- Email: [email protected]
A meta-analysis of effectiveness of influenza vaccine in persons aged 65 years and over living in the community
Vaccine 20 (2002) 1831–1836
A meta-analysis of effectiveness of influenza vaccine in persons aged 65 years and over living in the community Trang Vu a,∗ , Stephen Farish b,1 , Mark Jenkins b,1 , Heath Kelly c,2 a
c
Victorian Public Health Training Program, Charles Connibere Building, The Royal Melbourne Hospital, Flemington Road, Parkville, Vic. 3050, Australia b Epidemiology and Biostatistics Unit, Department of Public Health, School of Population Health, The University of Melbourne, Melbourne, Vic. 3010, Australia Epidemiology Division, Victorian Infectious Diseases Reference Laboratory, 10 Wreckyn Street, North Melbourne, Melbourne, Vic. 3051, Australia Received 24 July 2001; received in revised form 5 November 2001; accepted 5 December 2001
Abstract Aim: To estimate the effectiveness of inactivated influenza vaccine in persons aged 65 years and over living in the community. Scope: A meta-analysis of studies selected using predetermined criteria without language restriction. Conclusion: Influenza vaccine was effective in reducing influenza-like illness by 35% (95% confidence interval (CI) 19–47%), hospitalization for pneumonia and influenza by 33% (CI 27–38%), mortality following hospitalization for pneumonia and influenza by 47% (CI 25–62%); and mortality from all causes by 50% (CI 45–56%). © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Influenza vaccine; Effectiveness; Community-living
1. Introduction Although influenza affects all age groups, persons with underlying medical conditions and persons aged 65 years and over are at greatest risk of severe illness and possibly death [1,2]. As recommended by the World Health Organization, the major strategy for controlling influenza is annual immunization of those at greatest risk with an inactivated influenza vaccine [3]. However, published studies on influenza vaccine effectiveness (VE) have produced inconsistent results. The only randomized double-blind placebo-controlled trial, conducted in The Netherlands in the 1991–1992 influenza season, found that the vaccine reduced serologically-confirmed influenza by 50% (95% CI 39–65%) [4]. However, the reduction was only 23% (95% CI 51–61%) in persons 70 years of age and over. One cohort and two case-control studies have reported low estimates of VE with wide confidence intervals, including the possibility that the vaccine had no effect [5–7]. ∗ Corresponding author. Tel.: +1-613-934-22608; fax: +1-613-934-22665. E-mail addresses: [email protected] (T. Vu), [email protected] (S. Farish), [email protected] (M. Jenkins), [email protected] (H. Kelly). 1 Tel.: +1-613-83447276; fax: +1-613-93476136. 2 Tel.: +1-613-93422608; fax: +1-613-93422665.
A previously published meta-analysis of influenza VE in the elderly concentrated largely on residents of nursing homes [8]. The only meta-analysis of influenza VE in persons aged 65 years and over living in the community is a Spanish language publication [9] limited to one influenza-related outcome. With the aim of estimating influenza VE for all major influenza-related outcomes for persons aged 65 years and over living in the community, we performed a comprehensive and systematic review of the available literature and a meta-analysis on studies that satisfied specified inclusion and exclusion criteria.
2. Methods We followed guidelines for preparing systematic reviews and meta-analyses, using multiple sources of information without language restriction [10–12]. The cut-off date for the literature search was the 31 December 2000. Differences in the effectiveness of whole virion, subunit virion and split virion vaccines were outside the scope of this study. Additionally, we excluded studies examining differences between single and multiple vaccinations, influenza vaccine immunogenicity or cost-effectiveness studies and studies investigating the additive benefits of combined influenza and pneumococcal vaccination.
0264-410X/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 0 2 ) 0 0 0 4 1 - 5
1832
T. Vu et al. / Vaccine 20 (2002) 1831–1836
Table 1 Inclusion and exclusion criteria for studies selected for review
Table 2 Influenza-related outcomes assessed in this study
Inclusion criteria: Inactivated influenza vaccine was used The study period was determined by influenza surveillance The study population comprised of community-living persons aged 65 years and over. For this meta-analysis, independent living in retirement villages was regarded as community-living
Outcome assessed
Number of studiesa
Influenza-like illness Outpatient visits for pneumonia and influenza Hospitalization for all respiratory conditions Hospitalization for pneumonia and influenza Mortality following hospitalization for pneumonia and influenza Mortality from all causes
3 2 4 9 3
Exclusion criteria: A cross-sectional design was used Influenza strains in the vaccine did not match influenza strains in circulation or the degree of vaccine antigenic match was not reported The comparability of the study groups, with respect to age, gender and the presence of underlying medical conditions, was not reported The study was conducted in a mixed population of institutionalized and community-living persons and estimates for community-living persons were not reported separately The study was conducted in many age groups and estimates for persons aged 65 years and over were not reported separately. However, the study was included if more than 50% of participants were 65 years and over The number of participants was 30 or fewer The publication had been duplicated, was a letter, opinion or debate
2.1. Study identification and appraisal A literature search to identify potential studies used the terms “influenza vaccine”, “VE”, “vaccine efficacy” and “elderly”. We combined these terms with the logical operator “not” and the term “nursing home” to exclude studies involving institutionalized elderly. Biomedical databases used in the search included Medline, Biosis, FirstSearch, Bandolier, Cochrane Library, Current Contents, Effectiveness Matters, Derwent Drug File, American College of Physicians Journal Club and Database of Abstracts of Reviews of Effectiveness (DARE). Influenza-dedicated databases, including FluNet (the World Health Organization), the CDC Influenza Home Page (Center for Disease Control and Prevention) and the Influenza Bibliography (National Institute for Medical Research, London) were also included in the search, as were several government Internet sites. Articles selected for inclusion were searched manually to identify further publications. Two prominent researchers in the field were asked to assist in identifying unpublished studies and to review our bibliography. Inclusion and exclusion criteria for the studies identified by this search are shown in Table 1. Two authors appraised and selected the studies independently using separate standardized forms for different study designs. A quality rating system was not used. 2.2. Data synthesis In this meta-analysis, vaccination status was defined as vaccinated or unvaccinated. Where available, ratio measures of influenza-related outcomes comparing vaccinated
4
a
Some studies investigated more than one outcome and/or were conducted over several influenza seasons.
