Vaccines for preventing influenza in the elderly (Review) Jefferson T, Di Pietrantonj C, Al-Ansary LA, Ferroni E, Thorning S, Thomas RE ThisisareprintofaCochranereview,preparedandmaintainedbyTheCochraneCollaborationandpublishedinTheCochraneLibrary 2010,Issue2 http://www.thecochranelibrary.com Vaccinesforpreventinginfluenzaintheelderly(Review) Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Analysis1.1.Comparison1Influenzavaccinesversusnovaccination-Cohortstudiesinnursinghomes,Outcome1ILI. 114 Analysis1.2.Comparison1Influenzavaccinesversusnovaccination-Cohortstudiesinnursinghomes,Outcome2 Influenza. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Analysis1.3.Comparison1Influenzavaccinesversusnovaccination-Cohortstudiesinnursinghomes,Outcome3 Pneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Analysis1.4.Comparison1Influenzavaccinesversusnovaccination-Cohortstudiesinnursinghomes,Outcome4 HospitalisationforILIorpneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . 118 Analysis1.5.Comparison1Influenzavaccinesversusnovaccination-Cohortstudiesinnursinghomes,Outcome5Deaths fromfluorpneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 Analysis1.6.Comparison1Influenzavaccinesversusnovaccination-Cohortstudiesinnursinghomes,Outcome6All deaths. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 Analysis1.7.Comparison1Influenzavaccinesversusnovaccination-Cohortstudiesinnursinghomes,Outcome7 Influenzacases(clinicallydefinedwithoutcleardefinition). . . . . . . . . . . . . . . . . . . 123 Analysis2.1.Comparison2Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-dwellers,Outcome1 ILI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Analysis2.2.Comparison2Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-dwellers,Outcome2 Influenza. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Analysis2.3.Comparison2Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-dwellers,Outcome3 Pneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Analysis2.4.Comparison2Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-dwellers,Outcome4 Hospitalisationforfluorpneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . 127 Analysis2.5.Comparison2Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-dwellers,Outcome5 Hospitalisationforanyrespiratorydisease. . . . . . . . . . . . . . . . . . . . . . . . . 128 Analysis2.6.Comparison2Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-dwellers,Outcome6 Deathsfromfluorpneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Analysis2.7.Comparison2Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-dwellers,Outcome7 Deathsfromrespiratorydisease. . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Analysis2.8.Comparison2Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-dwellers,Outcome8 Alldeaths. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Analysis2.9.Comparison2Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-dwellers,Outcome9 Hospitalisationforheartdisease. . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Analysis2.10.Comparison2Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-dwellers,Outcome 10Combinedoutcome:alldeathsorsevererespiratoryillness. . . . . . . . . . . . . . . . . . 133 Analysis3.1.Comparison3Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-riskgroups, Outcome1Influenza. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Analysis3.2.Comparison3Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-riskgroups, Outcome2Pneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Vaccinesforpreventinginfluenzaintheelderly(Review) i Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. Analysis3.3.Comparison3Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-riskgroups, Outcome3Hospitalisationforinfluenzaorpneumonia. . . . . . . . . . . . . . . . . . . . 