;366(24):2294---2304. 5. Lehmann HC, Hartung H-P, Kieseier BC, Hughes RAC. Guillain-Barre syndrome after exposure to influenza virus. Lancet Infect Dis. 2010;10(9):643---651. 6. Stowe J, Andrews N, Wise L, Miller E. Investigation of the temporal association of Guillain---Barre syndrome with influenza vaccine and influenzalike illness using the United Kingdom General Practice Research Database. Am J Epidemiol. 2009;169(3): 382---388.
8. 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(12):1880---1887. 9. Tam CC, Rodrigues LC, O’Brien SJ. Guillain-- Barre syndrome associated with Campylobacter jejuni infection in England, 2000-2001. Clin Infect Dis. 2003;37(2): 307---310. 10. Hughes RAC, Cornblath DR. Guillain---Barre syndrome. Lancet. 2005;366(9497):1653---1666. 11. 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(2):105-- 123. 12. Schonberger LB, Hurwitz ES, Katona P, Holman RC, Bregman DJ. Guillan---Barre syndrome—its epidemiology and associations with influenza vaccination. Ann Neurol. 1981;1981(9):31---38. 13. Juurlink DN, Stukel TA, Kwong J, et al. GuillainBarre syndrome after influenza vaccination in adults— a population-based study. Arch Intern Med. 2006;166 (20):2217---2221. 14. Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barre syndrome and the 1993 and 1993-1994 influenza vaccines. N Engl J Med. 1998;339(25):1797--1802.
We thank Paige Lewis, Matthew Wise, and Matthew Biggerstaff for their assistance in obtaining GBS surveillance and influenza vaccine coverage data, and Paul Gargiullo for critical review of analytic methods.
15. Centers for Disease Control and Prevention. Update: influenza activity—United States, 2009---10 season. MMWR Morb Mortal Wkly Rep. 2010;59(29): 901-908.
Human Participant Protection
16. Centers for Disease C, Prevention. Update on influenza A (H1N1) 2009 monovalent vaccines. MMWR Morb Mortal Wkly Rep. 2009-Oct-9 2009;58(39): 1100---1101.
This project was reviewed by the Centers for Disease Control and Prevention institutional review board and determined to be surveillance and not human participant research.
References 1. Sejvar JJ, Baughman AL, Wise M, Morgan OW. Population incidence of Guillain---Barre syndrome: a systematic review and meta-analysis. Neuroepidemiology. 2011;36 (2):123---133. 2. Shui IM, Rett MD, Weintraub E, et al. Guillain-Barre syndrome incidence in a large United States cohort (20002009). Neuroepidemiology. 2012;39(2):109---115.
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17. VAESCO. 2009. Available at: http://ecdc.europa. eu/en/healthtopics/pandemic_preparedness/2009_ pandemic_vaccines/pages/vaccine-safety.aspx. Accessed November 28, 2012. 18. Huang WT, Chen WW, Yang HW, et al. Design of a robust infrastructure to monitor the safety of the pandemic A (H1N1) 2009 vaccination program in Taiwan. Vaccine. 2010;28(44):7161---7166. 19. Salmon DA, Akhtar A, Mergler MJ, et al. Immunization-safety monitoring systems for the 2009 H1N1 monovalent influenza vaccination program. Pediatrics. 2011;127:S78---S86.
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20. Andrews N, Stowe J, Al-Shahi Salman R, Miller E. Guillain---Barre syndrome and H1N1 (2009) pandemic influenza vaccination using an AS03 adjuvanted vaccine in the United Kingdom: self-controlled case series. Vaccine. 2011;29(45):7878---7882. 21. De Wals P, Deceuninck G, Toth E, et al. Risk of Guillain---Barre syndrome following H1N1 influenza vaccination in Quebec. JAMA. 2012;308(2):175---181. 22. Dieleman J, Romio S, Johansen K, et al. Guillain--Barre syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccine: multinational case-control study in Europe. BMJ. 2011;343:d3908.
36. Influenza 2009---10. 2010. Available at: http:// www.cdc.gov/flu/pastseasons/0910season.htm. Accessed November 28, 2012. 37. Griffin MR, Monto AS, Belongia EA, et al. Effectiveness of non-adjuvanted pandemic influenza A vaccines for preventing pandemic influenza acute respiratory illness visits in 4 US communities. PLoS ONE. 2011;6(8). 38. Sivadon-Tardy V, Orlikowski D, Rozenberg F, et al. Guillain---Barre syndrome, greater Paris area. Emerg Infect Dis. 2006;12(6):990---993.
