186
ORIGINAL ARTICLE
Estimating Air Travel–Associated Importations of Dengue Virus Into
Italy
Mikkel B. Quam, MScIH,∗† Kamran Khan, MD, MPH,‡§ Jennifer Sears, MPH,§ Wei Hu, MS,§
Joacim Rocklöv, PhD,∗|| and Annelies Wilder-Smith, MD, PhD∗†¶
∗ Department
of Public Health and Clinical Medicine, Epidemiology and Global Health Unit, Umeå University, Umeå,
Västerbotten, Sweden; † Institute of Public Health, University of Heidelberg, Heidelberg, Germany; ‡ Division of Infectious
Diseases, University of Toronto, Toronto, ON, Canada; § St. Michael’s Hospital, Keenan Research Centre, Li Ka Shing
Knowledge Institute, Toronto, ON, Canada; || Umeå Centre for Global Health Research, Umeå, Sweden; ¶ Lee Kong Chian
School of Medicine, Nanyang Technological University, Singapore, Singapore
DOI: 10.1111/jtm.12192
Background. Southern Europe is increasingly at risk for dengue emergence, given the seasonal presence of relevant mosquito
vectors and suitable climatic conditions. For example, Aedes mosquitoes, the main vector for both dengue and chikungunya, are
abundant in Italy, and Italy experienced the first ever outbreak of chikungunya in Europe in 2007. We set out to estimate the extent
of dengue virus importations into Italy via air travelers.
Methods. We attempted to quantify the number of dengue virus importations based on modeling of published estimates on dengue
incidence in the countries of disembarkation and analysis of data on comprehensive air travel from these countries into Italy’s largest
international airport in Rome.
Results. From 2005 to 2012, more than 7.3 million air passengers departing from 100 dengue-endemic countries arrived in Rome.
Our Importation Model, which included air traveler volume, estimated the incidence of dengue infections in the countries of
disembarkation, and the probability of infection coinciding with travel accounted for an average of 2,320 (1,621–3,255) imported
dengue virus infections per year, of which 572 (381–858) were “apparent” dengue infections and 1,747 (1,240–2,397) “inapparent.”
Conclusions. Between 2005 and 2012, we found an increasing trend of dengue virus infections imported into Rome via air
travel, which may pose a potential threat for future emergence of dengue in Italy, given that the reoccurring pattern of peak
importations corresponds seasonally with periods of relevant mosquito vector activity. The observed increasing annual trends of
dengue importation and the consistent peaks in late summer underpin the urgency in determining the threshold levels for the
vector and infected human populations that could facilitate novel autochthonous transmission of dengue in Europe.
D
engue is a significant international health
concern.1 According to the World Health
Organization,2 dengue is the most important
mosquito-borne viral disease with a 30-fold greater
incidence compared to the incidence reported
50 years ago.3 While most of the disease burden
associated with dengue is present in areas with a
tropical and subtropical climate, increasing evidence suggests that temperate areas are also at
Corresponding Author: Mikkel B. Quam, MScIH,
Department of Public Health and Clinical Medicine, Epidemiology and Global Health, Umeå University, SE-901
87 Umeå, Sweden. E-mail: [email protected],
[email protected]
© 2015 International Society of Travel Medicine, 1195-1982
Journal of Travel Medicine 2015; Volume 22 (Issue 3): 186–193
risk.4 – 7 Many factors including viral evolution, climate change, settlement dynamics, socioeconomic
conditions, globalization, commercial trade, and human
travel may be contributing to the currently observed
geographical expansion of dengue mosquito vectors’
range and the increasing case incidence of dengue
infections.8
Air travel can be an important conduit for the
introduction of vector-borne disease leading to emergence in naive areas suitable for dengue transmission, including parts of Europe.9 – 14 As travel and
international trade continue to increase into Europe,
increasing interconnectivity between dengue-endemic
and naive areas raises the potential risk for introduction of such diseases.15 The role of travel in the expansion of dengue is underscored considering that dengue
187
Estimated Dengue Imported Into Italy by Flight
infections account for the second most common cause of
fever among those returning from international travel in
the tropics.16
The recent introduction of relevant mosquito vectors
into Southern Europe and the increasing numbers of
imported dengue cases via travelers suggest that Europe
may be increasingly at risk for dengue emergence in the
foreseeable future.17 Reports of locally acquired dengue
occurred in 2010 in France and Croatia, following
importation and expansion of the dengue vector Aedes
albopictus along the Mediterranean and importation of
the dengue virus via travelers.18 – 20 Further illustration
of dengue risk to Europe is the 2005 introduction of the
dengue vector, Aedes aegypti, into the Portuguese island
of Madeira, that led to a dengue outbreak of >2000
cases in 2012.21 While only a few autochthonous cases
occurred in France and Croatia in 2010, the large 2012
epidemic in Madeira exported numerous cases to other
European destinations.22 – 24
Information on air travel, air passenger flow, and
commercial trade routes linking areas of endemic disease activity to non-endemic areas has been employed to
predict the risks of vector-borne disease importation in
several studies.6,9,12,13,25 – 28 DengueTools recently developed a simple novel importation index based on air
travel volume and reported dengue cases to explore
the origin of the dengue outbreak in Madeira, thereby
showing that modeling based on global travel patterns
can be an effective additional tool to identify the importation pathways of dengue.10,29 Mathematical modeling
using flight data can therefore be helpful in quantifying
the possibility of dengue emergence in new areas.6,9,25
BioDiaspora is an initiative to evaluate the probable
pathways of international dissemination of infectious
diseases via the global airline transportation network
(www.biodiaspora.com).
