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Seroprevalence of hepatitis A infection in a low endemicity country: a systematic review Pham, Ba'; Duval, Bernard; De Serres, Gaston; Gilca, Vladimir; Tricco, Andrea C.; Ochnio, Jan; Scheifele, David W. Jul 7, 2005

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ralssBioMed CentBMC Infectious DiseasesOpen AcceResearch articleSeroprevalence of hepatitis A infection in a low endemicity country: a systematic reviewBa' Pham*†1,2, Bernard Duval†3, Gaston De Serres†3, Vladimir Gilca†4, Andrea C Tricco†1, Jan Ochnio†5 and David W Scheifele†5Address: 1BioMedical Data Sciences, GlaxoSmithKline, Ontario, Canada, 2Chalmers Research Group, Children's Hospital of Eastern Ontario Research Institute, Ontario, Canada, 3Centre De Recherche du CHUQ, Institut Nationale Sante Publique du Quebec, Quebec, Canada, 4Centre de Recherche du CHUQ, Quebec, Canada and 5Vaccine Evaluation Centre, University of British Columbia, British Columbia, CanadaEmail: Ba' Pham* - ba.z.pham@gsk.com; Bernard Duval - bernard.duval@ssss.gouv.qc.ca; Gaston De Serres - gaston.deserres@ssss.gouv.qc.ca; Vladimir Gilca - vladimir.gilca@ssss.gouv.qc.ca; Andrea C Tricco - andrea.tricco@utoronto.ca; Jan Ochnio - jochnio@interchange.ubc.ca; David W Scheifele - dscheifele@cw.bc.ca* Corresponding author    †Equal contributorsAbstractBackground: In Canada – a low endemicity country, vaccines for hepatitis A virus (HAV) are currently recommendedto individuals at increased risk for infection or its complications. Applying these recommendations is difficult because theepidemiology of HAV infection is poorly defined, complex, and changing. This systematic review aimed to 1) estimateage-specific prevalence of HAV antibody in Canada and 2) evaluate infection-associated risk factors.Methods: MEDLINE (1966–2005) and EMBASE (1980–2005) were searched to identify relevant studies for thesystematic review. Archives for the Canada Diseases Weekly Report (1975–1991) and Canada Communicable DiseaseReport (1992–2005) were searched for relevant public health reports. Data were abstracted for study and participants'characteristics, age-specific prevalence, and risk factors.Results: A total of 36 reports describing 34 unique studies were included.The seroprevalence in Canadian-born children was approximately 1% in ages 8–13, 1–6% in 20–24, 10% in 25–29, 17%in 30–39, and increased subsequently. In age groups below 20 and 20–29, age-specific seroprevalence generally remainedconstant for studies conducted across geographic areas and over time.Compared to Canadian-born individuals, subjects born outside Canada were approximately 6 times more likely to beseropositive (relative risk: 5.7 [95% CI 3.6, 9.0]). Travel to high risk areas in individuals aged 20–39 was associated witha significant increase in anti-HAV seropositivity (RR 2.8 [1.4, 5.5]). Compared to heterosexuals, men having sex with menwere only at a marginally higher risk (adjusted odds ratio 2.4 [0.9, 6.1]). High risk for seropositivity was also observedfor Canadian First Nations and Inuit populations.Conclusion: Results from the current systematic review show that in this low endemicity country, disease acquisitionoccurs in adulthood rather than childhood. The burden of disease is high; approximately 1 in 10 Canadians had beeninfected by ages 24–29. The increase in prevalence in young adults coincides with disease importation and increasingfrequency of risk factors, most likely behavioral-related ones.Gaps in seroprevalence data were identified rendering the application of current immunization recommendations Published: 07 July 2005BMC Infectious Diseases 2005, 5:56 doi:10.1186/1471-2334-5-56Received: 11 May 2005Accepted: 07 July 2005This article is available from: http://www.biomedcentral.com/1471-2334/5/56© 2005 Pham et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 11(page number not for citation purposes)difficult. A nationwide prevalence survey for all Canadians is needed. This is essential to quantify the effectiveness of current recommendations and conduct