Vaccine preventable diseases in returned international travelers: Results from the GeoSentinel...

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Vaccine 28 (2010) 7389–7395

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Vaccine

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accine preventable diseases in returned international travelers:esults from the GeoSentinel Surveillance Network

ndrea K. Boggilda,∗, Francesco Castelli b, Philippe Gautretc, Joseph Torresid,e,rank von Sonnenburgf, Elizabeth D. Barnettg, Christina A. Greenawayh,oh-Lian Limi, Eli Schwartz j,k, Annelies Wilder-Smith i,l,ary E. Wilsonm, for the GeoSentinel Surveillance Network1

Tropical Disease Unit, UHN-Toronto General Hospital, 200 Elizabeth Street, North Wing, 13th Floor, Room 1350, Toronto, ON, M5G 2C4, CanadaDept. of Infectious and Tropical Diseases, University of Brescia, Piazza Spedali Civili 1, 25123 Brescia, ItalyDept. of Infectious Diseases and Tropical Medicine, Hopital Nord, AP-HM, 13015 Marseille, FranceDept. of Infectious Diseases, University of Melbourne, Parkville, Victoria, AustraliaDept. of Infectious Diseases, Austin Hospital, 145 Studley Road, Heidelberg, VIC 3084, AustraliaDept of Infectious Diseases and Tropical Medicine, University of Munich, Georgenstr. 5, 80799 Munich, GermanyMaxwell Finland Laboratory for Infectious Diseases, Boston Medical Center, 670 Albany Street, Room 625, Boston University, Boston, MA 02118, United StatesDivision of Infectious Diseases, SMBD Jewish General Hospital, Pavilion G, #143, 3755 Ch. De la Cote Sainte-Catherine, Montreal, QC, H3T 1E2, CanadaDept. of Infectious Diseases, Tan Tock Seng Hospital, 11 Jalan, Tan Tock Seng, Singapore 308433, SingaporeCenter for Geographic Medicine, Chaim Sheba Medical Center, Tel Hashomer 52621, IsraelSakler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelNational University Singapore, SingaporeHarvard School of Public Health, Dept. of Global Health and Population, 665 Huntington Ave, Boston, MA 02115, United States

r t i c l e i n f o

rticle history:eceived 26 January 2010eceived in revised form 1 September 2010ccepted 2 September 2010

a b s t r a c t

Vaccine preventable diseases (VPDs) threaten international travelers, but little is known about their epi-demiology in this group. We analyzed records of 37,542 ill returned travelers entered into the GeoSentinelSurveillance Network database. Among 580 (1.5%) with VPDs, common diagnoses included enteric fever

vailable online 17 September 2010

eywords:mmunizationurveillance

(n = 276), acute viral hepatitis (n = 148), and influenza (n = 70). Factors associated with S. typhi includedVFR travel (p < 0.016) to South Central Asia (p < 0.001). Business travel was associated with influenza(p < 0.001), and longer travel with hepatitis A virus (p = 0.02). 29% of those with VPDs had pre-travel con-sultations. At least 55% of those with VPDs were managed as inpatients, compared to 9.5% of those withnon-VPDs. Three deaths occurred; one each due to pneumococcal meningitis, S. typhi, and rabies. VPDsare significant contributors to morbidity and potential mortality in travelers. High rates of hospitalization

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make them an attractive

. Introduction

Travelers risk exposure to many infections, including manyhat are potentially preventable with vaccines [1–7]. Little empiric

∗ Corresponding author at: Tropical Disease Unit, UHN-Toronto General Hospital,00 Elizabeth Street, 13th Floor, North Wing, Room 1350, Toronto, ON, M5G 2C4,anada. Tel.: +1 416 340 3675; fax: +1 647 439 0827.

E-mail address: andrea.boggild@utoronto.ca (A.K. Boggild).1 Members of the GeoSentinel Surveillance Network are listed at the end of the

ext.

264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.oi:10.1016/j.vaccine.2010.09.009

t for pre-travel intervention.© 2010 Elsevier Ltd. All rights reserved.

ever, the overall burden of VPDs among all ill returned travelersis unknown. Variables that may contribute to the risk of VPDs intravelers include age, purpose of travel, destination, and pretravelpreparation. Among travelers who presented with fever and werediagnosed with a VPD, those whose reason for travel was visitingfriends and relatives (VFRs) were over-represented [2]. Rates ofhospitalization for ill travelers with fever and VPDs were high at60% [2], but there are no data on rates of hospitalization in thosepresenting with VPDs that includes those without fever.