23. Greene SK, Rett M, Weintraub ES, et al. Risk of confirmed Guillain---Barre syndrome following receipt of monovalent inactivated influenza A (H1N1) and seasonal influenza vaccines in the Vaccine Safety Datalink Project, 2009---2010. Am J Epidemiol. 2012;175(11):1100---1109. 24. Tokars JI, Lewis P, DeStefano F, et al. The risk of Guillain---Barre syndrome associated with influenza A (H1N1) 2009 monovalent vaccine and 2009-2010 seasonal influenza vaccines: results from self-controlled analyses. Pharmacoepidemiol Drug Saf. 2012;21(5):546--552. 25. Wise ME, Viray M, Sejvar JJ, et al. Guillain---Barre syndrome during the 2009-2010 H1N1 influenza vaccination campaign: population-based surveillance among 45 million Americans. Am J Epidemiol. 2012;175(11): 1110---1119. 26. Grimaldi-Bensouda L, Alperovitch A, Besson G, et al. Guillain---Barre syndrome, influenzalike illnesses, and influenza vaccination during seasons with and without circulating A/H1N1 viruses. Am J Epidemiol. 2011;174(3):326---335. 27. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Guillain---Barre syndrome and influenza virus infection. Clin Infect Dis. 2009;48(1):48---56. 28. Centers for Disease Control and Prevention. Preliminary results: surveillance for Guillain---Barre syndrome after receipt of influenza A (H1N1) 2009 monovalent vaccine—United States, 2009---2010. MMWR Morb Mortal Wkly Rep. 2010;59(21):657---661. 29. Center for Disease Control and Prevention. Emerging infections program. 2012. Available at: http://www. cdc.gov/ncezid/dpei/eip. Accessed November 28, 2012. 30. International Classification of Diseases, Ninth Revision. Geneva, Switzerland: World Health Organization; 1980. 31. Sejvar JJ, Kohl KS, Gidudu J, et al. Guillain---Barre syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine. 2011;29(3):599---612. 32. Brighton Collaboration. 2012. Available at: http:// brightoncollaboration.org/public. Accessed November 28, 2012. 33. Centers for Disease C, Prevention. Interim results: influenza A (H1N1) 2009 monovalent vaccination coverage—United States, October-December 2009. MMWR Morb Mortal Wkly Rep. 2010;59(2):44---48. 34. Haukoos JS, Lewis RJ. Advanced Statistics: bootstrapping confidence intervals for statistics with “difficult” distributions. Acad Emerg Med. 2005;12(4):360---365. 35. H1N1 influenza vaccination. 2009. Available at: http://www.cdc.gov/h1n1flu/vaccination/public/ vaccination_qa_pub.htm#s_and_d. Accessed November 28, 2012.
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Cumulative Risk of Guillain–Barre´ Syndrome Among Vaccinated and Unvaccinated Populations During the 2009 H1N1 Influenza Pandemic Claudia Vellozzi, MD, MPH, Shahed Iqbal, PhD, MBBS, MPH, Brock Stewart, PhD, Jerome Tokars, MD, MPH, and Frank DeStefano, MD, MPH
Guillain---Barré syndrome (GBS) is an acute, monophasic, autoimmune neurologic disorder of the peripheral nerves characterized primarily by muscle weakness and loss of reflexes. Estimates of GBS incidence range from 0.8 to 1.9 cases per 100 000 person-years, are higher in males, and increase with age.1,2 Although the exact causes of GBS are unknown, they are thought to be triggered by antigenic stimulation resulting in demyelination and damage to the peripheral nerves.3,4 GBS has been shown to be associated with antecedent gastrointestinal or upper respiratory tract illnesses, including influenza.5---9 Rarely, GBS may follow vaccination.10---12 During the 1976 swine-origin influenza A pandemic, the risk of GBS was found to be increased by nearly 8 fold in the 6 weeks following receipt of the swine-origin influenza vaccine.11 After 1976, several studies have assessed the risk of GBS following seasonal inactivated influenza vaccines demonstrating either no increased risk or a small increased risk of approximately 1 to 2 additional GBS cases per 1 million vaccine doses administered.13,14 However, the 1976 GBS incident influenced the approach to the 2009 H1N1 vaccine safety monitoring efforts, and GBS became a primary focus of surveillance activities. The pandemic (H1N1) 2009 influenza virus began widespread circulation during the first half of the influenza season with illness peaking during October and November 2009.15 At the same time, influenza A (H1N1) 2009 monovalent vaccines (pH1N1 vaccines) became available in early October 200916 and were administered rapidly and broadly throughout the United States. During this time the United States and several countries worldwide implemented enhanced pH1N1 vaccine safety monitoring.17---19 Many programs have subsequently published their surveillance and evaluation findings for the risk of GBS during the
Objectives. We sought to assess risk of Guillain–Barre´ syndrome (GBS) among influenza A (H1N1) 2009 monovalent (pH1N1) vaccinated and unvaccinated populations at the end of the 2009 pandemic. Methods. We applied GBS surveillance data from a US population catchment area of 45 million from October 15, 2009, through May 31, 2010. GBS cases meeting Brighton Collaboration criteria were included. We calculated the incidence density ratio (IDR) among pH1N1 vaccinated and unvaccinated populations. We also estimated cumulative GBS risk using life table analysis. Additionally, we used vaccine coverage data and census population estimates to calculate denominators. Results. There were 392 GBS cases; 64 (16%) occurred after pH1N1vaccination. The vaccinated population had lower average risk (IDR = 0.83, 95% confidence interval = 0.63, 1.08) and lower cumulative risk (6.6 vs 9.2 cases per million persons, P = .012) of GBS. Conclusions. Our findings suggest that at the end of the influenza season cumulative GBS risk was less among the pH1N1vaccinated than the unvaccinated population, suggesting the benefit of vaccination as it relates to GBS. The observed potential protective effect on GBS attributed to vaccination warrants further study. (Am J Public Health. 2014;104:696–701. doi:10.2105/AJPH.2013. 301651)