cost-effectiveness evaluations of alternative immunization programs, if necessary.BMC Infectious Diseases 2005, 5:56 http://www.biomedcentral.com/1471-2334/5/56BackgroundHepatitis A virus (HAV) is prominent in many areas of theworld [1-3]. In North America, infection rates havedeclined with better hygiene practice and public sanita-tion but remain heterogeneous across geographic andsocioeconomic strata [4-6]. Further decline is possiblewith HAV vaccines which provide consistent, long-lastingprotection and have been available since the mid-1990s[7,8]. In the United States, universal vaccination of chil-dren and youth has been in place for about 6 years in highendemicity areas [9], leading to historically low ratesnationally in recent years [10]. In Canada, the currentnational immunization guide recommends HAV vaccinesfor individuals at increased risk of infection or its compli-cations. The guide also states that a universal immuniza-tion program should be considered, but furtherdiscussion is needed nationally [11].Applying the Canadian recommendations is difficultbecause the epidemiology of HAV infection in Canada ispoorly defined, complex, and changing [8]. Reported ratesdiffer substantially by province, gender, and age [12]. Therates show repeated peaks and troughs [13] and the lastpeak occurred in mid-1990 [12,13]. It was during the sub-sequent period of decline that vaccines were used as a toolto enhance HAV control [8].Evaluating the impact of the current recommendations isalso difficult. Data are needed to distinguish between acyclical decline and a further decline associated with therecommendations [10]. Such assessment is important toinform future immunization policies. A combination oftimely case-notification data, prevalence data, and riskfactor data is required for both the application and evalu-ation of the recommendations.Case-notification data is of limited use due to under-detection of sub-clinical infection and under-reporting ofconfirmed cases [8,14]. A useful means that circumventthese limitations is to measure the prevalence of HAVantibody [15]. Following an acute infection, antibody toHAV develops in virtually every instance, remainingdetectable for decades, and providing a reliable marker ofpast infection. In the United States, countrywide seroprev-alence surveys and sentinel surveillance have been con-ducted to provide insight into HA epidemiology, and torationalize and evaluate immunization programs[10,15,16]. In Canada, similar surveys exist but are lim-ited in scope and comprehensiveness [17-19]. Conse-quently, risk factor data are also limited and fragmented[12,17]. The current systematic review aimed to 1) esti-mate age-specific prevalence of hepatitis A antibody inCanada and 2) evaluate infection-associated risk factors.MethodsMEDLINE (Jan. 1966 – Mar. 2005) and EMBASE(Jan.1980 – Mar. 2005) were searched to identify citationsof potentially relevant studies for the systematic review(MeSH terms: "hepatitis" exploded AND "Canada"exploded). A study report was included if it containedprevalence data of HAV-antibody (detected through seraor saliva samples, hereafter referred to as seroprevalence)for a Canadian population. Reasons for exclusion werecategorized and reported. Citations were screened inde-pendently by two reviewers. Full-text study reports fromcitations deemed relevant by one reviewer were obtained.Archives for the Canada Diseases Weekly Report (Jan.1975 – Dec. 1991, the last year of reporting) and CanadaCommunicable Disease Report (Jan. 1992 – Mar. 2005)were also searched for potentially relevant public healthreports [20]. Two reviewers independently reviewed bothpublished and public health reports. Discrepancies wereresolved through discussion. Back referencing and authorsearches of all included studies were conducted. Otherpotentially relevant reports were obtained by contactingHA experts and related public health units.From the included reports, data were independentlyabstracted for study and participants' characteristics. Age-specific prevalence of HAV antibody data