ARTICLE IN BRIEF
In a retrospective study of hospitalizations for Guillain-Barré syndrome (GBS) and recent vaccinations, of any kind, over a 13-year period, investigators found a very small risk for GBS.
A retrospective analysis of Guillain-Barré syndrome cases representing 33 million person-years has found little evidence that a recent vaccination increases a person's risk of developing the acute nerve disorder.
Researchers at the Kaiser Permanente Vaccine Study Center in Oakland, CA, conducted a retrospective study of hospitalizations for Guillain-Barré syndrome (GBS) and recent vaccinations, of any kind, over a 13-year period.
The findings were reported in the July 15 issue of Clinical Infectious Diseases.
The team identified 415 cases of GBS, but only 25 individuals had received any vaccine within the six weeks prior to onset. In contrast, 277 cases, or 66.7 percent, involved patients who had recently experienced respiratory or gastrointestinal symptoms. Moreover, the incidence trended higher during the peak flu season in California, late February through mid-March.
A neurologist reviewed each suspected case, and confimation was based on the Brighton Collaboration GBS definition. [See “Brighton Collaboration Case Definition (Level 1): Guillain-Barré.”] Only confirmed cases were included; cases of Miller Fisher syndrome, a GBS variant, were excluded.
Using a new, case-centered design, the team then compared the odds of vaccination in the six and 10 weeks prior to onset of GBS to the odds of vaccination during the same time intervals, in all matched individuals in the entire Kaiser Permanente Northern California population.
“This is the largest and longest study [in the United States] to date,” lead investigator Roger Baxter, MD, co-director of the vaccine study center, told Neurology Today in a telephone interview. “Our findings should provide reassurance that if there is a risk of GBS following any vaccine, it is extremely low. In fact, it appears to be too small to quantify.”
“People who have had GBS should be vaccinated, but those whose GBS arose within six weeks of a flu shot, and there are very few of these, should discuss possible risks and not get it unless the doctor thinks they really need it,” said Dr. Baxter.
In a study published in Clinical Infectious Diseases in March 2012, he and his colleagues identified 550 GBS cases over 33 million person-years — 179 who received 989 vaccines, including inactivated influenza vaccines — with107 people with a prior diagnosis of GBS. Among 550 total cases of GBS, 18 initially had onset within six weeks of vaccination and, of these, two were revaccinated without a recurrence of GBS. Only six individuals, or 1.1 percent, had a second diagnosis of GBS, but none had any vaccine exposure in the two months prior to the second onset of GBS.
GBS is an acute polyradiculoneuropathy in which an individual's immune system first attacks the protective myelin sheath surrounding nerves. Early symptoms include tingling or pain in the extremities. Most patients recover, but in some instances it can affect the autonomic nervous system, causing paralysis, respiratory failure, and even death. Although it is uncommon, with an estimated 1-2 cases per 100,000 individuals each year, GBS is the most common cause of acute non-trauma-related paralysis.
In 2011, a special committee at the Insitute of Medicine published an 800-page review of published evidence of vaccine-related adverse effects, including GBS. The panel concluded that there was little or no risk. Further, a 2011 study published in the New England Journal of Medicine found only 11 cases among almost 90 million Chinese persons inoculated against the 2009-2010 influenza season.
Because GBS is rare, controlled epidemiological studies are very difficult, as is drawing any conclusions about causality, which makes such a large study important, said Dr. Baxter. More often, he noted, GBS is associated with a recent infectious disease — most published reports have found that around two-thirds of all cases are preceded by a gastrointestinal or respiratory infection within the prior three months.
“I think that there is a biologic plausibility that a person exposed to vaccine antigens might develop an autoimmune response that could affect the peripheral nerves, but the incidence since the 1976 outbreak has been so negligible that it would probably take 33 billion person years to detect any risk,” he said.
And although cases are so rare, vaccine manufacturing processes have changed, and monitoring has become much more vigilant, there continues to be a perception that vaccines increase GBS risk, even among health professionals.
In a recent study on GBS cases during the 2009 H1N1 flu vaccine season, Dr. Baxter said he and researchers at the Centers for Disease Control and Prevention (CDC) found that many patients, doctors, and even neurologists, mistakenly believed influenza vaccinations were associated with an increased risk of GBS.