and unvaccinated persons, adjusted for age, gender and the presence of underlying medical conditions, were recorded. Unadjusted measures were used if they were the only results reported. For case-control studies that used more than one control group, the controls whose influenza vaccine coverage was more like the cases were used in the meta-analysis. We used the formula VE = (1 − RR) × 100, where RR is the relative risk of influenza-related outcomes in vaccinated compared with unvaccinated persons. In case-control studies, the RR was approximated by the odds ratio. We calculated summary estimates of VE for all major influenza-related outcomes listed in Table 2 using the random-effects model described by DerSimonian–Laird and the general-variance based method of the fixed-effects model [13,14]. The use of methods based on both models allowed for a form of sensitivity analysis [11]. Subgroup analysis was not performed because of the insufficient number of subgroups. We investigated the variation between studies using statistical tests for heterogeneity [11]. Data synthesis was performed separately for each study design and, if no statistical evidence of heterogeneity was found, results from all designs were pooled to obtain summary estimates of VE [12]. Publication bias was investigated using the Begg and Mazumdar adjusted rank correlation test [15]. Stata for Windows (Version 6) was used to perform calculations and to produce graphs [16].
3. Results 3.1. Studies included in the meta-analysis Database and website searches identified 49 relevant publications, including 12 publications in languages other than English. Of the latter group, six satisfied the inclusion/exclusion criteria and were translated by qualified translators [9,17–21]. No additional publications or unpublished studies were identified by manual searches or by the two prominent researchers in the field. We excluded 34 of the 49 publications. Table 3 summarizes nine studies excluded for reasons other than being a duplication, debate or opinion. The excluded studies were
T. Vu et al. / Vaccine 20 (2002) 1831–1836 Table 3 Summary of studies excluded for reasons other than duplication, opinion or debate Author
Reason for exclusion
Ikematsu and Kashiwagi [19] Jianping et al. [22] Schoenbaum et al. [23] Gene et al. [18] Connolly et al. [24] Bonvehi et al. [25] Carrat et al. [26]
Vaccine antigenic match not reported Vaccine antigenic match not reported Vaccine antigenic match not reported Comparability of study groups unknown Comparability of study groups unknown Comparability of study groups unknown Estimates for community-living elderly not reported Estimates for community-living elderly not reported Small study
Ahmed et al. [27] Nguyen-Van-Tam and Nicholson [28]
conducted between 1968 and 1996, in a range of settings in many countries. Most were non-experimental with sample sizes ranging from 300 to more than 80,000. The lack of information regarding the comparability of study groups and the absence of information about vaccine antigenic match to circulating influenza virus strains were the most common reasons for exclusion.
1833
The remaining 15 studies eligible for inclusion in the meta-analysis are summarized in Table 4. They were performed over a similar time period to the excluded studies, with similar study designs and sample sizes. The majority of included studies were conducted exclusively in persons living in the community aged 65 years and over. 3.2. Vaccine effectiveness For the outcome hospitalization for pneumonia and influenza, we calculated VE separately for case-control and cohort studies and combined these estimates following a non-significant test for heterogeneity. For the other outcomes of interest, the number of studies was too small to perform analysis by study design and all eligible studies were combined. Fig. 1 presents fixed-effects model estimates of influenza VE for the outcomes of interest. The smallest reduction (6–26%) was found for the outcome outpatient visits for pneumonia and influenza whereas the largest reduction (25–62%) was associated with the outcome mortality following hospitalization for pneumonia and influenza. The choice of model did not alter these estimates and there was no statistical evidence of heterogeneity, except for the
Table 4 Summary of eligible studies by influenza-related outcomesa Outcome
Author
Study design
VE as percentages (95% CI)
Influenza-like illness
Govaert et al. [4]
48 (5–71)
Stuart et al. [29] Sandrini et al. [21]
Randomised double-blind placebo-controlled trial Clinical trial Cohort
51 (30–66) 26 (−3 to 46)
Outpatient visits for P&I
Nichol [30] Mullooly et al. [31]
Cohort Case-control
15 (4–25) 29 (−27 to 60), 43 (−39 to 76)
Hospitalization for all respiratory conditions
Lopez et al. [20]
Cohort
10 (−78 to 54)
Nichol [30] Ahmed et al. [7] Fedson et al. [32]
Cohort Case-control Case-control
32 (29–40) 19 (0–82) 17 (1–32), 32 (20–43)
Hospitalization for P&I
Barker and Mullooly [33] Nichol [30] Barker et al. [5] Fedson et al. [32] Foster et al. [34] Mullooly et al. [31] Ohmit and Monto [35] Puig-Barbera and Marquez Calderon [36] Strikas et al. [6]
Cohort Cohort Case-control Case-control Case-control Case-control Case-control Case-control Case-control
74 39 17 37 33 31 31 79 14
Mortality following hospitalization for P&I
Barker and Mullooly [33]
Cohort
85 (−144 to 99)
Fedson et al. [32] Mullooly et al. [31]
Case-control Case-control
64 (19–84), 54 (7–77) 33 (−6 to 58)
Stuart et al. [29] Fleming et al. [37] Lopez et al. [20] Nichol [30]
Clinical trial Cohort Cohort Cohort
81 75 3 50
Mortality from all causes
a
(−8 to 94) (26–52) (−43 to 51), 41 (1–65), 12 (−34 to 32) (15–53), 39 (19–53) (8–52) (17–42), 40 (1–64) (4–51), 32 (7–50) (45–92) (−12 to 34)
(21–95) (21–92) (−63 to 42) (44–56)
For studies conducted over several seasons or in many subgroups, separate estimates of VE are recorded, if available; P&I: pneumonia and influenza.
