Abstract

Background

Influenza is a common vaccine‐preventable disease among international travelers, but few data exist to guide use of reciprocal hemisphere or out‐of‐season vaccines.

Methods

We analyzed records of ill‐returned travelers in the GeoSentinel Surveillance Network to determine latitudinal travel patterns in those who acquired influenza abroad.

Results

Among 37,542 ill‐returned travelers analyzed, 59 were diagnosed with influenza A and 11 with influenza B. Half of travelers from temperate regions to the tropics departed outside influenza season. Twelve travelers crossed hemispheres from one temperate region to another, five during influenza season. Ten of 12 travelers (83%) with influenza who crossed hemispheres were managed as inpatients. Proportionate morbidity estimates for influenza A acquisition were highest for travel to the East‐Southeast Asian influenza circulation network with 6.13 (95% CI 4.5–8.2) cases per 1000 ill‐returned travelers, a sevenfold increased proportionate morbidity compared to travel outside the network.

Conclusions

Alternate hemisphere and out‐of‐season influenza vaccine availability may benefit a small proportion of travelers. Proportionate morbidity estimates by region of travel can inform pre‐travel consultation and emphasize the ease of acquisition of infections such as influenza during travel.

Influenza is a common vaccine‐preventable disease among international travelers.1–6 Influenza circulates year‐round in tropical regions and seasonally in temperate regions with peak transmission from October to March in the northern hemisphere (NH) and from April to October in the southern hemisphere (SH). Little is known about influenza epidemiology in those who cross hemispheres during the alternate hemisphere's influenza season.6 US travel medicine practitioners have expressed interest in access to SH influenza vaccine in years with mismatch between circulating strains, 4 but few data exist to guide use of reciprocal hemisphere or out‐of‐season vaccines.

We analyzed travelers in the GeoSentinel Surveillance Network 7,8 to determine latitudinal travel patterns in those who acquired influenza abroad. We also sought to elucidate the frequency of cross‐hemispheric influenza acquisition in travelers during years of NH and SH vaccine mismatch.

Methods

The GeoSentinel Surveillance Network comprises 54 travel/tropical medicine clinics on six continents, which contribute anonymous, clinician‐ and questionnaire‐based travel data on ill travelers to a centralized database; 7,8 for additional details see http://www.geosentinel.org. The questionnaire constitutes prospectively established variables of interest, including demographic and travel‐related data, reason for most recent travel, inpatient or outpatient status, pre‐travel history, and limited clinical information. Final diagnoses are assigned by a physician from a standardized list of >500 etiologic or syndromic diagnoses.7,8 Returning travelers who attended a GeoSentinel clinic between April 1997 and December 2007, and whose final diagnosis was probable or confirmed were eligible for analysis.2 Persons traveling for immigration or who sought care during travel were excluded.

“Influenza” represented infections with either influenza A or influenza B virus. To assign a “confirmed” diagnosis in GeoSentinel, best available national reference diagnostics are used according to applicable regional and national standards. In the case of influenza, this would include biological confirmation by one or more of direct fluorescent antigen detection, cell culture with immunofluorescent antigen detection, or nucleic‐acid amplification testing such as polymerase chain reaction (PCR). A probable diagnosis of influenza would be restricted to patients with classical presentation (ie, fever plus one or more respiratory symptoms such as cough, dyspnea, coryza, or sore throat) and exposure history with laboratory exclusion of competing etiologies.7 Returning travelers assigned a final diagnosis of “influenza‐like illness” were excluded to capture only those cases of influenza with a higher degree of diagnostic certainty, as noted above. Countries in northern or southern temperate regions were defined as having latitude ≥23° N or ≥23° S, respectively, and an epidemiologic pattern of seasonal influenza circulation. “Tropical” countries were defined as those at latitude <23° N or <23° S with potential year‐round circulation of influenza. Countries spanning temperate and tropical regions (eg, China), were classified based on most likely region of exposure according to most populous cities and highly frequented airports. Cross‐hemispheric travelers were those who embarked from one hemisphere with seasonal influenza circulation to another, regardless of layovers.

Differences in continuous and categorical variables were compared using two‐tailed t‐testing and Yates corrected chi‐square analysis, respectively. Proportionate morbidity was estimated based on number of patients with a latitudinal or regional pattern of influenza acquisition divided by total number of ill travelers to that region and is reported as proportion per 1000 ill travelers. Analysis was performed using SigmaStat 2.03 software (SPSS Inc., Chicago, IL, USA), and significance was set at p≤ 0.05.

