Influenza vaccination in the elderly: effectiveness not in doubt

In a recent review the effectiveness of influenza vaccination in the elderly was brought into question. Selection bias, which would occurr if healthy people were more likely to be vaccinated than their infirm peers, and the use of non-specific outcomes, such as death from all causes, were considered to have contributed to the effectiveness of the vaccine as to morbidity and mortality being overestimated. However, a recent study has shown that even when potential bias and residual confounding were addressed, influenza vaccination was associated with a significant reduction in the risk of influenza-related morbidity and mortality among community-dwelling elderly persons. Direct estimates of influenza-related morbidity were hampered by delayed and insufficiently sensitive diagnostics. Excess studies, however, comparing morbidity and mortality during periods with and without influenza predominance, present reliable indirect estimates in favour of vaccination. While the vaccination rate of high-risk subjects in The Netherlands is traditionally high, the age limit for influenza vaccination was lowered from 65 to 60 in 2008, taking into account influenza-related morbidity and mortality in healthy people aged 60 to 65 years and the undisputed effectiveness of vaccination against influenza.     

Assessing the effectiveness of high-dose influenza vaccine in preventing hospitalization among seniors,and observations on the limitations of effectiveness study design

BackgroundThe availability of high-dose (HD) influenza vaccine for seniors should decrease influenza-related hospitalization. Studies to date show a range of mostly moderate increased HD vaccine effectiveness (VE). While a ‘healthy vaccinee’ phenomenon can inflate VE, for influenza and particularly an HD vaccine targeted at frailer adults, an ‘at-risk vaccinee’ bias may deflate VE estimates. We assessed senior HD vaccine effectiveness against influenza-related hospitalization by linking immunization registry records to hospitalizations. We also examined whether adding strata typically ignored in case-control matching schemas, such as residence areas, exact age, and provider biases, would increase VE.MethodsFor the 2016–17 influenza season in the Portland metropolitan area, the differential VE for the HD vaccine in preventing PCR-confirmed influenza hospitalization was assessed by a nested series of models across matching strata. For an exact match for high-dose and standard-dose seniors, matching elements included exact age, gender, residence type, race-ethnicity, provider bias, and residence area (zipcode).ResultsAs a first step, a simple aggregate comparison of influenza-related hospitalization risk showed no added HD effectiveness. For the nested models, adding strata increased VE. In the final model, among 23,712 matched pairs of HD to SD vaccinated seniors, the HD vaccine was 30.7% (95%CI: 8–48%) more effective in preventing influenza-related hospitalization.ConclusionFor this study, the high-dose influenza vaccine provided superior protection for seniors against influenza hospitalization. Including matching elements as exact year of age and residence zipcode all added to the calculation of VE. As a warning, non-matched or overly simple matched VE study designs may substantially under-estimate VE.     

Influenza vaccine effectiveness against influenza-associated hospitalization in children: A systematic review and meta-analysis

Vaccination remains the most effective way to prevent influenza infection, albeit vaccine effectiveness (VE) varies by year. Compared to other age groups, children and elderly adults have the highest risk of developing influenza-related complications and requiring hospitalization. During the last years, “test negative design” (TND) studies have been implemented in order to estimate influenza VE. The aim of this systematic review and meta-analysis was to summarize the findings of TND studies reporting influenza VE against laboratory-confirmed influenza-related hospitalization in children aged 6 months to 17 years. We searched the PubMed and Embase databases and identified 2615 non-duplicate studies that required detailed review. Among them, 28 met our inclusion criteria and we performed a random-effects meta-analysis using adjusted VE estimates. In our primary analysis, influenza vaccine offered significant protection against any type influenza-related hospitalization (57.48%; 95% CI 49.46–65.49). When we examined influenza VE per type and strain, VE was higher against H1N1 (74.07%; 95% CI: 54.85–93.30) and influenza B (50.87%; 95% CI: 41.75–59.98), and moderate against H3N2 (40.77%; 95% CI: 25.65–55.89). Notably, influenza vaccination offered higher protection in children who were fully vaccinated (61.79%; 95% CI: 54.45–69.13), compared to those who were partially vaccinated (33.91%; 95% CI: 21.12 – 46.69). Also, influenza VE was high in children less than 5 years old (61.71%; 95% CI: 49.29–74.12) as well as in children 6–17 years old (54.37%; 95% CI: 35.14–73.60). In conclusion, in the pediatric population, influenza vaccination offered significant protection against influenza-related hospitalization and complete annual vaccination should be encouraged.     