1834
T. Vu et al. / Vaccine 20 (2002) 1831–1836
model was used, the estimate became 14–71 and 32–78%, respectively. The Begg and Mazumdar adjusted rank correlation test for publication bias, performed on 12 studies investigating hospitalization for pneumonia and influenza, indicated no evidence of publication bias (P = 0.537). However, the test lacks power when the number of studies is 20 or fewer [38]. Therefore, we did not perform this test on the remaining studies because there were even fewer studies investigating the other outcomes.
4. Discussion
Fig. 1. Fixed-effects model estimates of influenza vaccine effectiveness in persons aged 65 years and over living in the community. Each horizontal line represents one outcome with the diamond being the point estimate of vaccine effectiveness and the outlying bars being the 95% confidence intervals.
outcome mortality from all causes. For this outcome, evidence of statistical heterogeneity was detected with the addition of the study by Lopez et al. [20], which was conducted when no influenza activity was detected. According to the fixed-effects model, the summary estimate of reduction in all-cause mortality with and without this study was 43–55 and 45–56%, respectively. When the random-effects
Results of this meta-analysis confirm that the influenza vaccine is effective in reducing influenza-related illness and death among persons 65 years and over living in the community. When there is a good match between influenza strains in the vaccine and those in circulation, vaccination would prevent approximately one in five cases of influenza-like illness, one in four hospitalizations for pneumonia and influenza and one in four deaths following hospitalization for these conditions. These estimates are independent of the model used, but may reflect biases in the selection of studies for inclusion in the meta-analysis. The biases may include those due to the databases searched, publication and language bias. However, as detailed in the Methods, we attempted to minimize these potential biases by searching multiple databases without language restriction, examining reference lists in retrieved publications and having prominent researchers in the field review the study bibliography for completeness. VE estimates reported by this meta-analysis may also be affected by biases in the primary studies. However, if the
Fig. 2. Comparison with results of other meta-analyses. Each horizontal line represents one study with the diamond being the point estimate of vaccine effectiveness and the outlying bars being the 95% confidence intervals.
T. Vu et al. / Vaccine 20 (2002) 1831–1836
biases are not systematic these estimates are likely to be conservative [39]. Despite being conducted in different countries, during different influenza seasons and using vaccines produced by different manufacturers, the studies showed no statistical heterogeneity. This argues for the reliability of the VE estimates from this meta-analysis. Moreover, the estimates from this meta-analysis were similar to those of three other meta-analyses. These studies were of elderly people living in the community (published in Spanish) [9], elderly persons living in nursing homes [8] and healthy adults [40]. Fig. 2 compares the results of the current study with the three other meta-analyses. The reduction of influenza-like illness estimated by the current study is similar to the estimate in the study of healthy adults. The estimate of reduction in hospitalization for pneumonia and influenza in this study is very similar to the result of the Spanish study. Differences between results produced by this study and the meta-analysis of studies in institutionalized elderly persons can be explained by the dissimilarity between the two populations with respect to age, disease risk, vaccination rate and rate of underlying medical conditions. All but one of the studies included in this meta-analysis were of non-experimental design and all were conducted in developed countries in North America and Europe. The influenza VE estimates obtained from this meta-analysis are thus likely to be applicable to most developed countries, but perhaps not to developing countries where the burden of influenza may be lower than that of other infectious diseases [41].
[5]
[6]
[7]
[8]
[9]
[10] [11]
[12]
[13] [14] [15]
Acknowledgements
[16] [17]
We would like to thank Dr. J.S. Nguyen-Van-Tam from the University of Nottingham and Dr. Kristin L. Nichol from the Veterans Affairs Medical Center (Minneapolis) for their comments on the bibliography. We are indebted also to Mr. Shigeru Takahashi and Ms. Qui Nguyen for their translation of a study written in Japanese, and to Dr. David Fairservice for his translation of Spanish and Italian articles. We thank Julianne Lynch for her helpful suggestions during the preparation of the manuscript.
[18]
[19] [20]
[21]
References [22] [1] Couch RB. Orthomyxoviruses. In: Baron S, editor. Medical microbiology. 2nd ed. Menlo Park (CA): Addison-Wesley, 1986. p. 855–64. [2] Berlin BS. Influenza. In: Youmans GP, Paterson PY, Sommers HM, editors. The biologic and clinical basis of infectious diseases. 3rd ed. Philadelphia: W.B. Saunders Company, 1986. p. 332–43. [3] Hannoun C. Private or national health insurance for adult vaccination in developed countries? Vaccine 1999;17(Suppl):S99–S101. [4] Govaert TM, Thijs CT, Masurel N, Sprenger MJ, Dinant GJ, Knottnerus JA. The efficacy of influenza vaccination in elderly
[23]
[24]
[25]
1835