6 weeks following the pH1N1 vaccine20---25; some but not all of the surveillance systems found a significant but small increased risk of GBS following pH1N1 vaccination. Most, however, were unable to adequately evaluate the potential confounding because of exposure to the pandemic (H1N1) 2009 influenza virus. Influenza and other respiratory illnesses have been associated with GBS,6---8,26,27 and it has been suggested that the absolute increase in risk of GBS is much higher after influenzalike illnesses (ILIs) than a potential increase in risk after vaccination.7,27 We hypothesized that the overall risk of GBS at the end of the 2009 influenza season (October 2009 through May 2010) may have been lower among the pH1N1 vaccinated population than the unvaccinated population. Surveillance for GBS using active-case finding through US Centers for Disease Control and Prevention’s (CDC’s) Emerging Infections Program (EIP) was implemented as part of enhanced pH1N1 vaccine
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safety monitoring activities25,28; we used these data to test our hypothesis. We evaluated the average and cumulative risk of incident GBS among those vaccinated with pH1N1 vaccine and those unvaccinated (did not receive pH1N1 vaccine) during the surveillance period of October 1, 2009, through May 31, 2010.
METHODS The EIP active surveillance for GBS started on October 1, 2009. However, because pH1N1 vaccines were not widely available during the first part of October, we restricted our analysis to October 15, 2009, through May 31, 2010. The data source and methodologies used are briefly described here. More detailed descriptions have been published previously.24,25
Data Source In 1995, CDC established the EIP in 10 sites (California [3 counties], Colorado [5 counties],
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Connecticut, Georgia [8 counties], Maryland, Minnesota, New Mexico, New York [excluding New York City], Oregon [3 counties], and Tennessee) for surveillance, prevention, and control of emerging infectious diseases. The EIP catchment area included nearly 45 million people who are representative of the US population in terms of age, gender, race, urban residence, population density, and percentage below poverty level. The EIP network is collaboration between local health departments, academic institutions, health care providers, public health and clinical laboratories, and federal agencies.29
Case Finding and Classification During the pH1N1 vaccination program, GBS cases were actively sought in the EIP catchment area during October 1, 2009, to May 31, 2010, primarily using a network of neurologists and other health care providers specifically established for this project. Hospital discharge data using International Statistical Classification of Diseases, Ninth Edition,30 code 357.0, were also reviewed periodically throughout and at the end of the surveillance period to capture cases possibly missed using the provider network. Trained surveillance officers reviewed medical records and used a standard form to abstract information on patient characteristics, onset date of symptoms, clinical presentation, and laboratory findings for suspected cases of GBS. A telephone questionnaire was also administered to persons with suspected GBS for additional clinical information and vaccination history. Surveillance officers classified cases according to Brighton Collaboration criteria,31 an international organization dedicated to vaccine safety and the development of adverse event case definitions.32 CDC subject matter experts reviewed complex cases; any unresolved case classification underwent further adjudication by a panel of 4 neurologists to make the final determination. Only confirmed (Brighton levels 1 and 2) and probable (Brighton level 3) GBS cases were included in the analysis.
Vaccination Records, Coverage, and Person-Time Calculation Dates of receipt of pH1N1 vaccine for the GBS cases were recorded from vaccination cards, vaccine registries, or providers
administering the vaccine, or via self-report (as recorded in the medical record or telephone interview) if a documented source was not available. We estimated the monthly pH1N1 vaccine coverage in the EIP catchment area by using survey data from the Behavioral Risk Factor Surveillance System (BRFSS) and the National 2009 H1N1 Flu Survey (NHFS). Previously published methods were used to combine monthly estimates from the 2 surveys.25,33 To calculate daily doses of pH1N1vaccine administered, monthly vaccine coverage data were multiplied by proportions of doses administered each day; we obtained daily vaccine data from a sample of private outpatient primary care provider offices in the EIP population compiled by SDI Health LLC (Plymouth Meeting, PA).25 SDI Health LLC obtains claims data from approximately 60% of outpatient primary care providers throughout the United States. We multiplied the total number of vaccine doses on a given date by the difference between that date and the end of the study period (i.e., May 31, 2010) to calculate person-time for those vaccinated with pH1N1 vaccine. Individuals contributed person-time to the unvaccinated group until they received vaccination, at which time they contributed to the vaccinated group.