were extractedfor Canadian-born participants, all Canadians includingindividuals born outside the country, and participantswith known risk factors [11]. Seroprevalence estimatesand 95% confidence intervals (CI) were derived assuminga binomial distribution for the number of seropositiveindividuals from the total numbers of tested individuals.Participants who reported receiving the HA vaccine wereexcluded from the prevalence estimates as they were likelyto have vaccine-induced antibody.If available, adjusted odds ratios (AOR) for seropositivityof both demographics and risk factors were extracted,together with the baseline risk of HAV seropositivity (i.e.,population, location and timing of the survey). When theAOR of a variable was not reported, HAV antibody datastratified by the variable were obtained to derive the unad-justed relative risk for seropositivity (URR). Relative riskwas used as it is a better risk estimate than the odds-ratioin the range of seroprevalence observed in this systematicreview [21]. If appropriate, a random effects model wasused to combine URRs across studies, together with anassessment for heterogeneity (i.e., chi-squared test).Information related to the risk of seropositivity was sum-marized for the following risk categories [11]: 1) travelersto high endemicity areas; 2) groups with high risk activi-ties such as men who have sex with men (MSM), illicitPage 2 of 11(page number not for citation purposes)drug users, and street people; 3) First Nations and Inuitpopulations; and 4) others (e.g., individuals with chronicBMC Infectious Diseases 2005, 5:56 http://www.biomedcentral.com/1471-2334/5/56Table 1: Study and participant characteristicsStudy Study DesignStudy Year n Population Location Age in yearsPUBLISHED LITERATUREMean ± SD or (range)Ochnio 2005* [22] P 2000–1 811 Grade 9 students British Columbia (14–15)Muecke 2004* [23] CC 2001 492 Day-care educators Montreal 37Minuk 2003 [24] P 1999 315 First Nations Manitoba 34 ± 15Ochnio 2001 [25] P 1998 494 Street youth, IDU, MSM Vancouver 19, 35, 34Smieja 2001 [26] CC 1997–8 179 IHD patients Hamilton 61 (38–81)Kiefer 2000 [27] R 1997 343 Hepatitis C patients Edmonton 40 (0–95)Allard 2001 [28] P 1995–97 353 Gay men Montreal 37Moses 2002 [29] P 1995–6 533 Street people Winnipeg 26 (11–65)Roy 2002 [30] R 1995–6 427 Street youth Montreal (14–25)Ochnio 1997 [31] P 1995–6 224 Grade 6 students Vancouver (10–12)De Serres 1997 [32] P 1995 85 Sewer workers Quebec 36 ± 7De Serres 1995 [33] CC 1995 228 Sewer workers Quebec 41 (28–64)Smieja 2003 [34] R 1993–5 3127 CV or high risk diabetes Canada 65Payment 1991 [18] P 1988–9 617 French-Canadian Montreal (9–79)Embil 1989 [35] P 1981–3 203619221/CF recruits2/CF malesNova Scotia, Quebec, Posted abroad1/(15–25)2/26 (17–53)Nicolle 1986 [36], Minuk 1985 [37]P 1982 172 Chesterfield Inlet Northwest Territories0 – 78Crewe 1983 [38] P 1981–2 304 Children attending outpatient clinic Halifax (0.5–16)Minuk 1982 [39]Minuk 1982 [40]P 1980 720 Inuit Northwest Territories(0.3–86)McFarlane 1980 [41] P, R 1980 243152293 & 2821/STD clinic patients2/Student nurses3/2 groups of blood donorsNova Scotia 1/(16–26)2/(18–24)3/(16–26) & (51–65)Buchner 1980 [42] R 1980 5097 Blood donors Toronto <21, >60Richer 1982 [55] R 1970–79 447 Samples of acute viral hepatitis Montreal Not reportedMinuk 1994 [43] P 1974–8 42 Household transmission Winnipeg 27 ± 12Minuk 2003 [44] SR 1980–2000 1706 Inuit and First Nations Various locations 0–60+McFarlane 1982 [45] P NR 154 Institutions Nova Scotia (13–28)McFarlane 1981 [46] P NR 130 Patients with hematological malignancyNova Scotia (4–76)GREY LITERATUREDuval 2005* [48] P 2003 1057 Canadian aged 8–13 Canada (8–13)Wu 2005 [47] R 1992–9 NR Subjects tested for HAV infection Manitoba Not reportedOchnio 2004 [49] P 2003 585 Young adults Vancouver (20–39)Cook 2000 [19] R 2000 1206 Women of child-bearing age British Columbia (15–44)Harb 2000 [50] P 1999 172 First Nations British Columbia (0–40+)Levy 2001 [51] P 1997 1000 University students Toronto 25 ± 5Ford-Jones 1995 [52] P 1993 122 Day-care providers