individuals. A randomized double-blind placebo-controlled trial. JAMA 1994;272(21):1661–5. Barker W, Raubertas R, Menegus M, O’Brien D, Freundlich C, Betts R. Case-control study of influenza vaccine effectiveness in preventing pneumonia hospitalization among older persons. In: Proceedings of the International Conference on Options for the Control of Influenza II. Monroe County, New York, 1989–1992, France: Courchevel, 1992. Strikas R, Cook P, Kuller L, et al. Case-control study in Ohio and Pennsylvania on prevention of hospitalisation by influenza vaccination York. In: Proceedings of the International Conference on Options for the Control of Influenza II. France: Courchevel, 1992. Ahmed AH, Nicholson KG, Nguyenvantam JS, Pearson JCG. Effectiveness of influenza vaccine in reducing hospital admissions during the 1989–1990 epidemic. Epidemiol Infect 1997;118(1):27– 33. Gross A, Hermogenes W, Sacks S, Lau J, Levandowski A. The efficacy of influenza vaccine in elderly persons: a meta-analysis and review of the literature. Ann Intern Med 1995;123(7):518–27. Puig-Barbera J, Marquez Calderon S. Effectiveness of influenza vaccine in the elderly: a critical review of the bibliography (Spanish). Med Clin (Barc) 1995;105:645–8. Cochrane Collaboration. The Cochrane Manual, Version 9904. July 1999. Petitti DB. Meta-analysis. Decision analysis, and cost-effectiveness analysis methods for quantitative synthesis in medicine. Oxford (New York): Oxford University Press, 1994. NHS Center for Reviews and Dissemination (CRD). Undertaking Systematic Reviews of Research on Effectiveness. CRD Guidelines for Those Carrying Out or Commissioning Reviews. CRD Report No. 4,1996. Dersimonian R, Laird N. Meta-analysis in clinical trials. Cont Clin Trials 1986;7:177–88. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 1987;9:1–30. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088–101. StataCorp. Stata Statistical Software, Release 6. College Station (TX): Stata Corporation, 1999. Crovari CP, Gasparini R, Crovari P. Ricerche sulla efficacia della vaccinazione influenzale: risultati in una comunita’ controllata per un biennio. Boll Lst Sieroter Milan 1980;59(4):306–13. Gene Badia J, Calero Munoz S, Castanera Ribe C, Gran Rovireta A. Efectividad de un programa de vacunacion antigripal en cuatro centros de atencion primaria. Gaceta Sanitaria 1991;5(26): 203–8 Ikematsu H, Kashiwagi S. Efficacy and adverse reactions of influenza vaccine in the elderly (Japanese). Nippon Rinsho 1997;55:2751–7. Lopez Hernandez B, Vazquez J, Fernandez E, Martinez B, Romero J, Arribas L. Efectividad de la vacunacion antigripal en ancianos. Atencion Primaria 1994;14(1):532–6. Sandrini MC, Pregliasco F, Mensi C, et al. Valutazione dell’immunogenicita e dell’efficacia sul campo (stagione 1994–1995) del vaccino antinfluenzale in una popolazione di anziani non istituzionalizzati. Annali Di Igiene 1997;9:373–9. Jianping H, Xin F, Changshun L, et al. Assessment of effectiveness of Vaxigrip. Vaccine 1999;17(Suppl):S57–8. Schoenbaum C, Mostow SR, Dowdle WR, Coleman MT, Kaye HS. Studies with inactivated influenza vaccines purified by zonal centrifugation. Bull Who 1969;41:531–5. Connolly AM, Salmon RL, Lervy B, Williams DH. What are the complications of influenza and can they be prevented? Experience from the 1989 epidemic of H3N2 influenza A in general practice. Br Med J 1993;306:1452–4. Bonvehi P, Nacinovich F, Ruttimann R, Vujacich C, Giannone C, Stamboulian D. Effectiveness of influenza vaccine in elderly people
1836
[26]
[27]
[28]
[29]
[30] [31]
[32]
[33]
T. Vu et al. / Vaccine 20 (2002) 1831–1836 living in the community in Argentina. Abstracts of the Interscience Conference on Antimicrobial Agents & Chemotherapy 1997;37:238. Carrat F, Tachet A, Rouzioux C, Housset B, Valleron A-J. Field investigation of influenza vaccine effectiveness on morbility. Vaccine 1998;16(9/10):893–8. Ahmed AE, Nicholson KG, Nguyen-Van-Tam JS. Reduction in mortality associated with influenza vaccine during the 1989–1990 epidemic. Lancet 1995;346(8975):591–5. Nguyen-Van-Tam JS, Nicholson KG. Influenza deaths in Leicestershire during the 1989/1990 epidemic: implications for prevention. Epidemiol Infect 1992;108:537–45. Stuart WH, Dull B, Newton LH, McQueen JL, Schiff ER. Evaluation of monovalent influenza vaccine in a retirement community during the epidemic of 1965–1966. JAMA 1969;209(2):232–8. Nichol KL. Complications of influenza and benefits of vaccination. Vaccine 1999;17:S47–52. Mullooly J, Bennett M, Hornbrook M, et al. Influenza vaccination programs for elderly persons: cost-effectiveness in a health maintenance organisation. Ann Intern Med 1994;121:947–52. Fedson DS, Wajda A, Nicol JP, Hammond GW, Kaiser DL, Roos LL. Clinical effectiveness of influenza vaccination in Manitoba (published erratum appears in JAMA, 1994;271:1578). JAMA 1993;270(16):1956–61. Barker W, Mullooly J. Influenza vaccination of elderly persons. Reduction in pneumonia and in influenza hospitalization and deaths. JAMA 1980;244(22):2547–9.
[34] Foster A, Talsma A, Furumoto-Dawson A, et al. Influenza vaccine effectiveness in preventing hospitalization for pneumonia in the elderly. Am J Epidemiol 1992;136(3):296–307. [35] Ohmit E, Monto S. Influenza vaccine effectiveness in preventing hospitalization among the elderly during influenza type A and type B seasons. Int J Epidemiol 1995;24(6):1240–8. [36] Puig-Barbera J, Marquez-Calderon S, Masoliver-Fores A, et al. Reduction in hospital admissions for pneumonia in non-institutionalised elderly people as a result of influenza vaccination: a case-control study in Spain. J Epidemiol Community Health 1997;51(5): 526–30. [37] Fleming DM, Watson JM, Nicholas S, Smith GE, Swan AV. Study of the effectiveness of influenza vaccination in the elderly in the epidemic of 1989–1990 using a general practice database. Epidemiol Infect 1995;115(3):581–9. [38] Sterne JAC, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000;53:1119–29. [39] Greenland S. Meta-analysis. In: Rothman KJ, Greenland S, editors. Modern epidemiology. Philadelphia: Lippincott-Raven,1998. p. 643–73. [40] Demicheli V, Rivetti D, Deeks JJ, Jefferson TO. Vaccines for preventing influenza in healthy adults (Cochrane review). The Cochrane Library, 1999. [41] Simonsen L. The global impact of influenza on morbility and mortality. Vaccine 1999;17:S3–S10.