136 Analysis3.4.Comparison3Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-riskgroups, Outcome4Hospitalisationforanyrespiratorydisease. . . . . . . . . . . . . . . . . . . . . 137 Analysis3.5.Comparison3Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-riskgroups, Outcome5Deathsfromrespiratorydisease. . . . . . . . . . . . . . . . . . . . . . . . 138 Analysis3.6.Comparison3Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-riskgroups, Outcome6Alldeaths. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Analysis3.7.Comparison3Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-riskgroups, Outcome7Hospitalisationforheartdisease. . . . . . . . . . . . . . . . . . . . . . . . 140 Analysis3.8.Comparison3Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-riskgroups, Outcome8Combinedoutcome:alldeathsorsevererespiratoryillness. . . . . . . . . . . . . . . 141 Analysis4.1.Comparison4Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-norisk groups,Outcome1Influenza. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 Analysis4.2.Comparison4Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-norisk groups,Outcome2Pneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 Analysis4.3.Comparison4Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-norisk groups,Outcome3Hospitalisationforinfluenzaorpneumonia. . . . . . . . . . . . . . . . . 144 Analysis4.4.Comparison4Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-norisk groups,Outcome4Hospitalisationforanyrespiratorydisease. . . . . . . . . . . . . . . . . . 145 Analysis4.5.Comparison4Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-norisk groups,Outcome5Deathsfromrespiratorydisease. . . . . . . . . . . . . . . . . . . . . 146 Analysis4.6.Comparison4Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-norisk groups,Outcome6Alldeaths. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 Analysis4.7.Comparison4Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-norisk groups,Outcome7Hospitalisationforheartdisease. . . . . . . . . . . . . . . . . . . . . 148 Analysis4.8.Comparison4Influenzavaccinesversusnovaccination-Cohortstudies-community-dwellers-norisk groups,Outcome8Combinedoutcome:alldeathsorsevererespiratoryillness. . . . . . . . . . . . 149 Analysis5.1.Comparison5Influenzaandpneumococcalvaccinesversusnovaccination-Cohortstudiesincommunity- dwellers,Outcome1ILI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 Analysis5.2.Comparison5Influenzaandpneumococcalvaccinesversusnovaccination-Cohortstudiesincommunity- dwellers,Outcome2Hospitalisationforinfluenzaorpneumoniaorrespiratorydisease. . . . . . . . . 151 Analysis5.3.Comparison5Influenzaandpneumococcalvaccinesversusnovaccination-Cohortstudiesincommunity- dwellers,Outcome3Deathsfrominfluenzaorpneumonia. . . . . . . . . . . . . . . . . . . 152 Analysis5.4.Comparison5Influenzaandpneumococcalvaccinesversusnovaccination-Cohortstudiesincommunity- dwellers,Outcome4Alldeaths. . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Analysis6.1.Comparison6Influenzavaccineswithadjuvantversusnovaccination -Cohortstudiesincommunity- dwellers,Outcome1ILI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 Analysis6.2.Comparison6Influenzavaccineswithadjuvantversusnovaccination -Cohortstudiesincommunity- dwellers,Outcome2Hospitalisationforinfluenzaorpneumoniaorrespiratorydisease. . . . . . . . . 155 Analysis6.3.Comparison6Influenzavaccineswithadjuvantversusnovaccination -Cohortstudiesincommunity- dwellers,Outcome3Alldeaths. . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 Analysis7.1.Comparison7Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-adjustedrates, Outcome1Hospitalisationforinfluenzaorpneumonia. . . . . . . . . . . . . . . . . . . . 