VPDs are costly at both an individual and societal level [8–10],though the collective economic burden of VPDs in returned travel-

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etwork database [11,12] to identify demographic and travel-elated predictors of VPDs, to determine the most well-representedegions for their acquisition, and to estimate minimum hospitaliza-ion rates for VPDs in this cohort.

. Methods

.1. Data source

The GeoSentinel Surveillance Network is comprised of 49 spe-ialized travel/tropical medicine clinics on 6 continents, whichontribute anonymous, clinician- and questionnaire-based travelata on all ill travelers examined, to a centralized Structureduery Language database [11,12]; for additional details seeww.geosentinel.org. To be included, patients must have crossed

n international border within 10 years of presenting to a GeoSen-inel clinic, and to have sought care for a presumed travel-relatedllness. The questionnaire constitutes prospectively establishedariables of interest, including demographic and travel-relatedata, reason for most recent travel, inpatient or outpatient status,re-travel advice, and clinical information. Pre-travel history is lim-

ted to the presence or absence of pre-travel consultation. Specificre-travel interventions such as immunization or malaria prophy-

axis are not recorded in the database. Thus, we do not have data onhich vaccinations, if any, members of the cohort received. Finaliagnoses are assigned by a physician from a standardized list of500 etiologic or syndromic diagnoses [11,12].

.2. Inclusion and exclusion criteria

All returning travelers who attended a GeoSentinel clinicetween March 1997 and December 2007 and whose finaliagnosis was probable or confirmed were eligible for analysisSupplementary Figure 1). The best available national referenceiagnostics are used for confirmed diagnoses. Probable diagnosesre restricted to patients with indisputable physical findings (e.g.,

able 1accine preventable diseases included in analysis.

Vaccine preventable disease

CholeraDiphtheriaJapanese encephalitisTick-borne encephalitis (TBE)Acute hepatitis due to A virusAcute hepatitis due to B virusInfluenza

MeaslesMeningitis secondary to Haemophilus influenzae, Neisseria meningitidis

(meningococcus), or Streptococcus pneumoniae (pneumococcus)Meningococcal sepsisMumpsPertussisRabiesRubellaEnteric fever secondary to Salmonella enterica serovar Typhi or

ParatyphiTetanusVaricellaYellow Fever

bbreviations: RTI, respiratory tract infection.

8 (2010) 7389–7395

2.3. Definitions

Countries were assigned to 1 of 9 regional classifications. Thecategory of ‘vaccine preventable diseases’ (VPD) represented infec-tions that had any likelihood of being prevented by vaccines ifvaccination was administered prior to travel (see Table 1 fora list of diseases with documented efficacies). We included S.paratyphi based on evidence that Ty21a live oral vaccine conferssome protection against S. paratyphi B [13]. Reactivation varicellazoster (shingles), chronic hepatitis B, and tuberculosis were notincluded.

2.4. Statistical analysis

Differences in categorical variables between those with andwithout VPDs were compared using calculated Odds Ratios (OR)with 95% confidence intervals (CI). ORs were calculated by compar-ing the odds of a particular VPD or VPDs as a group in the presenceand absence of a particular categorical variable (sex, purpose oftravel, region of travel). Differences in continuous variables (such asage, duration of travel) between those with and without particularVPDs were compared using 2-tailed t-testing. Differences betweengroups of continuous variables were compared using One-WayANOVA. Variables which achieved or trended toward statistical sig-nificance in univariate analysis, and those deemed to have potentialindependent contribution were entered into a forward stepwiselogistic regression model to evaluate the independent contributionof these variables to a VPD diagnosis in general, and to specificVPD diagnoses where sufficient numbers permitted (n > 30). Forregion of travel, proportionate morbidity was estimated based onthe number of patients with a given VPD divided by the total num-ber of ill travelers to that region, and is reported as the proportionper 1000 ill travelers. Data analysis was performed using SigmaStat2.03 software (SPSS Inc., Chicago, IL). Level of significance was setat p ≤ 0.05.

2.5. Role of the funding source

The funding source had no role in study design, data analysisand interpretation, or in writing the manuscript.