A meta-analysis of effectiveness of influenza vaccine in persons aged 65 years and over living in the community Trang Vu a,∗ , Stephen Farish b,1 , Mark Jenkins b,1 , Heath Kelly c,2 a
c
Victorian Public Health Training Program, Charles Connibere Building, The Royal Melbourne Hospital, Flemington Road, Parkville, Vic. 3050, Australia b Epidemiology and Biostatistics Unit, Department of Public Health, School of Population Health, The University of Melbourne, Melbourne, Vic. 3010, Australia Epidemiology Division, Victorian Infectious Diseases Reference Laboratory, 10 Wreckyn Street, North Melbourne, Melbourne, Vic. 3051, Australia Received 24 July 2001; received in revised form 5 November 2001; accepted 5 December 2001
Abstract Aim: To estimate the effectiveness of inactivated influenza vaccine in persons aged 65 years and over living in the community. Scope: A meta-analysis of studies selected using predetermined criteria without language restriction. Conclusion: Influenza vaccine was effective in reducing influenza-like illness by 35% (95% confidence interval (CI) 19–47%), hospitalization for pneumonia and influenza by 33% (CI 27–38%), mortality following hospitalization for pneumonia and influenza by 47% (CI 25–62%); and mortality from all causes by 50% (CI 45–56%). © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Influenza vaccine; Effectiveness; Community-living
1. Introduction Although influenza affects all age groups, persons with underlying medical conditions and persons aged 65 years and over are at greatest risk of severe illness and possibly death [1,2]. As recommended by the World Health Organization, the major strategy for controlling influenza is annual immunization of those at greatest risk with an inactivated influenza vaccine [3]. However, published studies on influenza vaccine effectiveness (VE) have produced inconsistent results. The only randomized double-blind placebo-controlled trial, conducted in The Netherlands in the 1991–1992 influenza season, found that the vaccine reduced serologically-confirmed influenza by 50% (95% CI 39–65%) [4]. However, the reduction was only 23% (95% CI 51–61%) in persons 70 years of age and over. One cohort and two case-control studies have reported low estimates of VE with wide confidence intervals, including the possibility that the vaccine had no effect [5–7]. ∗ Corresponding author. Tel.: +1-613-934-22608; fax: +1-613-934-22665. E-mail addresses: [email protected] (T. Vu), [email protected] (S. Farish), [email protected] (M. Jenkins), [email protected] (H. Kelly). 1 Tel.: +1-613-83447276; fax: +1-613-93476136. 2 Tel.: +1-613-93422608; fax: +1-613-93422665.
A previously published meta-analysis of influenza VE in the elderly concentrated largely on residents of nursing homes [8]. The only meta-analysis of influenza VE in persons aged 65 years and over living in the community is a Spanish language publication [9] limited to one influenza-related outcome. With the aim of estimating influenza VE for all major influenza-related outcomes for persons aged 65 years and over living in the community, we performed a comprehensive and systematic review of the available literature and a meta-analysis on studies that satisfied specified inclusion and exclusion criteria.
2. Methods We followed guidelines for preparing systematic reviews and meta-analyses, using multiple sources of information without language restriction [10–12]. The cut-off date for the literature search was the 31 December 2000. Differences in the effectiveness of whole virion, subunit virion and split virion vaccines were outside the scope of this study. Additionally, we excluded studies examining differences between single and multiple vaccinations, influenza vaccine immunogenicity or cost-effectiveness studies and studies investigating the additive benefits of combined influenza and pneumococcal vaccination.
0264-410X/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 0 2 ) 0 0 0 4 1 - 5
1832
T. Vu et al. / Vaccine 20 (2002) 1831–1836
Table 1 Inclusion and exclusion criteria for studies selected for review
Table 2 Influenza-related outcomes assessed in this study
Inclusion criteria: Inactivated influenza vaccine was used The study period was determined by influenza surveillance The study population comprised of community-living persons aged 65 years and over. For this meta-analysis, independent living in retirement villages was regarded as community-living
Outcome assessed
Number of studiesa
Influenza-like illness Outpatient visits for pneumonia and influenza Hospitalization for all respiratory conditions Hospitalization for pneumonia and influenza Mortality following hospitalization for pneumonia and influenza Mortality from all causes
3 2 4 9 3
Exclusion criteria: A cross-sectional design was used Influenza strains in the vaccine did not match influenza strains in circulation or the degree of vaccine antigenic match was not reported The comparability of the study groups, with respect to age, gender and the presence of underlying medical conditions, was not reported The study was conducted in a mixed population of institutionalized and community-living persons and estimates for community-living persons were not reported separately The study was conducted in many age groups and estimates for persons aged 65 years and over were not reported separately. However, the study was included if more than 50% of participants were 65 years and over The number of participants was 30 or fewer The publication had been duplicated, was a letter, opinion or debate
2.1. Study identification and appraisal A literature search to identify potential studies used the terms “influenza vaccine”, “VE”, “vaccine efficacy” and “elderly”. We combined these terms with the logical operator “not” and the term “nursing home” to exclude studies involving institutionalized elderly. Biomedical databases used in the search included Medline, Biosis, FirstSearch, Bandolier, Cochrane Library, Current Contents, Effectiveness Matters, Derwent Drug File, American College of Physicians Journal Club and Database of Abstracts of Reviews of Effectiveness (DARE). Influenza-dedicated databases, including FluNet (the World Health Organization), the CDC Influenza Home Page (Center for Disease Control and Prevention) and the Influenza Bibliography (National Institute for Medical Research, London) were also included in the search, as were several government Internet sites. Articles selected for inclusion were searched manually to identify further publications. Two prominent researchers in the field were asked to assist in identifying unpublished studies and to review our bibliography. Inclusion and exclusion criteria for the studies identified by this search are shown in Table 1. Two authors appraised and selected the studies independently using separate standardized forms for different study designs. A quality rating system was not used. 2.2. Data synthesis In this meta-analysis, vaccination status was defined as vaccinated or unvaccinated. Where available, ratio measures of influenza-related outcomes comparing vaccinated
4
a
Some studies investigated more than one outcome and/or were conducted over several influenza seasons.