Statistical Methods We first used incidence density methods to calculate the rates of GBS among the pH1N1 vaccinated and unvaccinated populations and estimate the incidence density ratios (IDR) overall and by different age groups (< 25 years, 25---64 years, ‡ 65 years); We used direct standardization method to calculate overall age adjusted rates for the vaccinated and unvaccinated groups. Exact binomial method was used to calculate 95% confidence intervals for the IDRs. The incidence density method measures the average rate of disease occurrence during a defined observation period. We also used life table analysis to calculate the cumulative probability of GBS risk for each day in the study period for the vaccinated versus unvaccinated groups. We then calculated the difference in the daily cumulative risks between the pH1N1 vaccinated and unvaccinated groups overall and by age groups (< 25 years, 25---64 years, ‡ 65 years). The life
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table analysis accounted for individuals being vaccinated and entering the vaccinated cohort at different times throughout the observation period to reconstruct cumulative risk measures according to vaccination status from the beginning to the end of the study period; the primary measure of interest was the difference in the cumulative proportion of GBS cases between the vaccinated and unvaccinated cohorts at the end of the observation period (i.e., May 31, 2010). We used bootstrapping methods to calculate 95% confidence intervals around the cumulative risks and to test the level of significance at .05 level.34 In addition, we used population estimates from US Census Bureau and vaccine coverage data to calculate the number of people in the vaccinated and unvaccinated groups. SAS version 9.3 (SAS Institute, Cary, NC) and R version 3.0.1 (Foundation for Statistical Computing, Vienna, Austria)34 were used for all analyses.
RESULTS A total of 707 suspected GBS cases were identified during the surveillance period between October 1, 2009, and May 31, 2010. After removing cases that did not meet Brighton case classification criteria (levels 1---3; n = 282; 40%) and cases with onset dates prior to October 15, 2009 (n = 33; 5%), 392 cases were included for this analysis; 84% met level 1 and 2 Brighton criteria. Sixty-four (16%) cases occurred at any time after pH1N1 vaccination. Most cases occurred among persons aged 25 to 64 years (Table 1). Slightly more than half of the cases (n = 34; 53%) following pH1N1 vaccination were among men. The incidence density rate of GBS for the entire period of surveillance among those vaccinated was found to be lower than among those who were not vaccinated (overall age-adjusted IDR = 0.83); this was consistent across all age categories; however, these associations were not statistically significant (Table 1). Figure 1 demonstrates the cumulative risk for the vaccinated and unvaccinated groups by date and for all ages combined using the life table analysis. The cumulative risk point estimates of GBS among the pH1N1vaccinated group were lower throughout the study period, however during a brief period (January through February) the risk was similar (but still
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TABLE 1—Frequency and Incidence Density Ratio of Guillain–Barre´ Syndrome Cases Among pH1N1 Vaccinated and Unvaccinated Population by Age Group: Emerging Infections Program Catchment Area, October 15, 2009—May 31, 2010 pH1N1 Vaccinated
Unvaccinated
Age, Years
Total Cases, No. (%)
No. Cases
No. PersonYearsa
Ratea
No. Cases
No. PersonYearsa
Ratea
IDR (95% CI)
< 25 25–64
60 (15.3) 232 (59.2)
14 35
25.75 26.74
0.54 1.31
46 197
68.47 126.73
0.67 1.55
0.81 (0.41, 1.50) 0.84 (0.57, 1.21)
‡ 65
100 (25.5)
15
6.27
2.39
85
28.70
2.96
0.81 (0.43, 1.41)
Overall
392 (100.0)
64
58.76
1.19b
328
223.90
1.43b
0.83 (0.63, 1.08)b
Note. CI = confidence interval; IDR = incidence density ratio; pH1N1 = influenza A (H1N1) 2009. The Emerging Infections Program includes 10 sites: California (3 counties), Colorado (5 counties), Connecticut, Georgia (8 counties), Maryland, Minnesota, New Mexico, New York (excluding New York City), Oregon (3 counties), and Tennessee. The sample size was n = 392. a 100 000 person-years. b Age-adjusted.
lower) to that of the unvaccinated group. The cumulative risk on the last day of the study period among the vaccinated group was significantly lower than that of the unvaccinated group (6.6 vs 9.2 cases per million persons, respectively; P = .012) for all ages, but not significantly different when stratified by the 3 age groups (< 25 years: P = .665; 25---64 years: P = .227; ‡ 65 years: P = .191; Table 2).