New strategies are needed to improve the accuracy of influenza vaccine effectiveness estimates among seniors

ObjectiveThe magnitude of the benefit of influenza vaccine among elderly individuals has been recently debated. Existing vaccine effectiveness estimates derive primarily from observational studies, which may be biased. In this paper, we provide a methodological examination of the potential sources of bias in observational studies of influenza vaccine effectiveness in seniors and propose design and analysis strategies to reduce bias in future studies.Study Design and SettingWe draw parallels to bias documented in observational studies of therapies in other areas of medical research including pharmacoepidemiology, discuss reasons why existing adjustment methods in influenza studies may not adequately control for the bias, and evaluate statistical approaches that may yield more accurate estimation of influenza vaccine effectiveness.ResultsThere is strong evidence for the presence of bias in existing observational estimates of influenza vaccine effectiveness in the elderly and the failure of current adjustment methods to reduce bias.ConclusionPromising approaches for reducing bias include obtaining more accurate information on confounders, such as functional status, avoiding all-cause death in favor of outcomes, such as pneumonia or influenza-related pneumonia, and evaluating the extent to which bias is reduced by these and other methods using the ‘control’ period before influenza season.     

Effectiveness of influenza vaccination in preventing influenza-like illness among community-dwelling elderly: population-based cohort study in Japan

A population-based cohort study was conducted during the 2003-2004 season to examine the effectiveness of influenza vaccine among community-dwelling elderly. The subjects consisted of 4787 elderly, ranging from 65 to 79 years. We either interviewed the elderly directly or their families regarding acute febrile illness, hospital visits, hospitalization and death by telephone every month. The vaccination status and physician-diagnosed clinical influenza (hereinafter referred as clinical influenza) were determined based on data obtained from the city office and hospitals, respectively. Influenza-like illness (ILI) was defined as an acute febrile illness (> or = 38.5 degrees C) during the epidemic period. After adjusting for confounders, vaccination decreased ILI significantly (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.17-0.85), but not clinical influenza (OR, 0.76; 95% CI, 0.28-2.06). The results were inconclusive for preventing hospitalization for influenza or pneumonia (OR, 0.37; 95% CI, 0.09-1.47) and death (OR, 3.68; 95% CI, 0.75-18.12), due to the inadequate sample size. In conclusion, the influenza vaccination was thus found to be associated with a decreased ILI during the epidemic period in community-dwelling elderly.     

Influenza and pregnant women: hospitalization burden, United States, 1998-2002

Women in later stages of pregnancy are at increased risk for serious influenza-related morbidity; thus, universal influenza vaccination of pregnant women is recommended. However, vaccine uptake in the United States has been suboptimal. We previously described the burden of severe influenza-related morbidity during pregnancy in the United States by examining hospitalizations of pregnant women with respiratory illness during influenza season. Nondelivery hospitalizations with respiratory illness had significantly longer lengths of stay than those without respiratory illness. Hospitalization characteristics associated with greater likelihood of respiratory illness were the presence of a high-risk condition for which influenza vaccination is recommended, Medicaid/Medicare as primary expected payer, and hospitalization in a rural area. These findings may be explained by these women being at higher risk of influenza-related morbidity or reflect disparities in receipt of influenza immunization. Universal vaccination of pregnant women to decrease influenza-related morbidity should be encouraged.     