Results

Among 37,542 ill‐returned travelers who fulfilled inclusion criteria, 70 had confirmed (n = 67) or probable (n = 3) influenza. Among these 70 cases, 84% (59) had a diagnosis of influenza A and 16% (11) influenza B.2 Median time to presentation for care following return from travel was 3 days (lower quartile 2; upper quartile 8). Latitudinal patterns of travel are summarized in Table 1 and Figure 1. Of travelers with influenza, 44 (63%) traveled from the NH or SH to tropical latitudes (Figure 1).

Table 1

Latitudinal patterns of travel among 70 ill‐returned travelers with influenza

Latitudinal pattern Number Percentage 
Travel from temperate NH to tropics 23 33 
Travel from temperate SH to tropics 21 30 
 NH and SH departures to tropics outside of influenza season when vaccine would be unavailable 21 30 
Cross‐hemispheric travel* 12 17 
 Travel from temperate NH to temperate SH 5.7 
 Travel from temperate SH to temperate NH 11 
Cross‐hemispheric travel* into reciprocal hemisphere during its influenza season 7.1 
 Travel from temperate NH to temperate SH during SH influenza season 1.4 
 Travel from temperate SH to temperate NH during NH influenza season 5.7 
Exclusive travel within NH or SH of residence, or tropics 12 17 
Travel from tropics to NH 10 
Travel from tropics to SH 1.4 
 Travel from tropics to NH or SH during influenza season 5.7 
Travel to countries of the ESEACN 51 73 
Resident of countries of the ESEACN 13 19 
Latitudinal pattern Number Percentage 
Travel from temperate NH to tropics 23 33 
Travel from temperate SH to tropics 21 30 
 NH and SH departures to tropics outside of influenza season when vaccine would be unavailable 21 30 
Cross‐hemispheric travel* 12 17 
 Travel from temperate NH to temperate SH 5.7 
 Travel from temperate SH to temperate NH 11 
Cross‐hemispheric travel* into reciprocal hemisphere during its influenza season 7.1 
 Travel from temperate NH to temperate SH during SH influenza season 1.4 
 Travel from temperate SH to temperate NH during NH influenza season 5.7 
Exclusive travel within NH or SH of residence, or tropics 12 17 
Travel from tropics to NH 10 
Travel from tropics to SH 1.4 
 Travel from tropics to NH or SH during influenza season 5.7 
Travel to countries of the ESEACN 51 73 
Resident of countries of the ESEACN 13 19 

ESEACN, East‐Southeast Asian influenza A circulation network; NH, northern hemisphere; SH, southern hemisphere.

*

Cross‐hemispheric travel refers to travel from one temperate region in one hemisphere to another temperate region in the other hemisphere.

Figure 1

Latitudinal representation of travel among 70 returned travelers with influenza. Sum of types of travel exceeds the total number of travelers with influenza due to multicountry and multiregion itineraries.

Figure 1

Latitudinal representation of travel among 70 returned travelers with influenza. Sum of types of travel exceeds the total number of travelers with influenza due to multicountry and multiregion itineraries.

Five individuals (7%) traveled from the NH or SH to the reciprocal hemisphere during the destinations' influenza season (Table 1). Of 12 travelers with influenza who crossed hemispheres into temperate regions, four (33%) also visited countries such as Sri Lanka (n = 1), Thailand (n = 1), Malaysia and Singapore (n = 1), and Hong Kong (n = 1), with theoretical year‐round circulation, during the same travel period. Of the six individuals traveling exclusively within the NH, 67% traveled during influenza season.

There were no significant differences in age, sex, purpose of travel, rates of pre‐travel encounters, or type of influenza (A vs B) between travelers with cross‐hemispheric compared with intra‐hemispheric or tropical influenza acquisition. Cross‐hemispheric travelers appeared to have more multicountry itineraries than those with either intra‐hemispheric or tropical travel, although this was not statistically significant (p = 0.095). Significantly more travelers with influenza who crossed hemispheres were inpatients compared to those within intra‐hemispheric acquisition (83% vs 48%, p = 0.026). Median age of cross‐hemispheric travelers with influenza managed as inpatients was 42.5 years (range 15–59 y). Median age of all travelers with influenza managed as inpatients (n = 38) was 35 years (range 15–63 y).