DISCUSSION
Rate/Million Persons
Using data from an active GBS case-finding surveillance program established during the 2009---2010 influenza season,25 our findings show that by the end of the surveillance period,
May 31, 2010, which coincided with the end of the influenza season, the cumulative risk of GBS ranked lower among the pH1N1 vaccinated population in the EIP catchment area compared with the unvaccinated population. This finding was consistent among all age groups. These differences may represent a protective effect of receipt of pH1N1 against pandemic (H1N1) 2009 influenza and the subsequent risk of GBS, contributing to an overall favorable benefit---risk profile of the vaccine. These findings are consistent with previous studies suggesting a protective effect of influenza vaccination on GBS, most likely attributed to the protection against influenza. In a case-control study from the United Kingdom
10 pH1N1 vaccinated Unvaccinated
8 6 4 2 0 Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Month Note. pH1N1 = influenza A (H1N1) 2009. The Emerging Infections Program includes 10 sites: California (3 counties), Colorado (5 counties), Connecticut, Georgia (8 counties), Maryland, Minnesota, New Mexico, New York (excluding New York City), Oregon (3 counties), and Tennessee.
FIGURE 1—Cumulative risk of Guillain–Barre´ among the pH1N1 vaccinated and unvaccinated groups by date and all ages combined: Emerging Infections Program catchment area, October 15, 2009—May 31, 2010.
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during 1991 to 2001, Tam et al. found a possible protective effect of influenza vaccination and GBS onset within 60 days of vaccination (odds ratio [OR] = 0.16; 95% confidence interval [CI] = 0.02, 1.25), yet the odds ratio for ILI was 18.64 (95% CI = 7.49, 46.37).7 In another study from the United Kingdom, Stowe et al. also demonstrated a similar protective association between influenza vaccine and GBS incidence within 30 days following vaccination (relative incidence [RI] = 0.58; 95% CI = 0.18, 1.86) and similar magnitude of association of GBS with ILI (RI = 16.6; 95% CI = 9.4, 29.5) using a self-controlled study design and data from 1990 to 2005.6 Our findings may have been more robust if the timing of vaccinations and influenza infections had been different during the H1N1 2009 pandemic. In the United States, vaccination coincided with peak influenza activity. Data from the World Health Organization and US surveillance systems showed the proportion of individuals testing positive for influenza A H1N1 peaked at 38.2% during the week ending October 24, 2009,15 and live attenuated and inactivated pH1N1 vaccines first became available October 5 and October 12, 2009, respectively.35 We found a similar pattern among the EIP catchment area for the timing of ILI and vaccine administration (Figure 2). Therefore much of the ILI was prior to or at the same time the pH1N1 vaccines became available and widely distributed. Furthermore, the pH1N1 vaccine likely provided good protection against pandemic (H1N1) 2009 virus, having been estimated to be 62% effective.36,37 With this effectiveness, if high vaccination coverage had been achieved prior to widespread influenza activity, more infections may have been prevented and consequently we may have observed a greater reduction in the cumulative incidence of GBS in the vaccinated population. The slightly higher cumulative GBS risk in the unvaccinated group demonstrated in this study may have been because of the high influenza activity of the pandemic with continued circulation of virus, albeit low, through May 2010 (Figure 2). A study in France during 1996 to 2004 evaluated the correlation of GBS with influenza-like illnesses and analyzed antiinfluenza antibodies; they found that GBS cases that were definitively linked to influenza were
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TABLE 2—Cumulative Risk of Guillain–Barre´ Syndrome on Last Day of Surveillance Among Unvaccinated and Vaccinated Groups, by Age Group: Emerging Infections Program Catchment Area, October 15, 2009—May 31, 2010 Differenceb Unvaccinated, Riska (95% CI)
pH1N1 Vaccinated, Riska (95% CI)
Riska (95% CI)
P
< 25
4.22 (3.07, 5.39)
3.69 (1.83, 5.91)
0.53 (–2.03, 2.85)
.655
25–64
9.73 (8.74, 10.71)
7.81 (5.28, 10.48)
1.92 (–1.19, 4.88)
.227
‡ 65 Overall
18.36 (14.92, 21.89) 9.16 (8.70, 9.61)
12.97 (6.55, 20.24) 6.58 (5.05, 8.24)
5.39 (–2.95, 12.82) 2.59 (0.56, 4.48)
.191 .012
Age, Years
Note. CI = confidence interval; pH1N1 = influenza A (H1N1) 2009. The Emerging Infections Program includes 10 sites: California (3 counties), Colorado (5 counties), Connecticut, Georgia (8 counties), Maryland, Minnesota, New Mexico, New York (excluding New York City), Oregon (3 counties), and Tennessee. a Per 1 000 000 persons. b Unvaccinated – vaccinated groups.