Vaccine efficacy

85–86% [1]99% [1]91% with 2 doses, 99% with 3 doses [1]>95% [34,35]85–99% [1,36]95% [37]70–90% in healthy adults and children; in elderly, 56% effective atpreventing RTI, 50% effective in preventing hospitalization, 68%effective in preventing death [1]95–100% [1,38]Meningococcal: conjugate, 87–98%; polysaccharide, 85–100% [1]Pneumococcal: conjugate, 89–97%; polysaccharide, 50–>80% [1]Meningococcal: conjugate, 87–98%; polysaccharide, 85–100% [1]80–95% [1]85–92% [1]100% immunogenicity with 3 doses [1]97% will form neutralizing antibodies [1]Ty21a: 51% [95% CI 35–63%] [1], 53–67% against S. typhi [13], 49%against S. paratyphi B [13]; Vi: 55% [95% CI 30–71%] against S. typhi [1]100% protective antibody development [1]80–98% [39,40]>90% generate neutralizing antibodies with 1 dose [1]

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Enteric FeverAcute Hepatitis A

InfluenzaAcute Hepatitis B

VaricellaMeasles

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Meningococcal SepsisRabies

Yellow FeverJapanese Encephalitis

Polio

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. Results

Among ill returned travelers, 37,542 fulfilled our inclusion cri-eria. Of these, 580 (1.5%) from 36 different GeoSentinel sitesad a final confirmed (503) or probable (77) VPD. High rates ofonfirmation occurred in viral hepatitis (99%), influenza (96%), vari-ella (87%), pertussis (80%), and bacterial meningitis (80%). Enterictyphoid and paratyphoid) fever, measles, and mumps all had lowerates of confirmation at 79%, 75%, and 50%, respectively. The mostommon VPDs recorded were enteric (typhoid and paratyphoid)ever (n = 276; S. typhi = 160, S. paratyphi = 88, typhoid unspeci-ed = 28), acute viral hepatitis (n = 148; hepatitis A = 97, hepatitis= 51), influenza (n = 70), varicella (n = 37), measles (n = 12), per-

ussis (n = 10), and bacterial meningitis (n = 10) (Fig. 1). No casesf yellow fever or Japanese encephalitis (JE) were recorded. Threeied: one each due to enteric fever caused by S. enterica Serovaryphi, pneumococcal meningitis, and rabies. Table 2 shows the

Table 3 compares the most common VPDs by age, pre-travelncounter, management setting, and trip duration. In univariate

able 2haracteristics of returned Travelers diagnosed with vaccine preventable diseases and orom 1997 to 2007.

Characteristic Ill Travelers with a VPD (n = 580)

Age (years)Median 30Interquartile range 24–40

Gender (%)Male 62.6Female 36.2

Reason for Travel (%)Tourism 56.2Business 17.6VFR 17.9Missionary 5.5Student 2.8

Duration of Travel (days)Median 32Interquartile range 14–92

Pre-Travel Encounter (%)Yes 29.0No 56.6

Management Setting (%)Inpatient 54.7Outpatient 44.3

a P-value based on Forward Stepwise Logistic Regression analysis.b P-value based on 2-tailed t-testing.

able 3omparison of the most common specific VPDs by age, pre-travel encounter, managemen

Vaccine preventabledisease

Totalnumber

Median age (years),interquartile range

Number (%pre-travel e

All in Database 37,542 34, 26–46 18,508 (49)All VPDs 580 30b, 24–40 168 (29)d

Enteric Fever 276 27c, 23–36 105 (38)HAV 97 30c, 24–42 22 (23)HBV 51 36c, 31–41 5 (10)Influenza 70 35c, 25–47 17 (24)Varicella 37 26c, 22.5–33 8 (22)Measles 12 28.5c, 24.5–31.5 2 (17)Pertussis 10 44.5c, 30–61 4 (40)Bacterial Meningitis 10 51c, 27–60 1 (10)

a The numbers reported may be an underestimate as they reflect place of initial evaluab p < 0.001 versus non-VPD cohort by 2-tailed t-testing.c p < 0.001 by One-Way ANOVA.d OR = 0.3 [95% CI 0.2, 0.4] versus non-VPD cohort.e OR = 11.4 [95% CI 9.6, 13.4] versus non-VPD cohort.f p < 0.001 by One-Way ANOVA.