Toronto Not reportedOchnio 1995 [53] P 1994–5 1019 Clients to travel clinic Vancouver (2–69+)Kocuipchyk 1995 [54] P 1991–2 505 Individuals attending travel clinic Edmonton (16–60+)Notes:*Study reported seroprevalence data for individuals with or without HAV vaccination.Abbreviations: Study design: P prospective data acquisition, R retrospective data acquisition, CC case control, SR systematic review. Population: IDU injection drug users, MSM men who have sex with men, IHD ischemic heart disease, CV cardiovascular, CF Canadian Forces, STD sexually transmitted disease.Page 3 of 11(page number not for citation purposes)BMC Infectious Diseases 2005, 5:56 http://www.biomedcentral.com/1471-2334/5/56hepatitis, household contacts, infected food handlers,etc.).ResultsLiterature searchA total of 36 reports describing 34 unique studies wereincluded in the systematic review (Table 1) [18,19,22-55].These were obtained from screening 413 potentially rele-vant citations and reviewing 66 full-text study reports and25 public health reports (Figure 1). Common reasons forexclusion at the screening stage included studies of hepa-titis B virus (n = 95), hepatitis C virus (n = 64), commen-taries (n = 24), and others (n = 121; Figure 1). Commonreasons for exclusion at the full-text review stage includedgeneral review of HAV (n = 9), no seroprevalence data (n= 17), and other viral hepatitis (n = 16; Figure 1).Overall, 74% (n = 25) of the included studies werereported in peer-reviewed journals while 26% (n = 9)were grey literature [20], including 9% (n = 3) publichealth reports, 14% (n = 5) abstracts, and 3% (n = 1)unpublished study (Table 2). HAV antibody was detectedusing serum samples in 28 studies and saliva samples in6. The median sample size was 427 and 793 for the pub-lished and grey literature studies, respectively. Only 21%(7/34) of all studies reported prevalence among Cana-dian-born participants and 29% (10/34) reported preva-lence data of all participants including foreign-bornindividuals. The majority of these studies (27/34)reported prevalence data of participants with known riskfactors.Age-specific seroprevalenceThe seroprevalence in Canadian-born children aged 8–13was 1% [95% CI: 0.5–2%] according to a national surveyconducted in 2003 [48]. The seroprevalence was 1–6% inages 20–24, approximately 10% in 25–29, 17% in 30–39,and increased subsequently (Figure 2). In age groupsbelow 20 and 20–29, age-specific seroprevalence gener-ally remained constant for studies conducted across geo-graphic areas in 1980, 1988, 1997, and 2003. Thisremained so despite differences in study methodology.There was no association between seropositivity and gen-der based on 9 population comparisons from 5 studies (n= 4158, URR: 1.0 [95% CI: 0.9, 1.1]) [22,31,35,41,54],which was consistent with results of 3 other studiesreporting adjusted risk estimates (Table 3) [25,34,48].Two studies in the early 1980's suggested that individualsliving in urban areas were 30% more likely to have HAVantibody compared to those in rural areas (n = 647, URR:1.3 [1.2, 1.5]) [41,46].be seropositive (n = 3008, URR: 5.7 [3.6, 9.0], Table 3)[30,31,49,51,53], which most likely occurred in theirbirth country. However, the possibility that infectionoccurred in Canada could not be ruled out. Age-specificseroprevalence estimates including these individuals var-ied substantially and could only be used to infer the levelof immunity in the population. For example, seropreva-lence among all Canadians aged <20 ranged from 2–16%[18,31,38,48,51] for which 3–25% of the sampled popu-Results of the literature searchFig re 1Results of the literature search.Citations from Medline & EMBASE Searches n=413Full text articles retrieved n=66Public health (PH) reports obtained bycontacting PH departments n=25Citations excluded n=347Reasons: HBV n=95; HCV n=64; HDV n=3;HEV n=6; HGV n=2; HBV/HCV n=18;Animal study n=14; Commentary n=24; Other n=121Articles excluded n=47Reasons: HAV articles: Review n=9, Guides n=5,No seroprevalence data n=17;Other viral hepatitis n = 16Public health reports