Italy harbors sizable populations of dengue’s
secondary mosquito vector, A. albopictus.30 Global
modeling of the relative Vectorial capacity (rVc) of
dengue based on climate reveals that Italy’s thermal
conditions could support dengue transmission during at
least three consecutive months per year and that this is
likely to increase in the future.7,31 Hence, Italy is considered theoretically suitable for dengue transmission.19,32
In 2007, Italy reported the first European outbreak
of chikungunya, sustained by A. albopictus, after it was
introduced via a viremic traveler to Northern Italy.33
In recent years, several studies have shown an observed
increase of dengue and chikungunya importations into
Europe and particularly into Italy.17,34 – 36 Specifically,
urban areas of Italy, such as Rome, have a high suitability for dengue transmission due to both greater
human population densities and environmental conditions comparable with places where dengue occurs
globally.31 Rome’s Fiumicino-Leonardo da Vinci International Airport (FCO) is one of Europe’s busiest hubs,
located in an urban area climatically suitable for dengue
transmission.12
We attempted to quantify the number of dengue
virus importations based on modeling of published
estimates on dengue incidence in the countries of
disembarkation and air travel data from these countries
into Rome’s largest international airport.
Methods
Importation Model
We developed a model to estimate the number of
importations of dengue virus via viremic air passengers
from dengue-endemic countries to Rome, Italy. Our
Importation Model (RI ) is represented by the following
formula:
RI = T × I × P
where RI estimated infected travelers importing dengue
within a time period to the destination airport, based
on the number of air travelers (T) arriving from a given
dengue-endemic country with the per-person incidence
(I) of dengue infection and temporal probability (p)
of dengue infection coinciding with travel as detailed
below. RI values estimating infected travelers importing dengue were calculated and analyzed for each time
period (quarter 2005–2012), for each of the countries meeting the inclusion criteria for dengue-endemic
departure countries.
Departures’ Level of Dengue Activity
A total of 100 countries with “complete, and good
consensus” on dengue activity were included as
dengue-endemic departure countries.37 The finest
spatial resolution available at the global scale for the estimations of dengue infections was at the country administrative level.38,39 Supplementary publications from the
studies by Bhatt and colleagues estimated country-level
incidence of both “apparent” (including symptomatic
and severe dengue infections) and “inapparent” (including asymptomatic infections) dengue infections using
a three-stage cartographical modeling approach.38
We applied these country-level annual estimates to our
model to generate estimates of imported “apparent” and
“inapparent” infections. Given that only 2010 global
infection estimations were available, we used dengue
case reporting data, collected by WHO regional offices,
to scale the 2010 annual estimates over the study period
2005–2012 for each of the included countries, thereby
better reflecting documented year-to-year variation of
dengue activity.40 – 43 Due to the lack of more comprehensive data on seasonal variation within all countries,
we analyzed only the annual dengue infection incidence
(I) rather than monthly incidence.38,39
Volume of Air Travelers
International Air Travel Association (IATA) datasets
were analyzed through close collaboration with BioDiaspora. BioDiaspora’s analysis included comprehensive air travel information collected from ∼4,000 IATA
J Travel Med 2015; 22: 186–193
188
airports globally from 2005 to 2012. Millions of air
travelers’ full flight itineraries, containing Rome as a
final destination city were sorted according to where the
passenger began their flight journey, then compiled by
country of departure, and finally aggregated quarterly.