Fig. 1. Magnitude of vaccine preventable diseases among a cohort of 37,542 illreturned travelers. Enteric Fever includes S. typhi and S. paratyphi. Bacterial Menin-gitis refers to that caused by meningococcus, pneumococcus, or Haemophilusinfluenzae b. TBE = tick-borne encephalitis.

analysis, travelers diagnosed with a VPD were younger than thosewith an alternate diagnosis (median age 30 years vs. 34 years,p < 0.001). Males were over-represented amongst those diagnosedwith a VPD versus those with a non-VPD (OR = 1.7 [95% CI 1.4, 2.0]).

ther entities among 37,542 ill returned Travelers presenting to GeoSentinel clinics

Ill Travelers without a VPD (n = 36,962) P value

34 <0.001a

26–46

50.4 <0.001a

48.4

62.714.2 Business: 0.38a

10.1 VFR: 0.05a

11.31.6

28 0.34a

14–90 0.003b

49.6 <0.001a

33.0

9.5 <0.001a

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t setting, and trip duration.

)ncounter

Number (%) hospitalizedat initial encountera

Median trip duration(days), interquartile range

3826 (10) 28, 14–90317 (55)e 32, 14–92153 (55) 55f, 21–151

55 (57) 36f, 11.5–7931 (61) 17.5f, 11.5–47.538 (54) 14f, 7–41.517 (46) 22, 14–75

8 (67) 14, 7–41.52 (20) 17, 11–3109 (90) 11, 8–11

tion.

7392 A.K. Boggild et al. / Vaccine 28 (2010) 7389–7395

South Central Asia

Eastern Europe

Northeast Asia

Southeast Asia

North Africa

Oceania/Australia

Western Europe

Latin America

Sub-Saharan Africa

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Proportionate Morbidity per 1000 Travelers

Enteric FeverHAVHBVInfluenzaVZVMeaslesPertussisBacterial MeningitisOther VPD

Fig. 2. Proportionate morbidity by region of exposure. Numbers are reported ascases per 1000 travelers returning from each region. Enteric Fever includes S. typhiaeH

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Table 4Demographic predictors of common specific vaccine preventable diseases.

Vaccine preventabledisease

Independent predictor OR [95% CI]

Enteric Fever due toS. typhi

VFR travel 3.3 [2.3, 4.6]

Travel to South Central Asia 6.5 [4.8, 8.9]Birth in India 9.8 [5.9, 16.1]

Acute hepatitis A virus Male sex 1.9 [1.3, 3.0]Longer trip duration (>30 days) 5.6 [3.5, 8.9]Birth in Italy 27.7 [17.6, 41.8]

Acute hepatitis B virus Male sex 3.9 [2.0, 7.8]Older age (Age >30 years) 2.3 [1.2, 4.4]Residence in Italy 37.3 [10.4, 134]

Influenza Male sex 1.5 [1.0, 2.3]Business travel 3.1 [1.8, 5.3]

nd S. paratyphi. “Other VPD” category includes mumps, rubella, cholera, tick-bornencephalitis, meningococcal sepsis, and rabies. Abbreviations: HAV, hepatitis A virus;BV, hepatitis B virus; VPD, vaccine preventable disease; VZV, varicella zoster virus.

ales were particularly over-represented among those with acuteiral hepatitis compared to females (OR = 2.8 [95% CI 1.9, 4.1]), with5/97 cases of acute hepatitis A, and 41/51 cases of acute hepatitis Bccurring in males. Trip duration was longer amongst GeoSentinelatients diagnosed with a VPD compared to those with an alter-ate diagnosis (median duration 32 days vs. 28 days, p = 0.003),hough within the category of VPD, trip duration was highly vari-ble. Twenty-nine percent of those diagnosed with a VPD soughtre-travel advice versus 49.6% of those with an alternate diagnosisOR = 0.3 [95% CI 0.2, 0.4]). While 63% of missionaries/volunteersnd 36% of tourists with VPDs sought a pre-travel encounter, only3% of business travelers, and 5% of VFRs with VPDs had done so.hile enteric fever was the most represented VPD acquired despite

pre-travel encounter (n = 105), hepatitis A, influenza, and varicellanfections were also reported amongst those who had a pre-travelisit (Table 3). At least 55% of patients diagnosed with a VPD wereanaged as inpatients.VFRs accounted for 18% of those with a VPD versus only 10% of

hose with a non-VPD (OR = 2.0 [95% CI 1.6, 2.4]). Only 67% of thoseho acquired a VPD were born in a developed country compared

o 82% of those without a VPD (OR = 0.4 [95% CI 0.3, 0.5]). Similarly,ewer of those acquiring a VPD resided in a developed-world coun-ry prior to travel compared to the non-VPD cohort (85% vs. 95%;R = 0.3 [95% CI 0.2, 0.4]).

