Our study yielded 2 important findings relevant to adults aged 50 years and older. First, laboratory-confirmed influenza was associated with nearly 10% of overall respiratory hospitalizations during 3 successive influenza seasons. Second, influenza vaccine had an estimated overall effectiveness of 61% for the prevention of influenza-associated hospitalizations.
The bulk of information on the burden of influenza in older adults has come from modeling studies that have used administrative databases to estimate influenza-associated hospitalizations. Thompson et al used national hospital discharge data collected over 22 seasons (1979–2001) to estimate average annual age-specific hospitalization rates [2
]. According to their estimates, influenza-associated hospitalizations increased remarkably with age from nearly 1 per 1000 persons aged 50–64 years to 17 per 1000 persons aged 85 years and older. Mullooly et al [18
] found a similarly high rate of estimated influenza-associated hospitalizations in older adults using data from 3 health maintenance organizations over 4 influenza seasons. Estimated hospitalizations among unvaccinated high-risk persons aged 50–64 years were 2 per 1000 and among unvaccinated persons 65 years and older, without and with high-risk conditions, were 3 per 1000 and 11 per 1000, respectively.
Few studies have examined the prevalence of influenza among older hospitalized adults using modern molecular diagnostic techniques. Falsey et al [19
] prospectively enrolled adults admitted for acute respiratory symptoms during 4 winter respiratory virus seasons (1999–2003) and used RT-PCR to assess the burden of hospitalizations due to both influenza and respiratory syncytial virus (RSV). Similar to our study, these investigators included both admissions for pneumonia and influenza and for other conditions such as chronic obstructive pulmonary disease and congestive heart failure exacerbations. Although they focused exclusively on adults aged 65 years and older, 11.6% (170 of 1471 patients) of their hospitalizations were due to influenza, remarkably similar to the 9% reported in our study. Both studies highlight the difficulties of performing vaccine effectiveness studies using nonspecific endpoints, such as acute respiratory hospitalizations, because a minority of hospitalizations in both studies were due to influenza.
The second major finding of our study was that the overall estimated vaccine effectiveness for the prevention of laboratory-confirmed influenza-associated hospitalizations was 61%, despite that 2 of the 3 seasons had considerable mismatch between the vaccine and circulating strains. Although the individual yearly estimates were nearly identical to the overall rate, the numbers were too small to detect meaningful between-year differences.
Although this was not a randomized control trial, our data are important for several reasons. First, the recent Cochrane review [5
] identified only 1 high-quality randomized clinical trial of influenza vaccine efficacy in older adults. In that trial, vaccine efficacy was reported to be 58% for the prevention of serologically confirmed influenza in healthy ambulatory adults aged ≥60 y [20
] and 57% (95% CI, −
36% to 87%) in those ≥70 y of age [21
]. Because that trial was relatively small and performed in healthy elderly persons, it did not provide data on vaccine effectiveness in frail elderly persons, or estimate effectiveness against influenza-associated hospitalizations or deaths, endpoints that have been the subject of recent controversy [22
]. The remainder of the 68 Cochran-reviewed studies of vaccine effectiveness evaluated nursing home patients, did not evaluate hospitalizations, or did not use laboratory-confirmed influenza hospitalizations as an end point. As noted previously, influenza admissions constitute only about 10% of acute respiratory hospitalizations during influenza seasons, introducing major misclassification of outcome into these other assessments.
A recent study by Herrera et al [23
], not included in the Cochrane analysis, evaluated influenza vaccine effectiveness for the prevention of hospitalization in adults 50–64 years of age using laboratory-confirmed influenza and community controls. Vaccine effectiveness was 35.6% (95% CI, 0%–63.2%) and 90.5% (95% CI, 68.1%–97.2%) for those with and without high-risk conditions, respectively. Methodologically, our study differed from the Herrera study in that we used hospitalized rather than community-based controls. Although the use of hospitalized controls has traditionally been considered a weaker design option than community-based controls, it may allow better control for factors associated with need for hospitalization. In addition, using influenza-negative hospitalized controls has been shown to be an efficient design for vaccine-effectiveness evaluations [24
] and has been used effectively in pediatric [25
] and adult outpatient settings [26
] to measure influenza-vaccine effectiveness. A second recent study, not included in the Cochrane review, by Baxter et al [27
] estimated influenza vaccine effectiveness against influenza-associated pneumonia and influenza hospitalizations. This study used models to estimate influenza-associated hospitalizations from nonspecific hospitalizations coupled with viral surveillance data and effectively accounted for frailty bias attributed to prior modeling studies. Average influenza vaccine effectiveness over the eleven study years was 28% (95% CI, 8.5%–30.0%) for those ages 50 to 64 years and 48% (95% CI, 12.4%–26.0%) for those 65 y and older.
One might expect that vaccination would be better at preventing serious outcomes (hospitalizations, deaths) than more mild disease. However, patients with more serious influenza-associated events are generally a select group of older persons with other comorbidities. Indeed, nearly all our enrolled patients had at least 1 high-risk condition and may have been less likely to mount a brisk immune response after vaccination. Despite this, our vaccine effectiveness estimates are remarkably similar to those reported in the only RCT conducted in healthy older adults [20
We chose a hospital-based case control design to assure that cases and controls were similar with respect to underlying risk factors for hospitalization. Although we enrolled only about 50% of eligible cases, exclusions were based mainly on patient or surrogate refusals and were unlikely to be influenced by influenza status, which was unknown at the time of enrollment. Those with influenza were actually remarkably similar to controls who were hospitalized with other acute respiratory illnesses. Although functional status was measured in only 1 study year, the distribution of functional status scores, using the Barthel Index, was similar in cases and controls and suggested that the enrolled patients were functioning well. () This likely limits the generalizability of our findings to the more highly functioning hospitalized adults. Although differences were noted between vaccinated and unvaccinated () participants, these differences were modest and were controlled for by propensity score adjustment. Three sensitivity analyses were conducted and yielded consistent results; 1 that excluded patients without confirmation of vaccination, the second that trimmed propensity scores to exclude those with very low or high propensity for vaccination, and the third that considered vaccinations after only 1 rather than 2 weeks prior to hospitalization. In addition, results were consistent when patients were stratified by year, age, sex, race, and smoking status, although these subgroups were small in number. Because of the limited number of cases, further detailed analyses such as estimation of effectiveness based on quantitative PCR, low risk medical conditions, age, and sex could not be performed.
Each year there are an estimated 300,000 hospitalizations attributable to influenza in the United States, most of which are in older adults [2
]. Based on our vaccine effectiveness estimates, these numbers would more than double in the absence of the current vaccination program. Better coverage with current vaccines and development of more effective influenza vaccines could reduce these numbers further. This study strongly supports the current United States policy of recommending annual influenza vaccination for older adults.
This work was supported by the Vaccine and Treatment Evaluation Units of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (grant N01 AI25462); the Centers for Disease Control and Prevention (grant 1U181P000184-01); the National Center for Research Resources at the National Institutes of Health (grant 5 K12 RR017697-05 to H.K.T.); the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (grant 1K23AI074863-01 to H.K.T.); and the Vanderbilt Clinical and Translational Science Award (grant 1 UL1 RR024975).
The funders did not participate in the design or conduct of the study; collection, management, analysis, or interpretation of the data; nor preparation, review, or approval of the manuscript.