and unvaccinated persons, adjusted for age, gender and the presence of underlying medical conditions, were recorded. Unadjusted measures were used if they were the only results reported. For case-control studies that used more than one control group, the controls whose influenza vaccine coverage was more like the cases were used in the meta-analysis. We used the formula VE = (1 − RR) × 100, where RR is the relative risk of influenza-related outcomes in vaccinated compared with unvaccinated persons. In case-control studies, the RR was approximated by the odds ratio. We calculated summary estimates of VE for all major influenza-related outcomes listed in Table 2 using the random-effects model described by DerSimonian–Laird and the general-variance based method of the fixed-effects model [13,14]. The use of methods based on both models allowed for a form of sensitivity analysis [11]. Subgroup analysis was not performed because of the insufficient number of subgroups. We investigated the variation between studies using statistical tests for heterogeneity [11]. Data synthesis was performed separately for each study design and, if no statistical evidence of heterogeneity was found, results from all designs were pooled to obtain summary estimates of VE [12]. Publication bias was investigated using the Begg and Mazumdar adjusted rank correlation test [15]. Stata for Windows (Version 6) was used to perform calculations and to produce graphs [16].
3. Results 3.1. Studies included in the meta-analysis Database and website searches identified 49 relevant publications, including 12 publications in languages other than English. Of the latter group, six satisfied the inclusion/exclusion criteria and were translated by qualified translators [9,17–21]. No additional publications or unpublished studies were identified by manual searches or by the two prominent researchers in the field. We excluded 34 of the 49 publications. Table 3 summarizes nine studies excluded for reasons other than being a duplication, debate or opinion. The excluded studies were
T. Vu et al. / Vaccine 20 (2002) 1831–1836 Table 3 Summary of studies excluded for reasons other than duplication, opinion or debate Author
Reason for exclusion
Ikematsu and Kashiwagi [19] Jianping et al. [22] Schoenbaum et al. [23] Gene et al. [18] Connolly et al. [24] Bonvehi et al. [25] Carrat et al. [26]
Vaccine antigenic match not reported Vaccine antigenic match not reported Vaccine antigenic match not reported Comparability of study groups unknown Comparability of study groups unknown Comparability of study groups unknown Estimates for community-living elderly not reported Estimates for community-living elderly not reported Small study
Ahmed et al. [27] Nguyen-Van-Tam and Nicholson [28]
conducted between 1968 and 1996, in a range of settings in many countries. Most were non-experimental with sample sizes ranging from 300 to more than 80,000. The lack of information regarding the comparability of study groups and the absence of information about vaccine antigenic match to circulating influenza virus strains were the most common reasons for exclusion.
1833
The remaining 15 studies eligible for inclusion in the meta-analysis are summarized in Table 4. They were performed over a similar time period to the excluded studies, with similar study designs and sample sizes. The majority of included studies were conducted exclusively in persons living in the community aged 65 years and over. 3.2. Vaccine effectiveness For the outcome hospitalization for pneumonia and influenza, we calculated VE separately for case-control and cohort studies and combined these estimates following a non-significant test for heterogeneity. For the other outcomes of interest, the number of studies was too small to perform analysis by study design and all eligible studies were combined. Fig. 1 presents fixed-effects model estimates of influenza VE for the outcomes of interest. The smallest reduction (6–26%) was found for the outcome outpatient visits for pneumonia and influenza whereas the largest reduction (25–62%) was associated with the outcome mortality following hospitalization for pneumonia and influenza. The choice of model did not alter these estimates and there was no statistical evidence of heterogeneity, except for the
Table 4 Summary of eligible studies by influenza-related outcomesa Outcome
Author
Study design
VE as percentages (95% CI)
Influenza-like illness
Govaert et al. [4]
48 (5–71)
Stuart et al. [29] Sandrini et al. [21]
Randomised double-blind placebo-controlled trial Clinical trial Cohort
51 (30–66) 26 (−3 to 46)
Outpatient visits for P&I
Nichol [30] Mullooly et al. [31]
Cohort Case-control
15 (4–25) 29 (−27 to 60), 43 (−39 to 76)
Hospitalization for all respiratory conditions
Lopez et al. [20]
Cohort
10 (−78 to 54)
Nichol [30] Ahmed et al. [7] Fedson et al. [32]
Cohort Case-control Case-control
32 (29–40) 19 (0–82) 17 (1–32), 32 (20–43)
Hospitalization for P&I
Barker and Mullooly [33] Nichol [30] Barker et al. [5] Fedson et al. [32] Foster et al. [34] Mullooly et al. [31] Ohmit and Monto [35] Puig-Barbera and Marquez Calderon [36] Strikas et al. [6]
Cohort Cohort Case-control Case-control Case-control Case-control Case-control Case-control Case-control
74 39 17 37 33 31 31 79 14
Mortality following hospitalization for P&I
Barker and Mullooly [33]
Cohort
85 (−144 to 99)
Fedson et al. [32] Mullooly et al. [31]
Case-control Case-control
64 (19–84), 54 (7–77) 33 (−6 to 58)
Stuart et al. [29] Fleming et al. [37] Lopez et al. [20] Nichol [30]
Clinical trial Cohort Cohort Cohort
81 75 3 50
Mortality from all causes
a
(−8 to 94) (26–52) (−43 to 51), 41 (1–65), 12 (−34 to 32) (15–53), 39 (19–53) (8–52) (17–42), 40 (1–64) (4–51), 32 (7–50) (45–92) (−12 to 34)
(21–95) (21–92) (−63 to 42) (44–56)
For studies conducted over several seasons or in many subgroups, separate estimates of VE are recorded, if available; P&I: pneumonia and influenza.