Fig. 2 depicts the proportionate morbidity by region of exposureor the most well-represented VPDs (see Supplementary Figure 2or a map of the regions of exposure for all patients and those withPDs). As a group, patients diagnosed with VPDs were more likely

o have traveled to South Central Asia (OR = 3.9 [95% CI 3.2, 4.6]), andess likely to have traveled to sub-Saharan Africa (OR = 0.3 [95% CI.2, 0.4]) or Latin America (OR = 0.4 [95% CI 0.3, 0.6]) than those withn alternate diagnosis. South Central Asia was the most likely regionf exposure to enteric (typhoid/paratyphoid) fever, accounting for1% of cases (OR = 9.6 [95% CI 7.5, 12.3]). Southeast Asia contributed3% of cases of influenza (OR = 4.1 [95% CI 2.5, 6.7]), and half of allases of measles (OR = 4.9 [95% CI 1.6, 15.2]).

In multivariate analysis, independent variables such as youngerge (p < 0.001), male sex (p < 0.001), lack of pre-travel advicep < 0.001), travel to South Central Asia (p < 0.001), and traveling forhe purpose of visiting friends and relatives (p = 0.05) were associ-ted with a VPD diagnosis among ill returned travelers comparedo those presenting with a non-VPD (Table 2). Birth or residence

Travel to North Asia 9.9 [5.6, 17.3]Travel to Southeast Asia 3.7 [2.3, 5.9]

Varicella virus Younger age (Age <25 years) 2.0 [1.0, 4.0]

Table 4 provides a list of independent demographic predic-tors of individual VPDs. Within the VPD category, independentvariables such as travel to South Central Asia (p < 0.001), trav-eling for VFR (p = 0.016), and being born in India (p < 0.001) orBangladesh (p < 0.001) appeared to account for the ability to pre-dict enteric fever due to S. typhi. For S. paratyphi, only travelto South Central Asia was predictive in the multivariate model(p < 0.001). Variables such as male sex (p = 0.004), birth in Italy(p < 0.001), and longer duration of travel [>30 days] (p = 0.02) wereindependently associated with a diagnosis of hepatitis A. Simi-larly, male sex was predictive of acute hepatitis B (p = 0.025), aswas older age (p < 0.001), and residence in Italy (p < 0.001). Vari-ables including male sex (p = 0.001), travel to Northern or SoutheastAsia (p < 0.001) for the purpose of business (p < 0.001) indepen-dently predicted a diagnosis of influenza. Variables independentlycontributing to a diagnosis of varicella included younger age(p = 0.001).

4. Discussion

Analysis of over 10 years of surveillance data in over 37,000 illreturned travelers has allowed us to identify potential predictorsof VPDs. We have identified younger age, male gender, and VFRtravel, particularly to South Central Asia, as independent risk fac-tors for VPDs. Birth or residence in Italy or Japan also predictedVPDs, which may reflect national immunization policies. This ispotentially important information for clinicians in these countries,especially because both Italy and Japan are among the top 10 con-tributors to international tourism expenditures, ranking 6th and7th, respectively [14].

Nearly 30% of those acquiring VPDs had had a pre-travel med-ical consultation. That cases of hepatitis A, varicella, and measleswere acquired despite pre-travel consultation speaks to a poten-tially lost opportunity for intervention, given the high efficacy ofthese vaccines [1]. However, we acknowledge that administra-tion of traditionally non-travel associated vaccines may be highlyvariable between countries and regions. It can be inferred thatmost individuals with acute hepatitis A, varicella, and measles didnot undergo pre-travel vaccination, though vaccine failure wouldbe another possibility. One limitation of this analysis is the lackof available vaccination history for individuals in the database,which makes it impossible to determine the number of vaccinefailures versus the number of VPDs among those unvaccinated. Pos-

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mproved vaccine uptake in the pre-travel medical setting shoulde encouraged.

