Elderly flu shots: No-brainer or no-gainer? Controversy, conflicting studies dog issue

New randomized clinical trial may be ethically off-limits

Though recent conflicting studies and commentaries have thoroughly confused the issue, the take-home message for infection control professionals — which passes muster with all but the most strident critics — is that the elderly should be immunized against seasonal influenza. Period.

However, there has been considerable controversy about how much benefit the elderly gain by getting the annual shot, particularly whether it will help them mount a sufficient immune response to stave off fatal flu infections. It seems almost heresy to ask such a question in the infectious disease world, but what if the seasonal vaccine provides little benefit to the elderly, particularly those ages 70 and beyond?

"They should not feel totally protected on this vaccine if they are over 70," says Lone Simonsen, PhD, MS, visiting professor and research director in the department of global health at the George Washington School of Public Health in Washington, DC.

One of the leading contrarians on the issue, Simonsen was among the first to point out that a substantial increase in elderly immunization rates in recent years has not translated to reductions in mortality.1 Other researchers point to clear benefits in reduced hospitalizations and reduced mortality in the 50% range.2 "Everybody is mighty confused," Simonsen says of the public and press reaction to the conflicting findings and studies. "But immune senescence is a well-known phenomenon. If you ask an immunologist, they will tell you that the T-cells and B-cells — the whole immune system — is going down as you age."

Still, it should be noted at the onset, that Simonsen is in favor of immunizing the elderly against seasonal flu to achieve whatever benefit can be gained. Though she has found fault with the methodology and perceived statistical biases of many vaccine efficacy studies, she endorses one study that found the immunized elderly had a 29% reduction in hospital admissions with laboratory-confirmed influenza.3

"Maybe you can protect one-quarter to one-third of them," Simonsen says. "That is certainly worth doing, but what we are pointing out is that there is room for improvement here. We need better vaccines for seniors and in general better approaches on how to protect them indirectly and with antivirals."

Indeed, the issue also has raised questions about how the elderly will fare during a pandemic and what additional measures may be needed to protect them. The debate has opened up many lines of inquiry about additional ways to protect the elderly against flu through new stronger vaccines, additional shots, antivirals, and other methods.

Most flu deaths in elderly

Annual influenza typically infects 5%-20% of the U.S. population, resulting in some 300,000 flu-related hospital admissions and 36,000 deaths. Some 90% of those deaths occur in the elderly.4,5 The push to get seniors immunized has resulted in one of the best immunization rates in any age group, with those over 65 approaching a 70% seasonal influenza vaccination rate. However, the benefit of the shots — particularly in reducing mortality — is open to some question and controversy.

"Certainly the influenza vaccine is not as effective at preventing respiratory illness in the elderly and people with compromised immune systems as it is in healthier younger people," says Carolyn Bridges, MD, associate director of science at the Centers for Disease Control and Prevention. "The controversy really has been about the benefit of influenza vaccine in terms of preventing influenza-related hospitalizations and deaths."

Part of the controversy is criticism of the cohort studies and methodology of the research that has been done. "It is very difficult to precisely draw out what the true benefit of the vaccine itself is when you have a lot of biases in studies with people deciding on their own whether or not to get flu vaccine," she says. "It can be tough to tell the actual benefit of the vaccine. The controversy really is what are the best ways to assess influenza vaccine effectiveness outside of randomized clinical trials."

In that regard, a recent editorial in the British journal Lancet said the only way to resolve the issue is to face the "ultimate taboo" and conduct large, placebo-controlled randomized clinical trials — that is if "governments [are] courageous and honest enough to reassess their cherished policies."6 With flu immunization now a standard recommendation for the elderly, administering a placebo-controlled trial would set off ethical challenges. "We recognize that the use of placebo in such trials would be ethically unappealing, but head-to-head trials that test the currently used inactivated vaccine against other vaccine formulations may be feasible," Simonsen argues in a recent review article.7

The oft-cited clinical trial that was done on the issue was conducted in Holland in the early 1990s.8 "In the one decent randomized clinical trial in the elderly that looked at vaccinated vs. placebo recipients in the Netherlands, vaccination prevented about 55% to 60% of laboratory-confirmed influenza cases. So it was not perfect," says Kristin Nichol, MD, MPH, MBA, core investigator in the center for chronic disease outcomes at the Minneapolis VA Medical Center.

Regarding that clinical trial, Simonsen is quick to point out that demonstration of vaccine benefit fell off at age 70. "It shows the vaccine works in younger seniors in their 60s, but when you get into your 70s, they saw a much lower apparent effectiveness," she tells Hospital Infection Control. "We don't know much about senior benefits because most of the studies are very biased and there is no gold standard clinical trial."

Mortality benefits challenged

In particular, Simonsen and other critics question flu vaccination studies in the elderly that claim reductions in mortality as much as 50%. "These studies have served to appease our minds in the sense that they have claimed astonishing benefits," she says. "They have basically claimed that you can prevent half of all winter deaths for any reason. That can't possibly be true."