excluded n=23Reasons: HAV incidence data only n=21;Other viral hepatitis n=2Relevant articles n = 19Relevant PH reports n = 2Relevant articles through expert contact n = 4Relevant articles through back referencing& author searches n = 11Included study reports n = 36Page 4 of 11(page number not for citation purposes)Compared to Canadian-born individuals, subjects bornoutside Canada were approximately 6 times more likely tolations were individuals born outside the countryBMC Infectious Diseases 2005, 5:56 http://www.biomedcentral.com/1471-2334/5/56[25,48,53]. This contrasted the 1% seropositivity forCanadian-born participants reported above.Risk factorsTravel-related data were available in 6 studies (Table 1)[23,35,48,49,53,54]. HAV antibody prevalence forCanadian-born individuals visiting a travel clinic was2.3% in ages 20–25 and 4.3% in ages 25–28 [53]. Theprevalence of seropositivity in these individuals was com-parable to that reported above for Canadian-born individ-uals. The risk related to travel among Canadian-born wasalso not significant in a study of day-care educators [23].Two population-based surveys reported travel-related risk[48,49]. In one study, travel to high risk areas by Cana-dian-born individuals aged 20–39 (approximately 12% ofstudy participants) was associated with a significantalence was 1.9% in Canadian-born non-vaccinated trave-lers and 1.3% in non-travelers; the association was againnot significant (Table 3) [48].Two studies evaluated HAV infection among MSM in twodifferent cities [25,28]. MSM participants on average had3 sexual partners over the preceding 6 months, accordingto one study [28]. Also, 18% of these individuals werefood handlers. Compared to heterosexuals, MSM wereonly at a marginally higher risk for seropositivity (n = 494,AOR 2.4 [0.9, 6.1]), according to the second study [25].However, the study sample was highly heterogeneous andincluded MSM, injection drug users (IDU), and streetyouth.Data on street-involved populations were available inTable 2: Study characteristicsPublished Literature (n = 25) Grey Literature (n = 9)Peer-reviewed study report (n = 25) Public health report (n = 3)Abstract (n = 5)Unpublished report (n = 1)Study DesignCase-control 2 0Prospective (P) data acquisition 16 7Retrospective (R) data acquisition 5 2P & R data acquisition 1 0Systematic review 1 0Sample Size>1000 4 3100 – 1000 19 6<100 2 0Median [1st, 3rd Quartile] 427 [224, 720] 793 [422, 1029]Mean (Min, Max) 877 (42, 5097) 708 (122, 1206)Timing of data collection2000 – 2004 2 31990 – 1999 12 61980 – 1989 7 01970 – 1979 2 0Not reported 2 0Populations with prevalence dataCanadian born subjects 4 3All Canadians¶ 6 4Participants with known risk factors 21 7Seropositivity testSerum samples 22 6Saliva samples 3 3Notes: ¶including subjects born outside of CanadaPage 5 of 11(page number not for citation purposes)increase in seropositivity (n = 407, URR: 2.8 [1.4, 5.5])[49]. In a national survey of children aged 8–13, the prev-three studies (Table 3) [25,29,30]. Seropositivity wasapproximately 5% in street youth aged 14–25 in Vancou-BMC Infectious Diseases 2005, 5:56 http://www.biomedcentral.com/1471-2334/5/56ver and Montreal [25,30]. In the Montreal study [30], theoutbreak in MSM (n = 376 cases from December 1994 toFebruary 1998 [28]) seemed to have little effect on theprevalence of anti-HAV among street youth, measuredduring the same period. Significant behavioral risk factorsfor seropositivity were reported for street-involved indi-viduals. These included IDU, history of sexually-transmit-ted disease, and high HAV-risk sexual activities (Table 3).Seroprevalence in Canadian First Nations and Inuit popu-95% and was approximately three times that of non-Abo-riginal Canadians residing in the same communitiesacross all ages [44]. For example, Minuk and colleaguesreported on a seroprevalence survey of 720 inhabitants ofan Inuit community (n = 850). Approximately 27% of thiscommunity were aged 0–9, 30% aged 10–19, 32% aged20–49, and 11% aged 50 or above [40].Among Canadian-born day-care educators, there