157 Analysis7.2.Comparison7Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-adjustedrates, Outcome2Hospitalisationforanyrespiratorydisease. . . . . . . . . . . . . . . . . . . . . 158 Analysis7.3.Comparison7Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-adjustedrates, Outcome3Hospitalisationforheartdisease. . . . . . . . . . . . . . . . . . . . . . . . 159 Analysis7.4.Comparison7Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-adjustedrates, Outcome4Alldeaths. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Analysis7.5.Comparison7Influenzavaccinesversusnovaccination-Cohortstudiesincommunity-adjustedrates, Outcome5Combinedoutcome:alldeathsorsevererespiratoryillness. . . . . . . . . . . . . . . 161 Vaccinesforpreventinginfluenzaintheelderly(Review) ii Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. Analysis8.1.Comparison8Influenzavaccinesversusnovaccination-Case-controlstudiesincommunity,Outcome1 Hospitalisationsforinfluenzaorpneumonia. . . . . . . . . . . . . . . . . . . . . . . . 161 Analysis8.2.Comparison8Influenzavaccinesversusnovaccination-Case-controlstudiesincommunity,Outcome2 Hospitalisationsforanyrespiratorydisease. . . . . . . . . . . . . . . . . . . . . . . . . 162 Analysis8.3.Comparison8Influenzavaccinesversusnovaccination-Case-controlstudiesincommunity,Outcome3 Deathsfrominfluenzaorpneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . 163 Analysis8.4.Comparison8Influenzavaccinesversusnovaccination-Case-controlstudiesincommunity,Outcome4 Pneumonia(nobetterdefined). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 Analysis9.1. Comparison 9Influenza and pneumococcal vaccinesversusnovaccination -Case-control studiesin community,Outcome1Hospitalisationsforinfluenzaorpneumonia. . . . . . . . . . . . . . . 164 Analysis10.1.Comparison10Influenzaandpneumococcalvaccinesversusnovaccination-Case-controlstudiesinnursing homes,Outcome1ILI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Analysis11.1.Comparison11Influenzavaccinesversusnovaccination-Case-controlstudiesincommunity-adjusted rates,Outcome1Hospitalisationsforinfluenzaorpneumonia. . . . . . . . . . . . . . . . . . 166 Analysis11.2.Comparison11Influenzavaccinesversusnovaccination-Case-controlstudiesincommunity-adjusted rates,Outcome2Hospitalisationsforanyrespiratorydisease. . . . . . . . . . . . . . . . . . 167 Analysis11.3.Comparison11Influenzavaccinesversusnovaccination-Case-controlstudiesincommunity-adjusted rates,Outcome3Deathsfrompneumoniaorinfluenza. . . . . . . . . . . . . . . . . . . . 168 Analysis12.1.Comparison12Influenzaandpneumococcalvaccinesversusnovaccination-Case-controlstudiesin community-adjustedrates,Outcome1Hospitalisationsforinfluenzaorpneumonia. . . . . . . . . . 169 Analysis13.1.Comparison13Influenzavaccinesversusplacebo-RCT-parenteralvaccine,Outcome1ILI. . . . 170 Analysis13.2.Comparison13Influenzavaccinesversusplacebo-RCT-parenteralvaccine,Outcome2Influenza. . 171 Analysis13.3.Comparison13Influenzavaccinesversusplacebo-RCT-parenteralvaccine,Outcome3Pneumonia. 172 Analysis13.4.Comparison13Influenzavaccinesversusplacebo-RCT-parenteralvaccine,Outcome4Alldeaths. . 172 Analysis14.1.Comparison14Vaccineversusplacebo-inactivatedaerosolvaccine,Outcome1ILI. . . . . . . 173 Analysis14.2.Comparison14Vaccineversusplacebo-inactivatedaerosolvaccine,Outcome2Influenza. . . . . 173 Analysis15.1.Comparison15Vaccineversusplacebo-liveaerosolvaccine,Outcome1Influenza. . . . . . . . 174 Analysis16.1.Comparison16SensitivityanalysisComparison01:subgroupanalysisbystudyquality,Outcome1ILI. 174 Analysis17.1.Comparison17Influenzavaccinesversusplacebo-RCT-parenteralvaccine-adverseevents,Outcome1 Generalmalaise. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 Analysis17.2.Comparison17Influenzavaccinesversusplacebo-RCT-parenteralvaccine-adverseevents,Outcome2 Fever. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 Analysis17.3.Comparison17Influenzavaccinesversusplacebo-RCT-parenteralvaccine-adverseevents,Outcome3 Upperrespiratorytractsymptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 Analysis17.4.Comparison17Influenzavaccinesversusplacebo-RCT-parenteralvaccine-adverseevents,Outcome4 Headache. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 Analysis17.5.Comparison17Influenzavaccinesversusplacebo-RCT-parenteralvaccine-adverseevents,Outcome5 Nausea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 Analysis17.6.Comparison17Influenzavaccinesversusplacebo-RCT-parenteralvaccine-adverseevents,Outcome6 Localtenderness/sorearm. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Analysis17.7.Comparison17Influenzavaccinesversusplacebo-RCT-parenteralvaccine-adverseevents,Outcome7 Swelling-erythema-induration. . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Analysis18.1.Comparison18Influenzavaccinesversusplacebo-RCT-liveaerosolvaccine-adverseevents,Outcome1 Generalmalaise. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 Analysis18.2.Comparison18Influenzavaccinesversusplacebo-RCT-liveaerosolvaccine-adverseevents,Outcome2 Fever. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 Analysis18.3.Comparison18Influenzavaccinesversusplacebo-RCT-liveaerosolvaccine-adverseevents,Outcome3 Upperrespiratorytractsymptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Analysis18.4.Comparison18Influenzavaccinesversusplacebo-RCT-liveaerosolvaccine-adverseevents,Outcome4 Lowerrespiratorytractsymptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 Vaccinesforpreventinginfluenzaintheelderly(Review) iii Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 Vaccinesforpreventinginfluenzaintheelderly(Review) iv Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. [InterventionReview] Vaccines for preventing influenza in the elderly TomJefferson1,CarloDiPietrantonj2,LubnaAAl-Ansary3,ElianaFerroni4,SarahThorning5,RogerEThomas6 1VaccinesField,TheCochraneCollaboration,Roma,Italy.2ServizioRegionalediRiferimentoperl’Epidemiologia,SSEpi-SeREMI -Cochrane VaccinesField, Azienda Sanitaria Locale ASLAL,Alessandria, Italy.3Departmentof Family &Community Medicine, Holderof“ShaikhAbdullahS.Bahamdan”ResearchChairforEvidence-BasedHealthCareandKnowledgeTranslation, Collegeof Medicine,KingSaudUniversity,Riyadh,SaudiArabia.4InfectiousDiseasesUnit,PublicHealthAgencyofLazioRegion,Rome,Italy. 5FacultyofHealthSciencesandMedicine,BondUniversity,GoldCoast,Australia.6DepartmentofMedicine,UniversityofCalgary, Calgary,Canada Contactaddress:TomJefferson,VaccinesField,TheCochraneCollaboration,ViaAdige28a,AnguillaraSabazia,Roma,00061,Italy. [email protected]@assr.it. Editorialgroup:CochraneAcuteRespiratoryInfectionsGroup. Publicationstatusanddate:Newsearchforstudiesandcontentupdated(conclusionschanged),publishedinIssue2,2010. Reviewcontentassessedasup-to-date: 6October2009. Citation: JeffersonT,DiPietrantonjC,Al-AnsaryLA,FerroniE,ThorningS,ThomasRE.Vaccinesforpreventinginfluenzainthe elderly.CochraneDatabaseofSystematicReviews2010,Issue2.Art.No.:CD004876.DOI:10.1002/14651858.CD004876.pub3. Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. ABSTRACT Background Vaccines have been the main global weapon to minimise the impact of influenza in the elderly for the last four decades and are recommendedworldwideforindividualsaged65yearsorolder.Theprimarygoalofinfluenzavaccinationintheelderlyistoreduce theriskofcomplicationsamongpersonswhoaremostvulnerable. Objectives To assess the effectiveness of vaccines in preventing influenza, influenza-like illness (ILI), hospital admissions, complications and mortalityintheelderly. Toidentifyandappraisecomparativestudiesevaluatingtheeffectsofinfluenzavaccinesintheelderly. Todocumenttypesandfrequencyofadverseeffectsassociatedwithinfluenzavaccinesintheelderly. Searchstrategy We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections(ARI)Group’sSpecialisedRegister (TheCochraneLibrary2009, issue 4);MEDLINE (January 1966 toOctoberWeek1 2009);EMBASE(1974toOctober2009)andWebofScience(1974toOctober2009). Selectioncriteria Randomised controlled trials (RCTs), quasi-RCTs, cohort and case-control studies assessing efficacy against influenza (laboratory- confirmedcases)oreffectivenessagainstinfluenza-likeillness(ILI)orsafety.Anyinfluenzavaccinegivenindependently,inanydose, preparationortimeschedule,comparedwithplaceboorwithnointerventionwasconsidered. Vaccinesforpreventinginfluenzaintheelderly(Review) 1 Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. Datacollectionandanalysis Wegroupedreportsfirstaccordingtothesettingofthestudy(communityorlong-termcarefacilities)andthenbylevelofviralcirculation andvaccinematching.Wefurtherstratifiedbyco-administrationofpneumococcalpolysaccharidevaccine(PPV)andbydifferenttypes ofinfluenza vaccines.Weanalysedthefollowingoutcomes: influenza, influenza-like illness,hospitaladmissions, complications and deaths. Mainresults Weincluded75studies.Overallweidentified100datasets.WeidentifiedoneRCTassessingefficacyandeffectiveness.Althoughthis seemedtoshowaneffectagainstinfluenzasymptomsitwasunderpoweredtodetectanyeffectoncomplications(1348participants). The remainder of our evidence base included non-RCTs. Due to the general low quality of non-RCTs and the likely presence of biases,whichmakeinterpretationofthesedatadifficultandanyfirmconclusionspotentiallymisleading,wewereunabletoreachclear conclusionsabouttheeffectsofthevaccinesintheelderly. Authors’conclusions Theavailableevidenceisofpoorqualityandprovidesnoguidanceregardingthesafety,efficacyoreffectivenessofinfluenzavaccines forpeopleaged65yearsorolder.Toresolvetheuncertainty,anadequatelypoweredpublicly-fundedrandomised,placebo-controlled trialrunoverseveralseasonsshouldbeundertaken. PLAIN LANGUAGE SUMMARY Vaccinesforpreventingseasonalinfluenzaanditscomplicationsinpeopleaged65orolder Influenzavaccinationofelderlyindividualsisrecommendedworldwideaspeopleaged65andolderareatahigherriskofcomplications, hospitalisations anddeathsfrominfluenza. Thisreviewlookedatevidencefromexperimentalandnon-experimentalstudiescarried outover40yearsofinfluenzavaccination.Weincluded75studies.Theseweregroupedfirstaccordingtostudydesignandthenthe setting(communityorlong-termcarefacilities).Theresultsaremostlybasedonnon-experimental(observational)studies,whichareat greaterriskofbias,asnotmanygoodqualitytrialswereavailable.Trivalentinactivatedvaccinesarethemostcommonlyusedinfluenza vaccines.Duetothepoorqualityoftheavailableevidence,anyconclusionsregardingtheeffectsofinfluenzavaccinesforpeopleaged 65yearsoroldercannotbedrawn.Thepublichealthsafetyprofileofthevaccinesappearstobeacceptable. BACKGROUND 2000,40outof51high-incomeormiddle-incomecountriesrec- ommendedvaccinationforallpersonsaged60or65orolder(van Essen2003).Upto290milliondosesofvaccineweredistributed Descriptionofthecondition worldwidein2003(WHO2005).AccordingtotheCentresfor Influenza vaccination of elderly individuals is recommended DiseaseControl(CDC),theprimarygoalofinfluenzavaccination worldwideaspeopleaged65andolderareathigherriskofcom- intheelderlyistoreducetheriskofcomplicationsamongpersons plications,hospitalisationsanddeathsfrominfluenza. who