Younger male travelers are over-represented in other studiesf travel-acquired illnesses [2,15], possibly due to differential sus-eptibilities to infection, risk-taking behaviors, riskier itineraries,nd lack of appropriate precautions [2]. In this study, males wereo less likely than females to have a pre-travel encounter, how-ver, we do not know whether males were less likely to receiveaccines. Male sex was independently predictive of VPDs includingepatitis A, hepatitis B, and influenza, which represent a spectrumf modes of transmission. Thus, it is difficult to invoke a purelyehavioral explanation for male over-representation within spe-ific VPD diagnoses. Another network-wide analysis of GeoSentinelata has identified that men are proportionately more likely thanomen to have febrile illnesses, vector-borne diseases, and sexu-

lly transmitted diseases after travel [16].VFR travel has been consistently linked to disproportionate

cquisition of travel-related infections such as malaria, hepatitis And B, and enteric (typhoid) fever compared to other types of travel-rs [2,15,17–19]. That VFRs are much less likely than other travelerso seek pre-travel counseling is probably contributory [2,19,20]. Inhis study, 29% of all ill returned travelers with a VPD had soughtre-travel advice, however, only 5% (5/104) of VFRs with VPDs hadad a pre-travel encounter. VFRs may also visit more rural, remotereas and have close contact with local residents, thereby poten-ially increasing their likelihood of exposure to these infections.

Travel for business was independently associated with a diagno-is of influenza. Business travelers were second only to VFRs in theirack of pre-travel advice (only 22.5% had a pre-travel encounter),nd the over-representation of influenza in this group may reflecthe perceived low-risk of business travel. Because business travel-rs tended to have a shorter median duration of travel, illnessesith short incubation periods, such as influenza, may be over-

epresented in this group. Two of the three deaths in this cohortccurred in business travelers, one each due to rabies and S. typhi.he third fatality, due to pneumococcal meningitis, occurred in aFR. Efforts to improve access to pre-travel interventions in bothusiness travelers and VFRs are likely worthwhile.

Enteric (typhoid/paratyphoid) fever was the most commonlyiagnosed VPD with 32% of cases caused by S. enterica Serovararatyphi. We included S. paratyphi under the umbrella of VPD dueo evidence that live oral Ty21a vaccine confers partial protectiongainst S. paratyphi B [13,21,22]. Analysis of pooled data from 2 ran-omized controlled field trials in Chile demonstrated a protectivefficacy of Ty21a against paratyphoid B of 49%, which approaches3–67% efficacy of the same vaccine against S. typhi [13], and cer-ainly rivals the efficacy of influenza vaccine in high-risk individuals1]. The injectable Vi polysaccharide vaccine confers no protectiono S. paratyphi [21–23], thus, in addition to more prolonged protec-ion, Ty21a has a scope of efficacy advantage over Vi polysaccharideaccine, despite its inconvenient schedule of administration (mul-iple doses over many days). We do not know the vaccination statusf the patient in this cohort who died with S. typhi.

Presence of hepatitis B in this cohort is notable for many reasons.cquisition of hepatitis B is a marker of potential exposure to otherlood- and body-fluid-borne infections such as HIV and hepatitis. Our study likely underestimates the presence of these infectionsecause routine screening for blood-borne pathogens was not done.mportation of transmissible VPDs, such as hepatitis B, has impli-ations for family members and other close contacts. The highlyfficacious hepatitis B vaccine [1] would have been expected to pre-

8 (2010) 7389–7395 7393

pendent predictors of hepatitis B acquisition, which may reflectrisk-taking behaviors and lack of protective measures (includingcondoms) while abroad. We cannot exclude the possibility thatsome cases of hepatitis B in this cohort were acquired before travelgiven the long incubation period of hepatitis B. Those with hep-atitis B had a shorter median duration of travel than those withother diagnoses (17.5 days vs. 28–32 days). Some of the 38% ofpatients with hepatitis B who presented within 6 weeks post-travelpotentially could have transmitted the virus during travel.

Measles, varicella, pertussis, influenza, and meningococcal, andHaemophilus influenzae b infections are potentially communicablediseases which require isolation of cases, and, in some instances,prophylaxis of contacts with antimicrobials or vaccines. The publichealth resources required to contain these infections, particularlywhen air travel is involved, can be enormous. In 2004, a single caseof imported measles in the US led to 2525 h of personnel timeexpended on reviewing flight manifests, contact tracing, estab-lishment and staffing of vaccination clinics, and quarantine [10].Importation of highly communicable infectious diseases is a clearrisk to unimmunized and susceptible populations. Since the mid-1990s, more than 80% of cases of measles in the US and Canada wereimported from measles-endemic countries, or were epidemiolog-ically related to an imported case [27,28], emphasizing the needfor adequate immunization of travelers and residents alike. Wecan infer that the containment costs associated with the 136 casesof highly communicable infections in our cohort were substantial,underscoring the significant public health implications of VPDs.