more likely to occur during seasons with high influenza activity.27 Previous studies using the EIP 2009---2010 GBS surveillance data reported an increased risk of GBS within 6 weeks following pH1N1 vaccination.24,25 This observed increased risk of GBS would also correspond to the peak of influenza activity during the 2009---2010 season (Figure 2) which was not assessed in the previous reports.24,25 In fact, most of the studies that reported an increase risk in GBS within a short interval (usually 6---8 weeks)
following pH1N1 vaccination could not adequately adjust for the potential confounding effects by ILI.23---25,38 Greene et al. found an association of GBS with pH1N1 vaccine (relative risk = 4.4; 95% CI = 1.3, 14.2); however, in a secondary analysis using a case-centered design, which controls for seasonality, the relative risk fell to 2.0 (95% CI = 0.5, 8.1).23 Although an association with influenza illness was not assessed, the effect of seasonality (and indirectly influenza as it is seasonal) does suggest that influenza illness 1.6 a
A/pH1N1
Percentage
10
b
ILI a Other (A/H1N1, A/H3N2, A−Unknown, B)
8
1.2
Weekly pH1N1 doses administered
6
0.8
4 0.4 2 0
0 3
17
Oct
31
14
Nov
28
12
Dec
26
9
23
Jan
6
20
Feb
6
20
Mar
3
17
Apr
1
15
May
Million Doses Administered
12
29
Weeks Ending in Corresponding Dates Note. ILI = influenza-like illness; pH1N1 = influenza A (H1N1) 2009. The Emerging Infections Program includes 10 sites: California (3 counties), Colorado (5 counties), Connecticut, Georgia (8 counties), Maryland, Minnesota, New Mexico, New York (excluding New York City), Oregon (3 counties), and Tennessee. a Laboratory confirmed cases from laboratories participating in the Centers for Disease Control and Prevention Viral Surveillance System (US and World Health Organization Collaborating Laboratories and National Respiratory and Enteric Virus Surveillance System). b The weekly percentage of outpatient visits for ILI among ILINet sentinel physicians in the Emerging Infections Program catchment area.
FIGURE 2—Proportion of ILI and laboratory confirmed influenza by virus strain type, and pH1N1 vaccinations by week: Emerging Infections Program catchment area, October 2009— May 2010.
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may be confounding the estimated association with pH1N1 vaccinations. The European consortium, Vaccine Adverse Events Surveillance and Communication (VAESCO), had similar findings detecting an association of GBS with pH1N1 vaccines (primarily adjuvanted; OR = 2.8; 95% CI = 1.3, 6.0); however, after controlling for ILI and receipt of seasonal influenza vaccines there was no longer an association (OR = 1.0; 95% CI = 0.3, 2.7).22 In any case, the attributable risk of GBS following pH1N1 vaccines reported by previous studies (estimated to be 1---5 per 1000 000 doses) is much lower than the estimated risk because of ILI (4---7 per 100 000 cases of influenza),13,14,23,25,27,38 suggesting that the risk of GBS following influenza vaccinations is outweighed substantially by the risks of GBS after influenza illness at the population level. A short period of risk after vaccination, such as the 6 weeks that was used in many of these studies, helps to determine if there is a causal association between GBS and vaccination. It may be important to identify an independent (not confounded) increased risk to help counsel patients, inform vaccination decisions and potentially provide valuable information for vaccine injury compensation. The cumulative risk assessment for the entire influenza season can elucidate the public health impact of vaccination and help inform influenza vaccination policy. Our analysis is bound by some limitations, many of which have been described in previous publications using these data.24,25 There may have been misclassification of GBS cases particularly among younger people where the diagnosis can be more difficult. However the surveillance officers were trained to use a standardized data collection abstraction form and neurologists adjudicated complex cases. The vaccinated population was calculated using survey coverage data from the BRFSS and NHFS that may have been impacted by nonresponse or self-reporting biases, including incorrect recall or confusion as to which influenza vaccine was received. It has been reported that survey data from BRFSS may have overestimated the 2009---2010 influenza vaccine coverage.25 Wise et al. performed a sensitivity analysis in their assessment of the incidence rate ratios for GBS 6 weeks following pH1N1 vaccines using the same data sources as this report and found that the estimates were
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insensitive to moderate errors in vaccine coverage data.25 Vaccination status for the GBS cases was not always from a documented source and we sometimes relied on patient history, but approximately three quarters of the vaccine histories were documented from vaccine registries or outpatient medical records. Case ascertainment and reporting biases may have also occurred. Physicians may have been more likely to suspect, diagnose or report GBS in persons recently vaccinated during a time of heightened surveillance and concern that the pH1N1 vaccine might be associated with GBS. Furthermore, toward the end of the influenza season and also when pH1N1 vaccination had declined there may have been surveillance fatigue and GBS cases may have been incompletely identified. This may have been particularly true for cases for which there was no vaccine exposure, hence underestimating the probability of incident GBS among the unvaccinated population. It is possible that some of the observed differences in GBS risks among pH1N1 vaccinated and unvaccinated population might be explained by differences in the underlying risk of GBS in these 2 groups such as different comorbidities or demographic characteristics. The “healthy vaccine effect” (when vaccination is deferred at the time of illness or for anyone with a history of GBS) may also contribute to the observed differences as well as any differences in underlying behaviors (i.e., hand washing, avoiding crowds) that may protect against influenza. Finally, we did not include assessments for seasonal influenza vaccines or seasonal influenza illnesses in our analyses or discussions, primarily because most epidemiological studies did not report an association between 2009---2010 seasonal influenza vaccines and GBS,20,23,24,26 and there was very little circulating seasonal influenza virus during the 2009---2010 season (Figure 2) to have any major impact on the findings. Confounding because of administration of seasonal influenza vaccine is unlikely because it would not have prevented a substantial proportion of influenza. In summary, we assert that our approach for assessing GBS risk over the entire study period rather than a stipulated short risk period (6---8 weeks) provides a broader public health perspective of the risk for GBS during a time when high influenza activity was intertwined
with simultaneous exposure to vaccination; however, the potential protective effect on GBS because of vaccination that we observed for the 2009 pandemic may warrant further study during seasonal influenza outbreaks. Contrary to analyses of risk shortly following vaccination, our findings suggest the cumulative risk of GBS was less among the vaccinated population during the pandemic and supports the benefit of influenza vaccination as it relates to GBS.