1834
T. Vu et al. / Vaccine 20 (2002) 1831–1836
model was used, the estimate became 14–71 and 32–78%, respectively. The Begg and Mazumdar adjusted rank correlation test for publication bias, performed on 12 studies investigating hospitalization for pneumonia and influenza, indicated no evidence of publication bias (P = 0.537). However, the test lacks power when the number of studies is 20 or fewer [38]. Therefore, we did not perform this test on the remaining studies because there were even fewer studies investigating the other outcomes.
4. Discussion
Fig. 1. Fixed-effects model estimates of influenza vaccine effectiveness in persons aged 65 years and over living in the community. Each horizontal line represents one outcome with the diamond being the point estimate of vaccine effectiveness and the outlying bars being the 95% confidence intervals.
outcome mortality from all causes. For this outcome, evidence of statistical heterogeneity was detected with the addition of the study by Lopez et al. [20], which was conducted when no influenza activity was detected. According to the fixed-effects model, the summary estimate of reduction in all-cause mortality with and without this study was 43–55 and 45–56%, respectively. When the random-effects
Results of this meta-analysis confirm that the influenza vaccine is effective in reducing influenza-related illness and death among persons 65 years and over living in the community. When there is a good match between influenza strains in the vaccine and those in circulation, vaccination would prevent approximately one in five cases of influenza-like illness, one in four hospitalizations for pneumonia and influenza and one in four deaths following hospitalization for these conditions. These estimates are independent of the model used, but may reflect biases in the selection of studies for inclusion in the meta-analysis. The biases may include those due to the databases searched, publication and language bias. However, as detailed in the Methods, we attempted to minimize these potential biases by searching multiple databases without language restriction, examining reference lists in retrieved publications and having prominent researchers in the field review the study bibliography for completeness. VE estimates reported by this meta-analysis may also be affected by biases in the primary studies. However, if the
Fig. 2. Comparison with results of other meta-analyses. Each horizontal line represents one study with the diamond being the point estimate of vaccine effectiveness and the outlying bars being the 95% confidence intervals.
T. Vu et al. / Vaccine 20 (2002) 1831–1836
biases are not systematic these estimates are likely to be conservative [39]. Despite being conducted in different countries, during different influenza seasons and using vaccines produced by different manufacturers, the studies showed no statistical heterogeneity. This argues for the reliability of the VE estimates from this meta-analysis. Moreover, the estimates from this meta-analysis were similar to those of three other meta-analyses. These studies were of elderly people living in the community (published in Spanish) [9], elderly persons living in nursing homes [8] and healthy adults [40]. Fig. 2 compares the results of the current study with the three other meta-analyses. The reduction of influenza-like illness estimated by the current study is similar to the estimate in the study of healthy adults. The estimate of reduction in hospitalization for pneumonia and influenza in this study is very similar to the result of the Spanish study. Differences between results produced by this study and the meta-analysis of studies in institutionalized elderly persons can be explained by the dissimilarity between the two populations with respect to age, disease risk, vaccination rate and rate of underlying medical conditions. All but one of the studies included in this meta-analysis were of non-experimental design and all were conducted in developed countries in North America and Europe. The influenza VE estimates obtained from this meta-analysis are thus likely to be applicable to most developed countries, but perhaps not to developing countries where the burden of influenza may be lower than that of other infectious diseases [41].
[5]
[6]
[7]
[8]
[9]
[10] [11]
[12]
[13] [14] [15]
Acknowledgements
[16] [17]
We would like to thank Dr. J.S. Nguyen-Van-Tam from the University of Nottingham and Dr. Kristin L. Nichol from the Veterans Affairs Medical Center (Minneapolis) for their comments on the bibliography. We are indebted also to Mr. Shigeru Takahashi and Ms. Qui Nguyen for their translation of a study written in Japanese, and to Dr. David Fairservice for his translation of Spanish and Italian articles. We thank Julianne Lynch for her helpful suggestions during the preparation of the manuscript.
[18]
[19] [20]
[21]
References [22] [1] Couch RB. Orthomyxoviruses. In: Baron S, editor. Medical microbiology. 2nd ed. Menlo Park (CA): Addison-Wesley, 1986. p. 855–64. [2] Berlin BS. Influenza. In: Youmans GP, Paterson PY, Sommers HM, editors. The biologic and clinical basis of infectious diseases. 3rd ed. Philadelphia: W.B. Saunders Company, 1986. p. 332–43. [3] Hannoun C. Private or national health insurance for adult vaccination in developed countries? Vaccine 1999;17(Suppl):S99–S101. [4] Govaert TM, Thijs CT, Masurel N, Sprenger MJ, Dinant GJ, Knottnerus JA. The efficacy of influenza vaccination in elderly
[23]
[24]
[25]
1835