In particular, Simonsen has a letter in press challenging the findings of Nichol's recently published paper in the New England Journal of Medicine, which showed flu vaccination in the elderly resulted in a 27% reduction in the risk of hospitalization and a 48% reduction in the risk of death.2 "We have developed a framework to detect bias in studies like that and we apply it to the new data provided in that paper. We show profound bias in all of the four indicators that we looked at," Simonsen says.

Nichol is well aware of the controversy but stands by the findings. "Our study demonstrates significant benefit," she tells HIC. "We conducted a number of analyses specifically to explore for some of the concerns that all of us have as epidemiologists with regard to the possibility of potentially confounding [findings]. We think the findings are very robust."

In the study, data were pooled from 18 cohorts of community-dwelling elderly members of one health maintenance organization (HMO) for 1990-1991 through 1999-2000 and from two other HMOs for 1996-1997 through 1999-2000. Logistic regression was used to estimate the effectiveness of the vaccine for the prevention of hospitalization for pneumonia or influenza and death after adjustment for important covariates. Additional analyses explored for evidence of bias and the potential effect of residual confounding. During 10 seasons, influenza vaccination was associated with significant reductions in the risk of hospitalization for pneumonia or influenza and in the risk of death among community-dwelling elderly people, the authors concluded.

"We included a sensitivity analysis that models the potential impact of an unmeasured confounder and still demonstrated significant benefit," Nichol says. "So from my perspective — particularly with regard to the question of mortality — even if there are unmeasured residual confounders in the studies, the suggestion is that there is still significant mortality benefit. Whether or not the exact number is known isn't as important as the conclusion that there appears to be some mortality benefit."

Even if the mortality issue is completely removed from the equation, the benefits of reduced hospitalizations would more than justify vaccinating the elderly against flu, she emphasizes.

"That is very relevant from the hospital perspective — the so-called controversy tends to focus on mortality — but our study shows significant benefit with regards to [fewer] hospitalizations," Nichol says. "Even if there was zero mortality benefit, just the hospitalization benefit would justify aggressive use of the vaccine."

Breakthrough flu in immunized

Still, the current reality is that the immunized elderly can still acquire influenza. In a study that primarily reported the benefits of using antivirals to reduce flu mortality, Canadian researchers found a high rate of vaccine failure in a prospectively identified cohort of patients with laboratory-confirmed influenza requiring hospital admission. Vaccinated patients hospitalized with flu included 186 (82%) of 227 patients more than 65 years old. "There was a significant burden of illness attributable to influenza in this highly vaccinated population," they noted. ". . . These data demonstrate that life-threatening influenza may still occur in highly vaccinated populations in years when the vaccine is well matched to the infecting strains."9

Despite the findings, the lead author of the study remains a strong proponent of flu vaccine in the elderly, reminding that it doesn't have to be very effective to be cost-effective. "You can't expect too much from [the vaccine], says Allison McGeer, MD, microbiologist and infectious disease consultant at Mount Sinai Hospital in Toronto. "It is important to recognize that in elderly populations there are limits to any of the current vaccines we have."

Those limits were dramatically driven home a few years ago when McGeer saw three nursing home residents with laboratory-confirmed infections with the exact same flu strain (A/Sydney) in successive years. "So even a previous infection was not enough to protect these people," she emphasizes. "If you can't protect with a previous infection, then what you can do with a vaccine is going to be limited."

That said, she finds the whole controversy somewhat puzzling given the aforementioned publication of a randomized clinical trail showing vaccine benefit.

"In most things in life when you have a randomized controlled trial, particularly in the setting of a lot of other evidence, it is a given [benefit]," she says. "For people to look at the data to say [the research] overestimates the effect, to my mind, is silly. A randomized control trial says it works and there is no place in medicine where we should be trying to second-guess that. [But] there is still a huge burden left despite vaccine and we need to worry about that."

An important caveat about McGeer's findings, Nichol notes, is that the study looked at patients hospitalized with influenza and then determined vaccination rates. That is very different from saying there will be a similarly high percentage of vaccine failure in community-dwelling elderly people, she says.

"We started with an entire population, looking at vaccinated and unvaccinated people, and then looking at how many were hospitalized or died," Nichol says. "But it is true even in our study, vaccinated people were hospitalized and vaccinated people died. It's not like it goes to zero. It's just that their risk — after taking into account age and comorbidities — is substantially lower."

That means influenza should not be ruled out in patients coming in to hospitals with flu-like symptoms and a history of vaccination, she notes. "There will be vaccine failures, so from the perspective of [immunized] people coming in to the hospital you should still think about influenza," Nichol says. "They might have it and you should still consider antiviral treatment if it is within the appropriate time frame."

In addition, hospitalized elderly patients should be offered flu vaccine if they have no history of immunization, Bridges adds. "It varies by hospital in terms of when they would do that — at the beginning on ending of a hospitalization," she says. "People who have been hospitalized within the last year also are a high priority for getting vaccine. The inactivated vaccine is the only one available for people 50 and older. It has been out there 60 years. It has a very strong safety profile, and there is certainly no reason why it can't be offered to hospitalized patients. In general, you want to give it to people when they are most likely to have the best immune response, but it is better to give it than to have a missed opportunity."


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