3. Hardy TA, Blum S, McCombe PA, Reddel SW. Guillain-Barr syndrome: modern theories of etiology. Curr Allergy Asthma Rep. 2011;11(3):197---204.
About the Authors
7. Tam CC, O’Brien SJ, Petersen I, Islam A, Hayward A, Rodrigues LC. Guillain---Barre syndrome and preceding infection with Campylobacter, influenza and Epstein---Barr virus in the General Practice Research Database. PLoS ONE. 2007;2(4).
Claudia Vellozzi, Shahed Iqbal, Brock Stewart, and Frank DeStefano are with the Immunization Safety Office, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA. Jerome Tokars is with the Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention. Correspondence should be sent to Claudia Vellozzi, MD, MPH, Immunization Safety Office, Centers for Disease Control and Prevention, 1600 Clifton Rd NE; MS d-26, Atlanta, GA 30333 (email: [email protected]). Reprints can be ordered at http://www.ajph.org by clicking the “Reprints” link. This article was accepted September 4, 2013. Note. The findings and conclusions are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
Contributors Claudia Vellozzi contributed to the conceptualization, design, interpretation of data, and drafting and revisions of the article. Shahed Iqbal contributed to the design, analysis, interpretation of data, and drafting of the article. Brock Stewart contributed to the analysis and revisions of the article. Jerome Tokars contributed to the interpretation of data and revisions of the article. Frank DeStefano contributed to the conceptualization, design, interpretation of data, and revisions of the article. All authors approved the final version to be published.
Acknowledgments
4. Yuki N, Hartung HP. Guillain---Barre syndrome. N Engl J Med. 2012;366(24):2294---2304. 5. Lehmann HC, Hartung H-P, Kieseier BC, Hughes RAC. Guillain-Barre syndrome after exposure to influenza virus. Lancet Infect Dis. 2010;10(9):643---651. 6. Stowe J, Andrews N, Wise L, Miller E. Investigation of the temporal association of Guillain---Barre syndrome with influenza vaccine and influenzalike illness using the United Kingdom General Practice Research Database. Am J Epidemiol. 2009;169(3): 382---388.
8. 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(12):1880---1887. 9. Tam CC, Rodrigues LC, O’Brien SJ. Guillain-- Barre syndrome associated with Campylobacter jejuni infection in England, 2000-2001. Clin Infect Dis. 2003;37(2): 307---310. 10. Hughes RAC, Cornblath DR. Guillain---Barre syndrome. Lancet. 2005;366(9497):1653---1666. 11. 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(2):105-- 123. 12. Schonberger LB, Hurwitz ES, Katona P, Holman RC, Bregman DJ. Guillan---Barre syndrome—its epidemiology and associations with influenza vaccination. Ann Neurol. 1981;1981(9):31---38. 13. Juurlink DN, Stukel TA, Kwong J, et al. GuillainBarre syndrome after influenza vaccination in adults— a population-based study. Arch Intern Med. 2006;166 (20):2217---2221. 14. Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barre syndrome and the 1993 and 1993-1994 influenza vaccines. N Engl J Med. 1998;339(25):1797--1802.
We thank Paige Lewis, Matthew Wise, and Matthew Biggerstaff for their assistance in obtaining GBS surveillance and influenza vaccine coverage data, and Paul Gargiullo for critical review of analytic methods.
15. Centers for Disease Control and Prevention. Update: influenza activity—United States, 2009---10 season. MMWR Morb Mortal Wkly Rep. 2010;59(29): 901-908.
Human Participant Protection
16. Centers for Disease C, Prevention. Update on influenza A (H1N1) 2009 monovalent vaccines. MMWR Morb Mortal Wkly Rep. 2009-Oct-9 2009;58(39): 1100---1101.
This project was reviewed by the Centers for Disease Control and Prevention institutional review board and determined to be surveillance and not human participant research.