Forty‐two travelers (42/59; 71%) with influenza A traveled to countries of the East‐Southeast Asian influenza A circulation network (ESEACN) 9,10 (Table 2), seven of whom (12%) also resided within the ESEACN. Proportionate morbidity for influenza A and travel to the ESEACN was 6.13 (95% CI 4.5–8.2) per 1000 ill travelers, compared with 0.875 (95% CI 0.6–1.4) per 1000 ill travelers for travel outside the network. Most influenza B cases (82%) occurred in travelers to the ESEACN; proportionate morbidity was 1.31 (95% CI 0.7–2.5) per 1000 ill travelers. Travel outside the network conferred a slightly lower proportionate morbidity estimate for influenza B of 0.36 (95% CI 0.1–1.4) per 1000 travelers. Nine travelers (9/70; 13%) with influenza visited more than one geographic region during their trip, and all nine visited at least one ESEACN country.

Table 2

Countries of the East‐Southeast Asian influenza A circulation network and the number of travelers with influenza to that region

Country/region Number of travelers with influenza (n = 70) who visited country/region (%)* Number of travelers with influenza A (n = 59) who visited country (%)* , Number of travelers with influenza B (n = 11) who visited country (%)* , 
China 15 (21.4) 11 (18.6) 4 (36.4) 
Thailand 11 (15.7) 10 (16.9) 1 (9.1) 
Indonesia 10 (14.3) 8 (13.6) 2 (18.2) 
Vietnam 7 (10) 7 (11.9) 
Hong Kong 7 (10) 6 (10.2) 1 (9.1) 
Singapore 5 (7.1) 5 (8.5) 
Malaysia 5 (7.1) 3 (5.1) 2 (18.2) 
Cambodia 3 (4.3) 3 (5.1) 
Laos 1 (1.4) 1 (1.7) 
Taiwan 1 (1.4) 1 (1.7) 
Country/region Number of travelers with influenza (n = 70) who visited country/region (%)* Number of travelers with influenza A (n = 59) who visited country (%)* , Number of travelers with influenza B (n = 11) who visited country (%)* , 
China 15 (21.4) 11 (18.6) 4 (36.4) 
Thailand 11 (15.7) 10 (16.9) 1 (9.1) 
Indonesia 10 (14.3) 8 (13.6) 2 (18.2) 
Vietnam 7 (10) 7 (11.9) 
Hong Kong 7 (10) 6 (10.2) 1 (9.1) 
Singapore 5 (7.1) 5 (8.5) 
Malaysia 5 (7.1) 3 (5.1) 2 (18.2) 
Cambodia 3 (4.3) 3 (5.1) 
Laos 1 (1.4) 1 (1.7) 
Taiwan 1 (1.4) 1 (1.7) 
*

Number of countries visited exceeds numbers of travelers due to multicountry itineraries.

Forty‐two visited the countries of the ESEACN.

Nine visited the countries of the ESEACN.

Nine travelers (9/33; 27%) with influenza having cross‐hemispheric (n = 12) or out‐of‐season departures (n = 21) to tropical regions received a pre‐travel encounter where influenza vaccine could have been administered had it been available. There was vaccine mismatch of the respective A or B strains between the hemispheres for three (3/12; 25%) of those with cross‐hemispheric influenza acquisition.

Conclusions

Analysis of 10 years of surveillance data in >37,000 ill‐returned travelers has enabled identification of travel patterns among those who acquired influenza. While cross‐hemispheric travel into reciprocal hemispheres during influenza season occurred in only five travelers, cross‐hemispheric travel of any kind was more likely to be associated with hospital‐based care than intra‐hemispheric or tropical travel and acquisition of influenza. Travelers with influenza were not at extremes of age where risk of complicated influenza infection is higher.

That 71% of travelers with influenza A traveled to the ESEACN (Figure 1) parallels known contributions of this network to the global burden of influenza A in any given season.9,10 The ESEACN is particularly relevant to travel and influenza due to the 6.6% annual growth in tourist arrivals to Asia and the Pacific since 1990, with arrivals to East Asia expected to reach 397 million by 2020.11 Travel to the ESEACN conferred an approximate 7‐fold and 3.6‐fold higher proportionate morbidity estimate for influenza A and B, respectively, than travel outside the network.

Thirty‐seven percent of travelers with influenza in this analysis engaged in multicountry itineraries during their most recent travel, which would have likely increased the contact time in airports and on airplanes. A small but measurable risk of influenza acquisition aboard commercial aircraft has been well documented, 12 with long haul flights conferring the highest risk of infection.13 Thus, transit‐related conditions may affect risk of influenza.