are mostvulnerable (ACIP2005; CDC 2004).To achieve thisgoal,CDCdefinedtwohigherprioritygroups:adultsaged65 yearsorolderandresidentsofnursinghomesandlong-termcare Descriptionoftheintervention facilities.Wepresentanup-to-date,comprehensiveassessmentof theeffectsofinfluenzavaccinesintheelderly.Thecurrentpan- Vaccineshavebeenthemainglobalweapontominimisetheim- demichascausedaheightenedinterestininfluenzavaccinesand pactofinfluenzaintheelderlyforthelastfourdecades.Intheyear Vaccinesforpreventinginfluenzaintheelderly(Review) 2 Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. theirperformance. Appendix1.Toassessrareadverseeffectswealsolookedforsurveil- lancestudies.Despitebeingnon-comparative,theyprovideinfor- mationaboutrareandsevereevents,possiblyrelatedtoinfluenza Howtheinterventionmightwork vaccines. Vaccinesworkbysimulatinganinfectionandstimulatingthebody toproduceantibodiesagainstthethreatandactivateotherdefence Typesofparticipants mechanisms. Elderlyparticipantsaged65yearsorolder,irrespectiveofsettings. Studies which assessed efficacy in selected groups affected by a specificchronic pathology (i.e.diabetes or cardiac disease)were Whyitisimportanttodothisreview excludedaswewereinterestedinthewholepopulation.Theques- Duetotheuniqueproductioncycleofinfluenzavaccines(theyare tionofwhetherthesevaccinesareeffectiveinspecificatriskpop- producedandtestedusingsurrogateoutcomes-antibodystimula- ulationsisthetopicofotherreviews. tion-aheadofeachinfluenza’season’),pastperformanceisprob- ablytheonlyreliablewaytopredictfutureperformance.Ofthe Typesofinterventions twoexistingsystematicreviewslookingattheeffectsofinfluenza vaccinesintheelderly,oneisnowoveradecadeoldanditsconclu- 1. Vaccinationwithanyinfluenzavaccinegiven sionsmaybeaffectedbythelackofinclusionofrecentevidence( independently,inanydose,preparationortimeschedule, Gross1995).Theotherreviewhasseveralmethodologicalweak- comparedwithplacebo,orwithnointervention. nesseswhichmayaffecttheauthors’conclusions(forexample,the 2. Wealsoconsiderednew,asyetunlicensed,typesofvaccines exclusionofstudieswithdenominatorssmallerthan30andpool- (forexample,liveattenuatedandDNAvaccines). ingofstudiesusingdifferentdesigns).Thisreviewalsoincludesa 3. Vaccinationofstaffinordertoprotectpatientsandresidents limitednumberofstudies(Vu2002).Anaccurateassessmentof admittedintohospitals,nursinghomesandlong-termcare theeffects(efficacy,effectivenessand safetyprofile)of influenza facilitieshasbeenassessedbyaseparatereview(Thomas2010). vaccines is essential to allow rational choice betweenalternative 4. Weexcludedstudiesinwhichavaccinewasadministered strategies. afterthebeginningoftheepidemicperiod. 5. Weexcludedoldoiladjuvantvaccineorvaccineswitha contentgreaterthan15µgofhaemagglutinin/strain/dosefrom thesafetyassessment. OBJECTIVES Typesofoutcomemeasures 1. Toidentifyandappraiseallthecomparativestudies evaluatingtheeffectsofinfluenzavaccinesintheelderly(aged65 yearsandolder),irrespectiveofsetting. Primaryoutcomes 2. Toassesstheeffectivenessofvaccinesinpreventing influenza,influenza-likeillness(ILI),hospitaladmissions, complicationsandmortalityintheelderly. Fortreatmentefficacyandeffectiveness 3. Todocumentthetypesandfrequencyofadverseeffects Weincludedoutcomesoccurringwithintheepidemicperiod(the associatedwithinfluenzavaccinesintheelderly. six-month winterperiod, ifnotbetterspecified).Whenauthors presenteddataaccordingtodifferentlevelsofviralcirculation,we onlyincludeddatarestrictedtohigherviralcirculation. 1. Casesofinfluenza,clinicallydefinedfromalistoflikely METHODS respiratoryandsystemicsignsandsymptoms.Weacceptedthe trialauthors’definitionofclinicalillnessbecausesomestates havetheirownofficialdefinition. Criteriaforconsideringstudiesforthisreview 2. Casesofinfluenza,laboratoryconfirmed(bymeansofviral isolation,serologicalsupportingevidence,orboth). 