References 1. Sejvar JJ, Baughman AL, Wise M, Morgan OW. Population incidence of Guillain---Barre syndrome: a systematic review and meta-analysis. Neuroepidemiology. 2011;36 (2):123---133. 2. Shui IM, Rett MD, Weintraub E, et al. Guillain-Barre syndrome incidence in a large United States cohort (20002009). Neuroepidemiology. 2012;39(2):109---115.
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17. VAESCO. 2009. Available at: http://ecdc.europa. eu/en/healthtopics/pandemic_preparedness/2009_ pandemic_vaccines/pages/vaccine-safety.aspx. Accessed November 28, 2012. 18. Huang WT, Chen WW, Yang HW, et al. Design of a robust infrastructure to monitor the safety of the pandemic A (H1N1) 2009 vaccination program in Taiwan. Vaccine. 2010;28(44):7161---7166. 19. Salmon DA, Akhtar A, Mergler MJ, et al. Immunization-safety monitoring systems for the 2009 H1N1 monovalent influenza vaccination program. Pediatrics. 2011;127:S78---S86.
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20. Andrews N, Stowe J, Al-Shahi Salman R, Miller E. Guillain---Barre syndrome and H1N1 (2009) pandemic influenza vaccination using an AS03 adjuvanted vaccine in the United Kingdom: self-controlled case series. Vaccine. 2011;29(45):7878---7882. 21. De Wals P, Deceuninck G, Toth E, et al. Risk of Guillain---Barre syndrome following H1N1 influenza vaccination in Quebec. JAMA. 2012;308(2):175---181. 22. Dieleman J, Romio S, Johansen K, et al. Guillain--Barre syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccine: multinational case-control study in Europe. BMJ. 2011;343:d3908.
36. Influenza 2009---10. 2010. Available at: http:// www.cdc.gov/flu/pastseasons/0910season.htm. Accessed November 28, 2012. 37. Griffin MR, Monto AS, Belongia EA, et al. Effectiveness of non-adjuvanted pandemic influenza A vaccines for preventing pandemic influenza acute respiratory illness visits in 4 US communities. PLoS ONE. 2011;6(8). 38. Sivadon-Tardy V, Orlikowski D, Rozenberg F, et al. Guillain---Barre syndrome, greater Paris area. Emerg Infect Dis. 2006;12(6):990---993.
23. Greene SK, Rett M, Weintraub ES, et al. Risk of confirmed Guillain---Barre syndrome following receipt of monovalent inactivated influenza A (H1N1) and seasonal influenza vaccines in the Vaccine Safety Datalink Project, 2009---2010. Am J Epidemiol. 2012;175(11):1100---1109. 24. Tokars JI, Lewis P, DeStefano F, et al. The risk of Guillain---Barre syndrome associated with influenza A (H1N1) 2009 monovalent vaccine and 2009-2010 seasonal influenza vaccines: results from self-controlled analyses. Pharmacoepidemiol Drug Saf. 2012;21(5):546--552. 25. Wise ME, Viray M, Sejvar JJ, et al. Guillain---Barre syndrome during the 2009-2010 H1N1 influenza vaccination campaign: population-based surveillance among 45 million Americans. Am J Epidemiol. 2012;175(11): 1110---1119. 26. Grimaldi-Bensouda L, Alperovitch A, Besson G, et al. Guillain---Barre syndrome, influenzalike illnesses, and influenza vaccination during seasons with and without circulating A/H1N1 viruses. Am J Epidemiol. 2011;174(3):326---335. 27. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Guillain---Barre syndrome and influenza virus infection. Clin Infect Dis. 2009;48(1):48---56. 28. Centers for Disease Control and Prevention. Preliminary results: surveillance for Guillain---Barre syndrome after receipt of influenza A (H1N1) 2009 monovalent vaccine—United States, 2009---2010. MMWR Morb Mortal Wkly Rep. 2010;59(21):657---661. 29. Center for Disease Control and Prevention. Emerging infections program. 2012. Available at: http://www. cdc.gov/ncezid/dpei/eip. Accessed November 28, 2012. 30. International Classification of Diseases, Ninth Revision. Geneva, Switzerland: World Health Organization; 1980. 31. Sejvar JJ, Kohl KS, Gidudu J, et al. Guillain---Barre syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine. 2011;29(3):599---612. 32. Brighton Collaboration. 2012. Available at: http:// brightoncollaboration.org/public. Accessed November 28, 2012. 33. Centers for Disease C, Prevention. Interim results: influenza A (H1N1) 2009 monovalent vaccination coverage—United States, October-December 2009. MMWR Morb Mortal Wkly Rep. 2010;59(2):44---48. 34. Haukoos JS, Lewis RJ. Advanced Statistics: bootstrapping confidence intervals for statistics with “difficult” distributions. Acad Emerg Med. 2005;12(4):360---365. 35. H1N1 influenza vaccination. 2009. Available at: http://www.cdc.gov/h1n1flu/vaccination/public/ vaccination_qa_pub.htm#s_and_d. Accessed November 28, 2012.
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