“This was a real eye-opener. Many continue to link GBS risk with flu vaccines from a study 40 years ago, while there has been no clear evidence of it since then. Moreover, improved surveillance and many studies have found that if there is any risk, it is minute.”
Daniel A. Salmon, MD, deputy director of the Institute for Vaccine Safety at Johns Hopkins University Bloomberg School of Public Health in Baltimore, said the findings are consistent with many smaller studies of vaccine-associated risk of GBS.
In an accompanying editorial, he and Neal A. Halsey, MD, professor of pediatric infectious diseases at the institute, called the current study “an important contribution to this body of evidence.”
Earlier this year Dr. Salmon and researchers from the CDC and other government agencies published a meta-analysis of data from six active surveillance systems that monitored GBS among 23 million vaccinated individuals after the 2009 H1N1 flu season. Published in The Lancet in March, the study found an estimated increase in GBS risk of about 2.35 per 23 million vaccinated persons, or 1-2 excess cases per million vaccinations. This is about the same as other current estimates, including a comprehensive review by an Institute of Medicine panel in a 2011 report.
“As in a number of other studies, the risk of GBS causally attributable to vaccines is extremely low and is greatly outweighed by the benefits of vaccination,” he told Neurology Today in a telephone interview.
“Dr. Baxter and his colleagues looked very hard at years of data, using excellent methodology, yet they found no risk. This shoud be very reassuring. Even in our meta-analysis of the 2009 flu season, where there was more GBS surveillance than ever before, we only found a very small risk.”
Nonetheless, ongoing active surveillance is necessary and will continue, although on a smaller scale, he said. “While there is less GBS surveillance today than in 2009, if something like 1976 happened today, we would know about it very quickly.”
Dr Salmon noted that that the CDC advises that those who are not at high risk for severe influenza complications and have experienced GBS within six weeks of a prior influenza vaccine generally should not be vaccinated. Nonetheless, the CDC recommends that patients tell their doctor if they ever had GBS, and let the physicians decide.
“Although data are limited, the established benefits of influenza vaccination might outweigh the risks for many persons who have a history of GBS and who also are at high risk for severe complications from influenza,” according to the CDC.
In late June, Canadian researchers published an analysis of GBS-vaccine risk using an even larger data set. In a June 30 advance publication by The Lancet Infectious Diseases, Jeffrey C. Kwong, MD, associate professor at the University of Toronto Dalla Lana School of Public Health, looked at hospital records for all patients treated for GBS over an 18-year period.
For 2,831 admissions for GBS, 330 patients had received a vaccine within six weeks, a risk that was 52 percent higher than developing it between nine and 42 weeks, with the greatest risk during the first two to four weeks. However the risk was much higher among unvaccinated influenza cases — 17.2 versus 1.03 admissions per million vaccinated individuals.
“The problem with most studies of this issue is that they are relatively small and because this disease is relatively rare, smaller studies lack sufficient power to detect it. Ours was much larger and we also used a different methodology than the study by Dr. Baxter and his colleagues,” Dr. Kwong told Neurology Today.
He and his colleagues used a risk-interval study design linked to universal health-care system databases in Ontario, based on physician billing claims from 1993 and 2011.
“I think the bottom line is that there is a small risk associated with vaccination, but that risk is substantially higher if you don't get a vaccine and contract the flu,” he said. “At the end of the day, if someone is afraid of getting GBS from a vaccine, they should be more afraid of developing it from the flu by not getting the vaccine.”
BRIGHTON COLLABORATION CASE DEFINITION (LEVEL 1): GUILLAIN-BARRÉ
* Acute onset of bilateral and relatively symmetric flaccid weakness/paralysis of the limbs with or without involvement of respiratory or cranial nerve-innervated muscle
* Decreased or absent deep tendon reflexes at least in affected limbs.
* Monophasic illness pattern, with weakness nadir reached between 12 hours and 28 days, followed by clinical plateau and subsequent improvement, or death
* Cerebrospinal fluid (CSF) with a total white cell count <50 cells/mm3 (with or without CSF protein elevation above laboratory normal values
* Electrophysiologic (NCS/EMG) findings consistent with GBS
—Source: Vaccine Healthcare Centers Network: http://www.vhcinfo.org
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