was aborderline significant association between risk of HAVSeropositivity rate (95% confidence interval) among Canadian-born study participantsFigure 2Seropositivity rate (95% confidence interval) among Canadian-born study participants.Page 6 of 11(page number not for citation purposes)lations were reported in four studies and summarized in asystematic review [44]. The prevalence ranged from 75–positivity and years of employment (Table 3) [23]. A his-tory of daycare attendance among grade 6 students wasBMC Infectious Diseases 2005, 5:56 http://www.biomedcentral.com/1471-2334/5/56Table 3: Assessment of risk factorsRisk factor n Risk MeasureRisk Estimate (95% CI)Population, Location, Timing of Data AcquisitionAge in yearsStudyDEMOGRAPHICS Mean ± SD or (range)Female versus Male 1003 AOR 2.2 (0.8, 6.25) School-aged children, Canada, 2003(8–13) [48]Female versus Male 3128 AOR 0.8 (0.6, 0.96) CV or high risk diabetes, Canada, 1993–565 [34]Female versus Male 494 AOR 1.3 (0.8, 2.3) SY, MSM, IDU, Vancouver, 1998 32 ± 11 [25]Female versus Male 4158 URR 1.0 (0.9. 1.1) [p = 0.30]*9 population comparisons from 5 studies(8–65+) [31,35,41,49,54]Urban versus Rural 647 URR 1.3 (1.2, 1.5) [p = 0.59]*3 population comparisons from 2 studies(16–76) [41,46]Born in high risk country versus born in Canada494 AOR 2.9 (1.1, 7.6) SY, MSM, IDU, Vancouver, 1998 32 ± 11 [25]Born in endemic country versus born in Canada1003 AOR 22.3 (6.6, 75.0) School-aged children, Canada, 2003(8–13) [48]Foreign-born versus Canadian-born 353 AOR 6.2 (2.6, 15.0) Gay men, Montreal, 1995–97 36 [28]Born in a high-income country versus moderate to low†492 AOR 20.8 (9.4, 46.0) Day-care educators, Montreal, 200137 [23]Foreign-born versus Canadian-born3008 URR 5.7 (3.6, 9.0) [p < 0.01]*5 population comparisons from 5 studies(2–69+) [30,31,49,51,53]TRAVEL TO HIGH RISK AREATravel to high risk area versus otherwise1003 AOR 1.4 (0.4, 4.8) School-aged children, Canada, 2003(8–13) [48]Travel to high risk areas versus otherwise407 URR 2.8 (1.4, 5.5) Canadian-born adults, Vancouver, 2003(20–39) [49]Ever travelled to a developing country‡492 AOR 2.4 (1.3, 4.2) Day-care educators, Montreal, 200137 [23]HIGH RISK ACTIVITIESMSM versus heterosexuals 494 AOR 2.4 (0.9, 6.1) SY, MSM, IDU, Vancouver, 1998 (25–34) [25]Sexual partners with VH history versus otherwise420 AOR 13.8 (4.2, 45.2) Street youths, Montreal, 1995–6 (14–25) [30]Insertive anal penetration versus otherwise420 AOR 5.1 (1.6, 16.7) Street youths, Montreal, 1995–6 (14–25) [30]History of STD versus no history 500 AOR 2.0 (1.2, 3.3) Street people, Winnipeg, 1995–6 26 (11–65) [29]History of IDU versus no history 494 AOR 6.5 (1.6, 26.3) SY, MSM, IDU, Vancouver, 1998 (25–34) [25]History of IDU versus no history 500 AOR 1.6 (0.99, 2.7) Street people, Winnipeg, 1995–6 26 (11–65) [29]FIRST NATIONS AND INUITNative versus Non-native 1003 AOR 5.2 (1.0, 26.0) School-aged children, Canada, 2003(8–13) [48]Aboriginal versus Non-aboriginal 500 AOR 6.6 (3.8, 11.5) Street people, Winnipeg, 1995–6 26 (11–65) [29]Inuit versus white in NWT 708 URR 4.5 (2.4, 8.5) Inuits, Baker Lake, NWT, 1980 (0.3–86) [39,40]4+ versus 1–3 household occupants 635 URR 1.1 (0.98, 1.3) Canadian Inuit, Baker Lake, 1980 (0.3–86) [39,40]OTHERSYears working in day-care, 5-year groups§339 AOR 1.3 (1.0, 1.8) Canadian-born day-care educators, Montreal, 200134 [23]History of daycare versus no 1278 URR 1.2 [0.7, 2.2] 2 population comparisons 8–13 [31,48]Page 7 of 11(page number not for citation purposes)history [p = 0.30]* from 2 studiesBMC Infectious Diseases 2005, 5:56 http://www.biomedcentral.com/1471-2334/5/56not associated with seropositivity [31]. Also, the seropos-itivity was 1.3–1.6 times higher in children aged 8–13who attended day-care, but no statistical difference wasevident in all participants, non-vaccinated participants, orthose without known risk factors [48].Other potential risk factors were also examined. From asample of 343 individuals who tested positive for hepati-tis C, 30% of those aged 20–29 were seropositive for HAV[27]. One prospective cohort