Temporal Probability of Infection
The incubation time for dengue in humans ranges from
3 to 10 days, with a median of 5 to 6 days.44,45 The
mean of 10 days (total period after an infecting bite until
the end of viremia) divided by 365 days (total annual
reporting period in days) represents the probability (p)
of infection temporally coinciding with travel.
Results
Our data showed that between 2005 and 2012, the FCO
saw arrivals from 7,368,891 air travelers coming from
100 countries having dengue activity. According to the
IATA data analysis, travel into FCO from countries
with dengue activity increased rapidly from 747,913 air
travelers in 2005 to 1,149,981 air travelers in 2012,
averaging 921,111 arrivals annually.
Table 1 shows the regional breakdown and top 10
dengue-endemic departure countries ranked according
to their likelihood of exporting dengue and their total
volume of air travelers arriving into FCO during 2011
and 2012. There are notable increases in importations
originating in the Americas and Asia. Due to the 2011
outbreak, the Bahamas reported dengue cases over three
orders of magnitude higher than average in 2011, thus
entering the top 10 countries list for the first and only
time during the study period 2005–2012.
Applying the Importation Model (RI ) to generate
the global cumulative expected infections departing
from all countries yielded a total estimated average
global exposure to importation of 2,320 (1,621–3,255)
infections per year, of which 572 (381–858) were
“apparent” dengue infections and 1,747 (1,240–2,397)
“inapparent” dengue infections. The total aggregated
mean number of importations increased from 1,634
(1,096–2,014) in 2005 to 3,256 (2,318–4,553) in 2012.
Our data analysis showed an overall upsurge in
flight-related dengue infection importations (RI ) of
100% between 2005 and 2012. Quarter 3, corresponding to July, August, and September, consistently
throughout all 8 years, posted the highest globally
aggregated RI estimates, while the lowest were in the
fourth quarter for most countries during most years.
Least squares linear regression analysis techniques
were employed to project quarterly total (“apparent”
and “inapparent”) infection importation (RI ) data into
the future, assuming that (RI ) continues along past
trends into the future, as displayed in Figure 1. During
2020, our model projects 1,413 (1,028–2,027) imported
dengue infections into FCO in the first quarter, 1,391
(1,008–1,978) in the second, 1,512 (1,088–2,173) in the
third, and 1,138 (839–1,646) in the fourth. Therefore,
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Quam et al.
we predict 5,465 (3,963–7,824) imported dengue infections in Rome for the year 2020, which is more than
three times the modeled estimates for 2005.
We identified the top 10 countries that contributed
about more than half of the total number of importations over the study period (Figure 2). During the
8-year study period, Brazil contributed more estimated
importations to Rome than any of the other countries due to high annual reported dengue incidence
and increasingly more air travelers. Brazil’s calculated
contribution of imported infections, accordingly, carried an average 15.3% of Rome’s total global exposure to imported dengue infections. Figure 2 illustrates
the temporal dynamics from 2005 to 2012 presented
by potentially infected air travelers flying into Rome’s
FCO airport from countries with known dengue activity. The intra-annual travel patterns differ among the 10
countries; however, they generally peak during the third
quarter of each year.
For the year 2012, we scaled air travel to Rome (T)
and dengue incidence (I) as percentiles of all countries to show the coalescing contribution of both factors in model-estimated dengue importations to Rome
(RI ). While North America and European countries
have substantially higher air travel to Rome than most
other counties (Figure 3A), the lack of dengue incidence (Figure 3B) negates the potential for importing
infection (Figure 3C). Brazil, Thailand, India, and the
Philippines, on the other hand, having much higher
dengue incidence (Figure 3B) and sufficient air travel to
Rome (Figure 3A) are the potential sources of imported
dengue infections.
Discussion
To estimate the potential for introduction of dengue
into Rome, air travel was regarded as a conduit for
vector-borne disease importation consistent with previous investigations.6,9,12 – 14,25,34 Our model included
air passenger volume, extent of dengue endemicity in the departure country, and the probability
that a traveler is infected around the time of travel.
Our findings showed that about 7.3 million travelers from 100 dengue-endemic countries arrived at
Rome’s international airport (FCO) between 2005
and 2012. Our findings estimate an average of
2,355 (1,610–3,429) imported dengue virus infections per year, 581 (377–890) “apparent” and 1,775
(1,233–2,539) “inapparent.”