3. Casesofinfluenza(asdefinedabove)admittedtohospital. Typesofstudies 4. Deaths(total). Weconsideredrandomisedcontrolledtrials(RCTs),quasi-RCTs, 5. Deathsduetoinfluenza(asdefinedabove)ortoits cohortandcase-controlstudies.Forstudydesigndefinitionssee complications. Vaccinesforpreventinginfluenzaintheelderly(Review) 3 Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. 6. Otherdirectorindirectindicatorofdiseaseimpact: MEDLINE(OVID) pneumonia;hospitalisationduetoanyrespiratorydisease, 1InfluenzaVaccines/ hospitalisationduetoheartdisease. 2Influenza,Human/tm,pc,im,mo,ep[Transmission,Prevention Weexcludedstudieswithgenericoutcomes(deathsfromallcauses, &Control,Immunology,Mortality,Epidemiology] forexample)andlong-term(oneyear)followupasmostillnesses 3Influenza,Human/ weremostlikelyduetocausesotherthaninfluenza.Weexcluded 4expInfluenzavirusA/ studiesreportingonlyserologicaloutcomes. 5expInfluenzavirusB/ 6(fluorinfluenza*).tw. 7or/3-6 Secondaryoutcomes 8Vaccines/ 9vaccines,attenuated/orvaccines,inactivated/ orexpvaccines, subunit/orexpvaccines,synthetic/orviralvaccines/ 10expImmunization/ Foradverseevents 11(vaccin*orimmuni*orinocul*).tw. 1. Localeventsforaerosolvaccines(upperrespiratorytract 12expAdjuvants,Immunologic/ infectionsymptomssuchascough,coryza,sorethroat, 13(vaccin*adj5adjuvant*).tw. hoarseness)withinsevendaysofvaccination. 14Squalene/ 2. Localeventsforparenteralvaccines(tenderness/soreness, 15(aluminiumorsqualeneorMF59orvirosom*).tw,nm. erythema,induration,armstiffness)withinsevendaysfrom 16or/8-15 vaccination. 177and16 3. Systemicevents(myalgia,fever,headache,fatigue, 181or2or17 indisposition,rash,angioedema,asthma)withinsevendaysfrom 19expAdult/ vaccination. 20Men/ 4. Rareevents(thrombocytopenia,neurologicaldisorders, 21Women/ GuillanBarréSyndrome(GBS). 22Retirement/ 23((old*orage*)adj3(people*orperson*oradult*orwomen* ormen*orcitizen*orresiden*)).tw. 24(pension*orretire*oradult*oragedorelderlyorsenior*or Searchmethodsforidentificationofstudies geriatric*).tw. 25long-termcare/ornursingcare/orpalliativecare/ 26homesfortheaged/ornursinghomes/ 27nursinghome*.tw. Electronicsearches 28or/19-27 Forthis2009updatewesearchedtheCochraneCentralRegister 2928and18 ofControlledTrials(CENTRAL),whichcontainstheCochrane AcuteRespiratoryInfections(ARI)Group’sSpecialisedRegister, theCochraneDatabaseofSystematicReviews,andtheDatabase Searchingotherresources of Abstracts of Reviews of Effects (The Cochrane Library 2009, There were no language or publication restrictions. The search Issue 4); MEDLINE (January 1966 toOctober Week12009); ofCENTRALincludedtrialreportsidentifiedbythesystematic EMBASE(1974toOctober2009)andWebofScience(1974to searchbyhandofthejournalVaccine. October2009). Inordertoidentifyadditionalpublishedandunpublishedstudies: We used the following search terms to search MEDLINE and CENTRAL.ThesearchtermswerecombinedwiththeCochrane • weusedtheScienceCitationIndextoidentifyarticlesthat HighlySensitiveSearchStrategyforidentifyingRCTsinMED- citetherelevantstudies; LINE:sensitivity-andprecision-maximisingversion(2008)revi- • wekeyedtherelevantstudiesintoPubMedandusedthe sion;Ovidformat(Lefebvre2008).Thissearchwasadaptedfor RelatedArticlesfeature; EMBASE (Appendix 5) and Web of Science (see Appendix 6). • wesearchedthebibliographiesofallrelevantarticles The below search terms were also combined with the SIGN ( obtained,anypublishedreviewsandproceedingsfromrelevant SIGN2009)searchstrategyforidentifyingobservationalstudies conferencesforadditionalstudies; (seeAppendix7)andMEDLINE,EMBASEandWebofScience • weexploredInternetsources:NHSNationalResearch were searched for observational studies. Details of the previous Register(http://www.update-software.com/national/),the searchareinAppendix4. metaRegisterofClinicalTrials(http://www.controlled- Vaccinesforpreventinginfluenzaintheelderly(Review) 4 Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. trials.com/)andthedigitaldissertationswebsite(http:// Generationoftheallocationsequence wwwlib.umi.com/dissertations); A=adequate,forexample,tableofrandomnumbersorcomputer- • wesearchedtheVaccineAdverseEventReportingSystem generatedrandomnumbers. website(http://www.vaers.org);and B=inadequate,forexample,alternation,dateofbirth,dayofthe • wecontactedvaccinemanufacturerslistedattheWHO weekorcaserecordnumber. website. C=notdescribed. Allocationconcealment Datacollectionandanalysis A=adequate-forexample,numberedorcodedidenticalcontain- ers administered sequentially, on-site computer system that can only beaccessedafterenteringthecharacteristicsof anenrolled Selectionofstudies participant,orseriallynumbered,opaque,sealedenvelopes. Two review authors(TOJ,EF)independently appliedinclusion B=possiblyadequate-forexample,sealedenvelopesthatarenot criteriatoallidentifiedandretrievedarticles. sequentiallynumberedoropaque. C=inadequate-forexample,opentableofrandomnumbers. D=notdescribed. Dataextractionandmanagement Tworeviewauthors(EFandLAA)independentlyperformeddata Blinding extractionusingadataextractionform(Appendix3).Tworeview A=adequatedouble-blinding-forexample,placebovaccine. authors (TOJ, CDP) checked data and entered these into cus- B=single-blind-thatistosay,blindedoutcomeassessment. tomisedsoftware. C=noblinding. Weextracteddataonthefollowing: • methodologicalqualityofstudies; • studydesign(Appendix1); Followup • descriptionofsetting; Averagedurationoffollowupandnumberoflossestofollowup. • characteristicsofparticipants; • descriptionofvaccines(contentandantigenicmatch); • descriptionofviralcirculationdegree; Non-experimentalstudies • descriptionofoutcomes; We made quality assessment of non-RCT studies in relation to • lengthofthefollowup; the presence of potential confounders which could make inter- • publicationstatus; pretationoftheresultsdifficult.Thequalityofcase-controland • dateofstudy;and cohortstudies(prospectiveandretrospective)wasevaluatedusing • locationofstudy. the appropriate Newcastle-Ottawa Scales (NOS) (Appendix 2). Becauseofthelackofempiricalevidenceontheimpactthatthe methodologicalqualityhasontheresultsofnon-RCTs,thisevalu- Assessmentofriskofbiasinincludedstudies ationwasonlyusedattheanalysisstageasameanofinterpretation oftheresultsandasetofsensitivity analyseswasperformedfor thisscope.Weclassifiedstudiesasatlowriskofbias(uptoone inadequate itemintheNOS),mediumriskofbias(uptothree Experimentalstudies inadequateitems),highriskofbias(morethanthreeinadequate All review authors independently assessed the methodological items)andveryhighriskofbias(whentherewasnodescription quality of theincluded studies using criteriafromthe Cochrane ofmethods). Handbook forSystematic ReviewsofInterventions(Higgins 2008) In case of disagreement between the review authors, TOJ arbi- andresultswereintroducedintothesensitivityanalysis. trated. Weclassifiedstudiesaccordingtothefollowingcriteria: Measuresoftreatmenteffect Randomisation We summarised efficacy (against influenza) and effectiveness A=individualparticipantsallocatedtovaccineorcontrolgroup. (againstinfluenza-likeillness)estimatesasriskratio(RR)(usinga B=groupsofparticipantsallocatedtovaccineorcontrolgroup. 95%confidenceinterval(CI))oroddsratio(OR)(usinga95% Vaccinesforpreventinginfluenzaintheelderly(Review) 5 Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.