followed 62 household con-tacts and 20 index cases over 6 months; the risk of infec-tion was 52% among other susceptible householdmembers [43]. Working in a sewage plant was not associ-ated with seropositivity [33].DiscussionThe seroprevalence data consolidated in this systematicreview had many limitations. Except for one national sur-vey in ages 8–13 [48], other studies were generally notrepresentative of the general population. Substantial vari-ation across studies was observed with respect to studypopulation, timing, sample size, and location. Reportingof data was inconsistent with respect to age stratificationand definition of risk factors. Some studies conductedafter the introduction of the vaccine around 1997 did nottake vaccine-induced HAV antibody into account. Thiswas, however, rectified in more recent studies [23,48,49].For example, the seroprevalence in a national survey ofchildren aged 8–13 was 2.7% overall and 2.0% after theexclusion of self-reported vaccinees [48]. The correspond-ing figures in a survey of young adults aged 20–39 were22% and 16%, respectively [49]. Given these limitations,should be stratified by participants' birthplace andaccount for vaccine-induced antibody.Results from the current systematic review show that dis-ease acquisition occurs in adulthood rather than child-hood [14]. In Canada, the increase in prevalence in youngadults coincides with disease importation and increasingfrequency of behavioral risk factors, such as risk activitiesamong MSM and street-involved populations. Even in thislow endemicity country, approximately 1 in 10 Canadianshad been infected by ages 24–29.A low level of HAV immunity in Canada is evident fromthis systematic review. Over 90% of Canadian-born indi-viduals aged 20–29, and over 80% of those aged 30–39remained unprotected. Canadians born outside the coun-try generally have a higher prevalence of HAV antibody,yet including these individuals did not significantlyimprove the percentage of protected Canadians. This lowlevel of immunity and persistent risk of exposure to HAVsuggest that outbreaks are possible in the future [14,47].For example, unprotected clients exposed to an infectedfood handler led to mass immunizations in the early2000's (Toronto 2002 [56], n = 19,208; London 2002[57], n = 16,320; Vancouver 2002 [58] n = 6,000).Clarifications are required to better understand the epide-miology of HAV in Canada, especially the inter-relationbetween timely case-notification data, seroprevalencedata, and risk factor data. In a study examining nationalcase-notification data from 1990–1999, estimated inci-dence of reported cases decreased while the average age ofSewer workers versus controls|| 228 URR 1.1 (0.8, 1.4) Sewer workers, Quebec City, 199341 (28–64) [33]3+ versus 0–3 siblings 502 URR 2.0 (1.7, 2.5) Travel clinic, Edmonton, 1991–2 (16–60+) [54]Current household income <20,000/yr¶153 AOR 5.3 (1.2, 24.2) Foreign-born day-care educators, Montreal, 200139.7 [23]Annual family income <30,000 vs ≥30,0001057 URR 0.7 (0.3, 2.0) School-aged children, Canada, 2003(8–13) [48]Abbreviations: AOR adjusted odds ratio. CV cardiovascular. SY street youth. MSM men who have sex with men. IDU injectable drug user. URR unadjusted relative risk. STD sexually transmitted disease. NWT North West Territory. G6 grade 6. yr yearNotes: *Meta-analytical estimates (95% CI) [p-value from a test of homogeneity] from random-effects models. † The day-care educator study included 492 participants, including 339 Canadian-born individuals and 153 foreign-born. The odds-ratio for "born in a high-income country versus moderate to low" was 20.8 (95% CI 9.4, 46.0) for all 492 participants, not reported for Canadian-born, and 4.6 (1.7, 12.2) for foreign-born. ‡ The odds-ratio for "ever traveled to a developing country" in the day-care educators study was 2.4 (1.3, 4.2) for all 492 participants, not significant for Canadian-born (estimated OR not available), and 8.1 (2.3, 29.0) for foreign-born. § The odds-ratio for "years working in day-care, 5-year groups" was not significant for