Our analysis showed clear quarterly variation in the
interconnectivity between Rome and dengue-endemic
areas with a peak of imported infections during the
third quarter of each year (July to September), consistent with reported importations to Italy and vector
activity that also peaked in August and September.34,46
Furthermore, our data substantiate an increasing trend
of importations over time. Future predictions based
on regression analysis indicate an estimated fourfold
increase of dengue importations by the year 2020
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Estimated Dengue Imported Into Italy by Flight
Table 1 2011–2012 annual incoming air travelers to Rome’s Fiumicino-Leonardo da Vinci International Airport (FCO) from
dengue-endemic areas with corresponding Risk of Introduction (RI ), aggregated globally according to region and top 10
departure countries
2011
Area of departure
Global total of 87 endemic
countries
Total Asia
2012
FCO air travelers
1,095,126
453,883
Total Americas
469,726
Total Africa
168,785
Total Oceania
2732
Brazil
143,728
India
79,201
Thailand
65,098
Philippines
35,968
Pakistan
9,042
Mexico
59,084
Bangladesh
21,750
Sri Lanka
18,852
Peru
22,920
Bahamas
2,850
Total of top 10 countries
458,493
RI *
Apparent (CI)
Inapparent (CI)
Area of departure
656 (439–976) Global total of 100 endemic
2,005 (1,430–2,795) countries
282 (185–437) Total Asia
862 (602–1,244)
275 (191–390) Total Americas
838 (619–1,123)
97 (62–143)
Total Africa
296 (203–413)
2.9 (1.5–5.5)
Total Oceania
8.6 (5.0–15.2)
141 (104–191) India
430 (332–554)
54 (39–73)
Brazil
164 (126–212)
48 (35–66)
Thailand
147 (112–192)
39 (25–61)
Mexico
118 (82–171)
33 (24–46)
Philippines
102 (77–133)
23 (17–32)
Dominican Republic
71 (53–93)
23 (17–31)
Sri Lanka
70 (53–91)
21 (14–32)
Venezuela
64 (46–92)
21 (14–30)
Peru
65 (46–87)
20 (11–33)
Bangladesh
61 (39–92)
423 (299–595) Total of top 10 countries
1,292 (966–1,717)
FCO air travelers
1,149,981
499,618
491,278
156,520
2,565
67,637
151,435
70,394
65,035
37,053
31,454
21,706
32,679
21,642
32,102
531,137
RI *
Apparent (CI)
Inapparent (CI)
803 (546–1,177)
2,453 (1,772–3,376)
375 (253–561)
1,144 (820–1,604)
338 (235–480)
1,032 (762–1,383)
88 (56–130)
269 (185–375)
2.6 (1.4–5.0)
7.8 (4.5–13.6)
130 (95–176)
397 (305–513)
110 (81–149)
336 (259–432)
63 (46–87)
193 (147–252)
62 (44–85)
190 (143–249)
61 (40–96)
186 (129–271)
41 (26–64)
125 (86–180)
40 (26–61)
121 (86–173)
22 (16–30)
67 (51–87)
20 (13–29)
61 (44–83)
17 (12–23)
51 (39–67)
566 (399–799)
1,727 (1,288–2,305)
FCO = Fiumicino-Leonardo da Vinci International Airport; CI = credible interval.
*Estimated apparent and inapparent dengue infections imported (0.25–0.975 credible interval).
compared with 2005. We identified 10 countries
having the highest modeled historic and expected
exportations of dengue to FCO: Brazil, Thailand, India,
Philippines, Mexico, Venezuela, Dominican Republic,
Singapore, Malaysia, and Sri Lanka.
Previous studies vary widely in approaching the
application of the global network of air travel. Most
models combined travel information with some measure
of disease occurrence, usually based on reported cases
to national and international authorities or another
modeled metric of risk based on surveillance data.
Here, we sought to synthesize most recent global
estimates to improve on the shortcomings in previous
models.6,9,13,25 Our Importation Model (RI ) is a modification of a model published by Seyler and colleagues
in 2009.6,9,34 In our study, we also included “inapparent infections” as defined by Bhatt and colleagues
in 2013, as “inapparent” infections are likely to
contribute to dengue virus transmission, although
the extent of contribution remains unknown.38,47
Furthermore, through collaboration with BioDiaspora, our analysis was able to use IATA passenger
full-route itineraries data. The longer study period over
8 years allowed us to look at both the intra-annual
and multiyear trends of flight travel and create
meaningful future projections.