Evidence of bias in estimates of influenza vaccine effectiveness in seniors

BACKGROUND: Numerous observational studies have reported that seniors who receive influenza vaccine are at substantially lower risk of death and hospitalization during the influenza season than unvaccinated seniors. These estimates could be influenced by differences in underlying health status between the vaccinated and unvaccinated groups. Since a protective effect of vaccination should be specific to influenza season, evaluation of non-influenza periods could indicate the possible contribution of bias to the estimates observed during influenza season. METHODS: We evaluated a cohort of 72,527 persons 65 years of age and older followed during an 8 year period and assessed the risk of death from any cause, or hospitalization for pneumonia or influenza, in relation to influenza vaccination, in periods before, during, and after influenza seasons. Secondary models adjusted for covariates defined primarily by diagnosis codes assigned to medical encounters. RESULTS: The relative risk of death for vaccinated persons compared with unvaccinated persons was 0.39 [95% confidence interval (95% CI), 0.33-0.47] before influenza season, 0.56 (0.52-0.61) during influenza season, and 0.74 (0.67-0.80) after influenza season. The relative risk of pneumonia hospitalization was 0.72 (0.59-0.89) before, 0.82 (0.75-0.89) during, and 0.95 (0.85-1.07) after influenza season. Adjustment for diagnosis code variables resulted in estimates that were further from the null, in all time periods. CONCLUSIONS: The reductions in risk before influenza season indicate preferential receipt of vaccine by relatively healthy seniors. Adjustment for diagnosis code variables did not control for this bias. In this study, the magnitude of the bias demonstrated by the associations before the influenza season was sufficient to account entirely for the associations observed during influenza season.     

The Relationship between Influenza Vaccination and Outpatient Visits for Upper Respiratory Infection by the Elderly in Taiwan

OBJECTIVE: To evaluate the effect of influenza vaccination on the reduction of the risk of outpatient visits for upper respiratory infection (URI) among the elderly in Taiwan. METHODS: The data for this observational study, consisting of 1729 people aged 65 years or older, were drawn from Taiwan's 2001 National Health Interview Survey. This survey data was then linked with National Health Insurance claim data for December 2001 to November 2002. Survival analysis of Cox proportional hazards model was performed to examine the risk of URI outpatient visits in elderly people vaccinated with the influenza vaccine and those not vaccinated during a year-long study period since the influenza season began. To adjust for potential self-selection bias, we used propensity score method to categorize individuals into two groups, based on the predicted probability of being vaccinated from a logistic regression of spatial random effect. Propensity score group 1 (PSG 1) were those with a predicted probability of being vaccinated lower than 0.5, and PSG 2 were those with a predicted probability of being vaccinated of 0.5 or higher. RESULTS: The overall vaccination rate was 50%. Logistic regression showed the probability of being vaccinated was related to the number of outpatient visits for URI before the influenza season began (odds ratio (OR) 1.07; 95% confidence interval (CI) 1.04-1.10). Our first survival analysis showed that being vaccinated significantly reduced the risk of URI outpatient visits in PSG 2 during the 1-year study period (hazard ratio 0.89; 95% CI 0.81-0.97). Separate survival analysis showed that being vaccinated reduced the risk of URI outpatient visits for both PSG groups during the first 3 months of the study period. CONCLUSION: Being vaccinated could reduce the risk of outpatient visits for URI among the elderly during the influenza season.     

Could a federal program to promote influenza vaccination among elders be cost-effective?