all 492 participants (estimated OR not available), 1.3 (1.0, 1.8) for Canadian-born, and not significant (estimated OR not available) for foreign-born. || Control subjects were outpatients undergoing lipid testing,. ¶ The odds-ratio for "current household income <20,000/yr" in the day-care educators study was not significant (estimated OR not available) for all 492 participants and Canadian-born and was 5.3 (1.2, 24.2) for foreign-born.Table 3: Assessment of risk factors (Continued)Page 8 of 11(page number not for citation purposes)improvements in the reporting of future HAV prevalencestudies are required. Most importantly, prevalence dataexposure and subsequent infection increased [12]. Giventhe low seroprevalence in Canadian youth, the currentBMC Infectious Diseases 2005, 5:56 http://www.biomedcentral.com/1471-2334/5/56results suggest that the average age of HA exposure isabove 24 and is increasing. While infection in children isoften sub-clinical or mild, infected adults often experiencemore severe symptoms [1,59].Results of the current systematic review are consistentwith low HAV endemicity patterns in developed countries[60-62]. A substantial burden of infection was observed inyoung Canadians and this did not decrease among succes-sive generations over the past 20 years. Similar observa-tions were reported elsewhere [63]. In these lowendemicity countries, outbreaks are common [64,65].Sources of outbreaks that are common in these countriesinclude infected food handlers [56,57], contaminatedfood importation [66,67], and unprotected immigrantswho visit friends and relatives in their original countries[68].In order to apply the current immunization recommenda-tions, substantial information pertaining to groups atincreased risk of HA infection or its complications isrequired. Results from this systematic review suggest thatthe risk of HA infection in these target groups was not welldocumented. With the exception of a few population-based surveys [48,49], most studies enrolled participantswith known risk factors and failed to include a controlgroup. In addition, some used residual sera obtained forother tests with virtually no risk factor data.ConclusionResults from the current systematic review show that inthis low endemicity country, disease acquisition occurs inadulthood rather than childhood. The burden of diseaseis high; approximately 1 in 10 Canadians had beeninfected by ages 24–29. The increase in prevalence inyoung adults coincides with disease importation andincreasing frequency of risk factors, most likely behavio-ral-related ones.Gaps in seroprevalence data were also identified in thissystematic review, rendering the application of currentrecommendations difficult. A nationwide prevalence sur-vey for all Canadians is needed. This is essential to quan-tify the effectiveness of current recommendations [10]and conduct cost-effectiveness evaluations of alternativeimmunization programs, if necessary [69].AbbreviationsG6 students grade 6 studentsCompeting interestsFunding for this systematic review was provided by Glax-oSmithKline Canada. BP and ACT are employed by Glax-Authors' contributionsBP contributed to the development of the research ques-tion and methodology, project management, systematicreview, data management and data analysis, derivation ofcharts and tables, and interpretation of the results. BD,GDS, DS contributed to the development of the researchquestion and methodology, acquisition of unpublisheddata, and interpretation of the results. JO and VG contrib-uted to the development of the research methodology,acquisition of unpublished data, derivation of charts andtables and interpretation of the results. ACT contributedto the development of the research methodology, projectmanagement, systematic review, derivation charts andtables and interpretation of the results. All of us contrib-uted to the manuscript writing and approved the final ver-sion of the manuscript.AcknowledgementsWe would like to thank Perica Sever for her continued support. 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