This analysis has several limitations. First, heterogeneity in laboratory diagnostics performed at each GeoSentinel site, including variable performance characteristics such as sensitivity and specificity, may have influenced the number of cases represented in the database. An acknowledged limitation is the lack of information regarding specific diagnostic tests used at individual GeoSentinel sites. That biological confirmation of infection may have occurred by one or more of antigen detection, cell culture, or PCR would necessarily influence the number of cases identified due to varying test performance. Second, the cohort represents only those ill‐returned travelers who presented to GeoSentinel clinics, thus, our conclusions may not extend to all ill‐returned travelers. Travelers with mild or short‐lived cases of influenza may have sought care in different settings or during travel, or not have sought medical attention at all. Seroepidemiologic studies of influenza among well‐returned travelers indicate seroconversion in 2.8%, 6 and among febrile returning travelers, the incidence of influenza is estimated to be between 5 and 15%.13 Thus, our findings likely represent a significant underestimate of cases of influenza among ill‐returned travelers. High hospitalization rates potentially indicate that only more severe infections were evaluated at a GeoSentinel site, thereby further underestimating the burden of influenza in travelers. Third, during influenza season in temperate countries, confirmatory diagnostic tests are not often sent once influenza is circulating within a community, and this study included only confirmed or probable diagnoses. Fourth, absence of immunization history limits our ability to quantify true potential influenza preventability in this cohort. Fifth, given the short incubation period of influenza, we cannot exclude the possibility that some travelers, especially those returning home during their influenza season, or residing in the tropics or ESEACN, became infected en route home or after travel. Influenza acquired abroad versus from the country of residence would be impossible to distinguish clinically. Finally, our data do not permit estimation of incidence rates or destination‐specific numerical risks for influenza.7,14

This is the single largest analysis of latitudinal patterns of influenza in travelers, to date, and is derived from a multicenter, heterogeneous population, reflecting the spectrum of travel demographics and destinations over a 10‐year period. Alternate hemisphere and out‐of‐season influenza vaccine availability may benefit a small proportion of travelers. As noted previously, while knowledge of influenza prevention among travelers appears to be good, translation of this knowledge into uptake of prevention measures such as vaccination, antiviral prophylaxis, and hand hygiene among travelers remains low.15,16 Proportionate morbidity estimates by region of travel can inform pre‐travel consultation and emphasize the ease of acquisition of infections such as influenza during travel. These data can inform broad‐level decision‐making in travel medicine, public health, and health care policy.

Acknowledgments

GeoSentinel: the Global Surveillance Network of the International Society of Travel Medicine is supported by Cooperative Agreement U50/CCU412347 from the Centers for Disease Control and Prevention.

Declaration of Interests

The funding source (the Centers for Disease Control and Prevention) had no role in study design, data analysis and interpretation, or in writing the manuscript.

A. K. B., F. v. S., P. L. L., E. S., and M. E. W. state that they have no conflicts of interest to declare. F. C. has received an honorarium to attend the Tamiflu Advisory Board once in 2006. P. G. was sponsored by Sanofi‐Pasteur to attend conferences. J. T. received speaking honoraria from GlaxoSmithKline and Sanofi‐Pasteur, and has received conference sponsorship from Sanofi‐Pasteur, Schering Plough, and Roche.

E. D. B. is on the Speaker's Bureau: Merck and GlaxoSmithKline, received honoraria from Novartis and Grant Support by Sanofi‐Pasteur and Intercell. C. G. has received an investigator initiated research grant from GlaxoSmithKline unrelated to influenza. A. W.‐S. has been sponsored by GlaxoSmithKline, Sanofi‐Pasteur, and Novartis to attend conferences and has received speaking honoraria. She is the Principal Investigator of a vaccine trial sponsored by Sanofi‐Pasteur.