individuals. A randomized double-blind placebo-controlled trial. JAMA 1994;272(21):1661–5. Barker W, Raubertas R, Menegus M, O’Brien D, Freundlich C, Betts R. Case-control study of influenza vaccine effectiveness in preventing pneumonia hospitalization among older persons. In: Proceedings of the International Conference on Options for the Control of Influenza II. Monroe County, New York, 1989–1992, France: Courchevel, 1992. Strikas R, Cook P, Kuller L, et al. Case-control study in Ohio and Pennsylvania on prevention of hospitalisation by influenza vaccination York. In: Proceedings of the International Conference on Options for the Control of Influenza II. France: Courchevel, 1992. Ahmed AH, Nicholson KG, Nguyenvantam JS, Pearson JCG. Effectiveness of influenza vaccine in reducing hospital admissions during the 1989–1990 epidemic. Epidemiol Infect 1997;118(1):27– 33. Gross A, Hermogenes W, Sacks S, Lau J, Levandowski A. The efficacy of influenza vaccine in elderly persons: a meta-analysis and review of the literature. Ann Intern Med 1995;123(7):518–27. Puig-Barbera J, Marquez Calderon S. Effectiveness of influenza vaccine in the elderly: a critical review of the bibliography (Spanish). Med Clin (Barc) 1995;105:645–8. Cochrane Collaboration. The Cochrane Manual, Version 9904. July 1999. Petitti DB. Meta-analysis. Decision analysis, and cost-effectiveness analysis methods for quantitative synthesis in medicine. Oxford (New York): Oxford University Press, 1994. NHS Center for Reviews and Dissemination (CRD). Undertaking Systematic Reviews of Research on Effectiveness. CRD Guidelines for Those Carrying Out or Commissioning Reviews. CRD Report No. 4,1996. Dersimonian R, Laird N. Meta-analysis in clinical trials. Cont Clin Trials 1986;7:177–88. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 1987;9:1–30. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088–101. StataCorp. Stata Statistical Software, Release 6. College Station (TX): Stata Corporation, 1999. Crovari CP, Gasparini R, Crovari P. Ricerche sulla efficacia della vaccinazione influenzale: risultati in una comunita’ controllata per un biennio. Boll Lst Sieroter Milan 1980;59(4):306–13. Gene Badia J, Calero Munoz S, Castanera Ribe C, Gran Rovireta A. Efectividad de un programa de vacunacion antigripal en cuatro centros de atencion primaria. Gaceta Sanitaria 1991;5(26): 203–8 Ikematsu H, Kashiwagi S. Efficacy and adverse reactions of influenza vaccine in the elderly (Japanese). Nippon Rinsho 1997;55:2751–7. Lopez Hernandez B, Vazquez J, Fernandez E, Martinez B, Romero J, Arribas L. Efectividad de la vacunacion antigripal en ancianos. Atencion Primaria 1994;14(1):532–6. Sandrini MC, Pregliasco F, Mensi C, et al. Valutazione dell’immunogenicita e dell’efficacia sul campo (stagione 1994–1995) del vaccino antinfluenzale in una popolazione di anziani non istituzionalizzati. Annali Di Igiene 1997;9:373–9. Jianping H, Xin F, Changshun L, et al. Assessment of effectiveness of Vaxigrip. Vaccine 1999;17(Suppl):S57–8. Schoenbaum C, Mostow SR, Dowdle WR, Coleman MT, Kaye HS. Studies with inactivated influenza vaccines purified by zonal centrifugation. Bull Who 1969;41:531–5. Connolly AM, Salmon RL, Lervy B, Williams DH. What are the complications of influenza and can they be prevented? Experience from the 1989 epidemic of H3N2 influenza A in general practice. Br Med J 1993;306:1452–4. Bonvehi P, Nacinovich F, Ruttimann R, Vujacich C, Giannone C, Stamboulian D. Effectiveness of influenza vaccine in elderly people
1836
[26]
[27]
[28]
[29]
[30] [31]
[32]
[33]
T. Vu et al. / Vaccine 20 (2002) 1831–1836 living in the community in Argentina. Abstracts of the Interscience Conference on Antimicrobial Agents & Chemotherapy 1997;37:238. Carrat F, Tachet A, Rouzioux C, Housset B, Valleron A-J. Field investigation of influenza vaccine effectiveness on morbility. Vaccine 1998;16(9/10):893–8. Ahmed AE, Nicholson KG, Nguyen-Van-Tam JS. Reduction in mortality associated with influenza vaccine during the 1989–1990 epidemic. Lancet 1995;346(8975):591–5. Nguyen-Van-Tam JS, Nicholson KG. Influenza deaths in Leicestershire during the 1989/1990 epidemic: implications for prevention. Epidemiol Infect 1992;108:537–45. Stuart WH, Dull B, Newton LH, McQueen JL, Schiff ER. Evaluation of monovalent influenza vaccine in a retirement community during the epidemic of 1965–1966. JAMA 1969;209(2):232–8. Nichol KL. Complications of influenza and benefits of vaccination. Vaccine 1999;17:S47–52. Mullooly J, Bennett M, Hornbrook M, et al. Influenza vaccination programs for elderly persons: cost-effectiveness in a health maintenance organisation. Ann Intern Med 1994;121:947–52. Fedson DS, Wajda A, Nicol JP, Hammond GW, Kaiser DL, Roos LL. Clinical effectiveness of influenza vaccination in Manitoba (published erratum appears in JAMA, 1994;271:1578). JAMA 1993;270(16):1956–61. Barker W, Mullooly J. Influenza vaccination of elderly persons. Reduction in pneumonia and in influenza hospitalization and deaths. JAMA 1980;244(22):2547–9.
[34] Foster A, Talsma A, Furumoto-Dawson A, et al. Influenza vaccine effectiveness in preventing hospitalization for pneumonia in the elderly. Am J Epidemiol 1992;136(3):296–307. [35] Ohmit E, Monto S. Influenza vaccine effectiveness in preventing hospitalization among the elderly during influenza type A and type B seasons. Int J Epidemiol 1995;24(6):1240–8. [36] Puig-Barbera J, Marquez-Calderon S, Masoliver-Fores A, et al. Reduction in hospital admissions for pneumonia in non-institutionalised elderly people as a result of influenza vaccination: a case-control study in Spain. J Epidemiol Community Health 1997;51(5): 526–30. [37] Fleming DM, Watson JM, Nicholas S, Smith GE, Swan AV. Study of the effectiveness of influenza vaccination in the elderly in the epidemic of 1989–1990 using a general practice database. Epidemiol Infect 1995;115(3):581–9. [38] Sterne JAC, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000;53:1119–29. [39] Greenland S. Meta-analysis. In: Rothman KJ, Greenland S, editors. Modern epidemiology. Philadelphia: Lippincott-Raven,1998. p. 643–73. [40] Demicheli V, Rivetti D, Deeks JJ, Jefferson TO. Vaccines for preventing influenza in healthy adults (Cochrane review). The Cochrane Library, 1999. [41] Simonsen L. The global impact of influenza on morbility and mortality. Vaccine 1999;17:S3–S10.