BACKGROUND: Influenza-related mortality predominately and disproportionately impacts the elderly. Rates of annual influenza vaccination among the elderly are approximately 65%, far below the Healthy People 2010 target of 90%. We estimated the cost-effectiveness of a 10-year federal program to promote influenza vaccine, intended to increase vaccination rates among persons > or = 65 years old. METHODS: Published estimates regarding influenza-associated mortality rates and vaccine efficacy among the US elderly were used to calculate the number needed to vaccinate (NNV) to prevent one all-cause death due to influenza, as well as the mortality reduction expected from increased vaccination rates. The costs per life-year saved were estimated for a hypothetical federal promotional campaign, patterned after a direct-to-consumer (DTC) advertising program (2006-2015). The base case scenario presumed a 25-percentage-point increase in vaccination rates to 90%; in sensitivity analyses, we examined programs that increased rates by 10-20 points. RESULTS: The base case NNV was 1116 (95% CI: 993-1348). Over the 10-year DTC-style influenza vaccine promotion program, 6516 (5576-7435) elderly lives would be saved. The incremental cost-effectiveness (C/E) of the program was dollar 16,300 (dollar 11,347-dollar 25,174) per life-year saved in 2006 and increased to dollar 199,906 (dollar 138,613-dollar 307,423) per life-year saved by 2015. Overall, the C/E for the 10-year program was dollar 37,621 (dollar 32,644-dollar 43,939) per life-year saved. Programs that yielded a 15-percentage-point increase or less in vaccination rates would have C/E values exceeding dollar 50,000 per life-year saved and save fewer than 4000 total lives. CONCLUSIONS: DTC-style promotional campaigns for influenza vaccine among elders may represent a cost-effective strategy for the federal government to pursue as a means of increasing elders' vaccination rates and reducing influenza-related mortality.     

A retrospective cohort study assessing relative effectiveness of adjuvanted versus high-dose trivalent influenza vaccines among older adults in the United States during the 2018–19 influenza season

PurposeTo evaluate the relative vaccine effectiveness (rVE) against influenza-related hospitalizations/emergency room (ER) visits, influenza-related office visits, and cardio-respiratory disease (CRD)-related hospitalizations/ER visits and compare all-cause and influenza-related costs associated with two vaccines specifically indicated for older adults (≥65 years), adjuvanted (aTIV) and high-dose trivalent influenza vaccine (TIV-HD), for the 2018–19 influenza season.MethodsA retrospective analysis of older adults was conducted using claims and hospital data in the United States. For clinical evaluations, adjusted analyses were conducted following inverse probability of treatment weighting (IPTW) to control for selection bias. Poisson regression was used to estimate the adjusted rVE against influenza-related hospitalizations/ER visits, influenza-related office visits, and any CRD-related hospitalizations/ER visits. For the economic evaluation, treatment selection bias was adjusted through 1:1 propensity score matching (PSM). All-cause and influenza-related costs associated with hospitalizations/ER, physician office and pharmacy visits were adjusted using generalized estimating equation (GEE) models.ResultsAfter IPTW and Poisson regression, aTIV (n = 561,315) was slightly more effective in reducing influenza-related office visits compared to TIV-HD (n = 1,672,779) (6.6%; 95% CI: 2.8–10.3%). aTIV was statistically comparable to TIV-HD (2.0%; 95% CI: −3.7%-7.3%) in preventing influenza-related hospitalizations/ER visits but more effective in reducing hospitalizations/ER visits for any CRD (2.6%; 95% CI: 2.0–3.2%). In the PSM-adjusted cohorts (n = 561,243 pairs), following GEE adjustments, predicted mean annualized all-cause and influenza-related total costs per patient were statistically similar between aTIV and TIV-HD (US$9676 vs. US$9625 and US$18.74 vs. US$17.28, respectively; both p > 0.05). Finally, influenza-related pharmacy costs were slightly lower for aTIV as compared to TIV-HD ($1.75 vs $1.85; p < 0.0001).ConclusionsDuring the 2018–19 influenza season, influenza-related hospitalization/ER visits and associated costs among people aged ≥ 65 were comparable between aTIV and TIV-HD. aTIV was slightly more effective in preventing influenza-related office visits and any CRD event as compared to TIV-HD in this population.