References

1
Wilson
ME
Weld
LH
Boggild
A
, et al.
Fever in returned travelers: results from the GeoSentinel Surveillance Network.
Clin Infect Dis
 
2007
;
44
:
1560
1568.
2
Boggild
AK
Castelli
F
Gautret
P
, et al.
Vaccine preventable diseases in returned international travelers: results from the GeoSentinel Surveillance Network.
Vaccine
 
2010
;
28
:
7389
7395.
3
Marti
F
Steffen
R
Mutsch
M.
Influenza vaccine: a traveler's vaccine?
Exp Rev Vaccines
 
2008
;
7
:
679
687.
4
Strikas
RA
Kozarsky
PE
Reed
C
, et al.
Should health‐care providers in the United States have access to influenza vaccines formulated for the southern hemisphere?
J Travel Med
 
2008
;
15
:
442
446.
5
Use of northern hemisphere influenza vaccines by travelers to the southern hemisphere.
MMWR Morbid Mortal Wkly Rep
 
2009
;
58
:
312.
Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5812a4.htm.(Accessed 2010 Oct 6)
6
Mutsch
M
Tavernini
M
Marx
A
, et al.
Influenza virus infection in travelers to tropical and subtropical countries.
Clin Infect Dis
 
2005
;
40
:
1282
1287.
7
Freedman
DO
Weld
LH
Kozarsky
PE
, et al.
Spectrum of disease and relation to place of exposure among ill returned travelers.
N Eng J Med
 
2006
;
354
:
119
130.
8
Freedman
DO
Kozarsky
PE
Weld
LH
Cetron
MS.
GeoSentinel: the global emerging infections sentinel network of the International Society of Travel Medicine.
J Travel Med
 
1999
;
6
:
94
98.
9
Russell
CA
Jones
TC
Barr
IG
, et al.
Influenza vaccine strain selection and recent studies on the global migration of seasonal influenza viruses.
Vaccine
 
2008
;
26S
:
D31
D34.
10
Russell
CA
Jones
TC
Barr
IG
, et al.
The global circulation of seasonal influenza A (H3N2) viruses.
Science
 
2008
;
320
:
340
346.
11
World Tourism Organization (UNWTO).
Tourism highlights.
2009
:. Available at: http://www.unwto.org/facts/eng/highlights.htm. (Accessed 2010 Oct 6)
12
Mangili
A
Gendreau
MA.
Transmission of infectious diseases during commercial air travel.
Lancet
 
2005
;
365
:
989
996.
13
Askling
HH
Rombo
L.
Influenza in travellers.
Curr Opin Infect Dis
 
2010
;
23
:
421
425.
14
Leder
K
Wilson
ME
Freedman
DO
Torresi
J.
A comparative analysis of methodological approaches used for estimating risk in travel medicine.
J Travel Med
 
2008
;
15
:
263
272.
15
Yanni
EA
Marano
N
Han
P
et al.
Knowledge, attitudes, and practices of US travelers to Asia regarding seasonal influenza and H5N1 avian influenza prevention measures.
J Travel Med
 
2010
;
17
:
374
381.
16
Helfenberger
S
Tschopp
A
Robyn
L
, et al.
Knowledge, attitudes, and practices of business travelers regarding influenza and the use of antiviral medication.
J Travel Med
 
2010
;
17
:
367
373.

Appendix

Appendix: Members of the GeoSentinel Surveillance Network

In addition to the authors, members of the GeoSentinel Surveillance Network who contributed data (in descending order) are: Karin Leder, Royal Melbourne Hospital, Melbourne, Australia; Hiroko Sagara, Yokohama Municipal Citizen's Hospital, Yokohama, Japan; Shuzo Kanagawa, International Medical Center of Japan, Tokyo, Japan; Philippe Parola, Fabrice Simon, and Jean Delmont, Hôpital Nord, Marseille, France; Phyllis E. Kozarsky and Carlos Franco‐Paredes, Emory University, Atlanta, GA, USA; Susan MacDonald, Beijing United Family Hospital and Clinics, Beijing, Peoples Republic of China; Cecilia Perret and Francisca Valdivieso, Pontificia Universidad Católica de Chile, Santiago, Chile; Prativa Pandey, CIWEC Clinic Travel Medicine Center, Kathmandu, Nepal; Robert Kass, Travellers Medical and Vaccination Centres of Australia, Adelaide, Australia (December 1997–March 2001 only); Louis Loutan and François Chappuis, University of Geneva, Geneva, Switzerland; Alejandra Gurtman, Mount Sinai Medical Center, New York City, NY, USA (October 2002–August 2005 only); Mogens Jensenius, Ullevål University Hospital, Oslo, Norway; DeVon C. Hale and Stefanie S. Gelman, University of Utah, Salt Lake City, UT, USA; and Susan McLellan; Tulane University, New Orleans, LA, USA (December 1999–August 2005 only).

See the Editorial by Robert Steffen, pp. 1–3 of this issue.