Recorded cases of yellow fever, JE, and polio were absent fromthis analysis. This finding may reflect good uptake of vaccinesagainst these potentially devastating illnesses, low relative-risksfor acquisition among travelers, or low likelihood of itinerarieswhich put travelers at risk for these infections, or a combinationof other unknown factors. It is tempting to conclude that relativerisks for these VPDs among travelers are extremely low, however,without accurate data on actual immunization rates and specificitineraries in this cohort, such a conclusion cannot be made. Stud-ies which investigate vaccine administration and quantifiable riskin travelers prospectively, are indicated.

This analysis has several limitations. First, the small numbers formany VPDs hindered our ability to analyze them individually. Sec-ond, the cohort analyzed represents only those ill returned travelerswho presented to a GeoSentinel clinic, thus, our conclusions maynot extend to all ill returned travelers. Travelers with mild or self-limited illnesses or illnesses with very short or very long incubationperiods may have sought care in different settings. Our study doesnot capture VPDs that developed during travel. Similarly, ill trav-elers returning from destinations perceived to be low-risk may beunder-represented in the database. Third, data on hospitalizationmay be influenced by regional variations in management guide-lines. Fourth, our data do not permit estimation of incidence rates ordestination-specific numerical risks for particular diseases [11,29].Finally, the absence of immunization history limits our ability toquantify the true potential preventability of VPDs in this cohort,given variation in vaccine efficacy. The actual potential preventabil-ity of enteric fever, the most well represented diagnosis in thecohort, cannot be estimated as those with ‘probable’ S. typhi mayhave had S. typhi or S. paratyphi, and those with S. paratyphi mayhave had S. paratyphi A, which is not at all prevented by Ty21avaccine. Nevertheless, it can be presumed that individuals whoacquired illnesses like hepatitis A, for which a highly efficaciousvaccine exists, did not receive pre-travel immunization. It is well

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This is the single largest analysis of VPDs in returned travelerso date, and is derived from a multicenter, heterogeneous popula-ion, reflecting the spectrum of travel demographics, destinations,nd purposes of travel over a 10-year period. The proportionateorbidity estimates by region of travel can inform the pre-travel

onsultation process, and reinforce that cosmopolitan infections,uch as influenza and varicella, can be acquired during travel. Ouresults underscore the importance of vaccination against entericever, especially for travelers to South Central Asia, and for thoseraveling to VFR. In addition, we have demonstrated that businessravelers constitute a risk group for acquisition of influenza, andhis should be considered by employers and physicians alike. That.5% of ill returned travelers with a VPD had a fatal outcome andt least 55% were hospitalized is a reminder that VPD are seriousnd expensive. Our data illustrate the point that many travelersre not properly immunized pre-travel. Pre-travel services, includ-ng not just vaccines but counseling for improved prevention ofnteric and other exposures, should be readily accessible to allravelers.

cknowledgments

In addition to the authors, members of the GeoSentinel Surveil-ance Network who contributed data (in descending order) are:iampiero Carosi, University of Brescia, Brescia, Italy; Grahamrown, Royal Melbourne Hospital, Melbourne, Australia; Hirokoagara, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan;ay S. Keystone and Kevin C. Kain, University of Toronto, Toronto,anada; Louis Loutan and Francois Chappuis, University of Geneva,eneva, Switzerland; Prativa Pandey, CIWEC Clinic Travel Medicineenter, Kathmandu, Nepal; Patricia Schlagenhauf, Rainer Weber,nd Robert Steffen, University of Zürich, Zürich, Switzerland;hyllis E. Kozarsky and Carlos Franco-Paredes, Emory University,tlanta, Georgia, USA; Philippe Parola, Fabrice Simon, and Jean Del-ont, Hôpital Nord, Marseille, France; DeVon C. Hale and Stefanie

. Gelman, University of Utah, Salt Lake City, Utah, USA; Mogensensenius, Ullevål University Hospital, Oslo, Norway; N. Jean Haul-

an, Davie Roesel, and Elaine C. Jong, University of Washington,eattle, Washington, USA; Alejandra Gurtman, Mount Sinai Medi-al Center, New York City, New York, USA (October 2002–August005 only); Lin H. Chen, Mount Auburn Hospital, Harvard Univer-ity, Cambridge, Massachusetts, USA; Effrossyni Gkrania-Klotsas,ddenbrooke’s Hospital, Cambridge, UK; Shuzo Kanagawa, Inter-ational Medical Center of Japan, Tokyo, Japan; Carmelo Licitrand Antonio Crespo, Orlando Regional Health Center, Orlando,lorida, USA; Susan MacDonald, Beijing United Family Hospitalnd Clinics, Beijing, Peoples Republic of China; Gerd-Dieter Bur-hard, Bernhard-Nocht-Institute for Tropical Medicine, Hamburg,ermany; Marc Shaw, Worldwise Travelers Health and Vaccinationentre, Auckland, New Zealand; David O. Freedman, University oflabama at Birmingham, Birmingham, Alabama, USA; Cecilia Perretnd Francisca Valdivieso, Pontificia Universidad Católica de Chile,antiago, Chile; Bradley A. Connor, Cornell University, New York,ew York, USA; Susan McLellan; Tulane University, New Orleans,ouisiana, USA (December 1999–August 2005 only); Michael W.ynch, Fresno International Travel Medical Center, Fresno, Califor-ia, USA; Anne McCarthy, University of Ottawa, Ottawa, Canada;. Bradley Sack and Robin McKenzie, Johns Hopkins University,altimore, Maryland, USA (December 1997–August 2007 only);ernon Ansdell, Kaiser Permanente, Honolulu, Hawaii, USA (Octo-er 1997–January 2003 only); Robert Kass, Travellers Medical and

8 (2010) 7389–7395

USA; and Robert Muller, Travel Clinic Services, Johannesburg, SouthAfrica (May 2004–June 2005 only).

Financial support: GeoSentinel: the Global Surveillance Networkof the International Society of Travel Medicine is supported byCooperative Agreement U50/CCU412347 from the Centers for Dis-ease Control and Prevention.

Contributors: AKB participated in the study conception anddesign, data collection, analysis, and interpretation, and writing ofthe manuscript, and has seen and approved the final version. Theauthor has no conflict of interest to declare. FC participated in thestudy design, data interpretation, and writing of the manuscript,and has seen and approved the final version. The author has thefollowing conflict of interest: was sponsored to attend conferencesand has received speaking honoraria by GlaxoSmithKline (2002).The author received an honorarium to attend the Dukoral Advi-sory Board once (2003). PG participated in the study design, datainterpretation, and writing of the manuscript, and has seen andapproved the final version. The author has the following conflict ofinterest: was sponsored by Sanofi-Pasteur to attend conferences. JTparticipated in the study design, data interpretation, and writing ofthe manuscript, and has seen and approved the final version. Theauthor has the following conflict of interest: received speaking hon-oraria from GlaxoSmithKline and Sanofi-Pasteur, and has receivedconference sponsorship from Sanofi-Pasteur, Schering Plough, andRoche. FvS participated in the study design, data interpretation, andwriting of the manuscript, and has seen and approved the final ver-sion. The author has no conflict of interest. EDB participated in thestudy design, data interpretation, and writing of the manuscript,and has seen and approved the final version. The author has the fol-lowing disclosures: Speaker’s Bureau: Merck and GlaxoSmithKline;Grant Support: SanofiPasteur. CG participated in the study design,data interpretation, and writing of the manuscript, and has seen andapproved the final version. The author has no conflict of interest toreport. PLL participated in the study design, data interpretation,and writing of the manuscript, and has seen and approved the finalversion. The author has the following potential conflict of inter-est: has received sponsorship to attend conferences from Novartis,MSD, and Pfizer within the past 5 years. ES participated in the studydesign, data interpretation, and writing of the manuscript, and hasseen and approved the final version. The author has no conflict ofinterest. AW-S participated in the study design, data interpretation,and writing of the manuscript, and has seen and approved the finalversion. The author has the following conflict of interest: has beensponsored by GlaxoSmithKline and Sanofi-Pasteur to attend con-ferences, and has received speaking honoraria. MEW participatedin the study conception and design, data collection, analysis, andinterpretation, and writing of the manuscript, and has seen andapproved the final version. The author has no conflict of interest todeclare.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.vaccine.2010.09.009.

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