The estimated numbers of dengue infections
modeled are far higher than the number of dengue
infections reported among travelers in Italy. An annual
average of less than 30 dengue notifications in Italy
was reported to the European Centre for Disease
Control (ECDC) over the period of 2008–2011.48
Over the same period, our findings averaged annually
641 (431–948) “apparent” and 2,030 (1,401–2,716)
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Quam et al.
Figure 1 Trends in global arrivals and estimated importations of dengue infections into Rome’s Fiumicino-Leonardo da Vinci
International Airport (FCO) from dengue-endemic departure countries. Total volume of air travelers into FCO from countries
with known dengue activity, plotted quarterly with circles corresponding to the left axis. The corresponding total dengue virus
importation (RI ) based on the estimated number of infections (asymptomatic and symptomatic) imported to Rome is plotted in
black quarterly using the right axis. The lower bounds of the credible interval (0.025 to mean value) and the upper bounds (mean
value t 0.975) are shown as gray lines. Linear regression analyses indicate continuing upward trends in future importation of dengue
infections into FCO (shaded area continued) from the present to the end of 2020, reaching an estimated 5,465 (3,963–7,824)
imported dengue infections for the year 2020.
Figure 2 Quarterly estimated imported dengue infections arriving at Rome’s Fiumicino-Leonardo da Vinci International Airport
(FCO) from top 10 dengue-endemic countries, 2005–2012. Comparison of trends in importations (RI ) of dengue infections to
Rome among the 10 highest dengue infection-exporting countries over the entire study period 2005–2012. Solid lines represent
the estimated number of incoming imported dengue infections to Rome per quarter from each of the countries. The dotted line
represents a threshold value of 1 imported infection per day, 365 per year. During periods of epidemic dengue activity and higher
travel to Rome, Brazil, Thailand, India, and Mexico have quarters above this threshold. Brazil, represented by the black line with
white squares, averages the highest estimated importation of infection via air travelers arriving in FCO over the 2005–2012 study
period.
“inapparent” dengue infections imported into Rome.
This discrepancy may have multiple reasons. First, as
detailed above, we report estimations of all dengue
infections imported and not just clinical cases of
dengue. Second, in rationalizing the new global estimated dengue infections against the reported dengue
J Travel Med 2015; 22: 186–193
notifications to the WHO, the ECDC, and the national
ministries of health, Bhatt and colleagues (2013)
suggest that ∼3.3% of the estimated total infections would actually be reported even in best case
scenario surveillance areas.38 Approximately 96.7%
of dengue infections are unlikely to be hospitalized
Estimated Dengue Imported Into Italy by Flight
191
(A)
(B)
(C)
Figure 3 Mapping of determining variables for estimated importations of dengue infection into Rome’s Fiumicino-Leonardo
da Vinci International Airport by country. The maps display the comparative contribution to the expected number of imported
dengue infections at the country level [Importations (RI )]. Variable T, based on travel data analysis, is displayed in (A), showing the
scaled intensity of air travel global interconnectivity with Rome. Variable I, based on estimated per-person incidence of dengue
infection (asymptomatic and symptomatic), is displayed in (B), showing the intensity of dengue activity in the endemic departure
countries. The combinations of T and I, displayed in (C), contribute to the model-generated Introduction Model (RI ) values, which
estimate the quantity of imported dengue infections to Rome. All countries’ values have been scaled as a percentile, where those
areas in white (first percentile) represent fewest air travelers, lowest dengue incidence, and least potential for being the source of
an imported dengue case to Rome. Darkest areas (99th percentile) represent areas with relatively greatest potential for dengue
exportation to Rome, due to simultaneously elevated dengue incidence and relatively higher air travel to Rome.
either because they are completely “inapparent,” or
“apparent” presenting with mild illness, or because
of low healthcare-seeking behavior. Third, despite
national plans for integrated human surveillance of
imported and locally acquired vector-borne diseases,
imported dengue to Italy is not legally notifiable.
Fourth, due to our choice of a probability of becoming
an imported infection (anytime up to 10 days after
an infecting bite), we may have an inherit overestimation. It is possible that some travelers who may
J Travel Med 2015; 22: 186–193
192
become imported infection cases would travel onward
in <10 days; therefore, their imported infection would
be in a destination other than Rome; however, data
regarding duration of stay were unavailable. Fifth, our
figures may be an overestimate as our model did not
take into account a change in travel behavior in infected
air travelers, eg, very ill dengue-infected travelers may
not board the flight. As we have no data on the proportion of sick travelers who will cancel their flight,
we assumed that all potentially infected travelers would
have boarded the flight. And lastly, our model did not
take into account age. In many dengue-endemic countries, children are predominantly affected but travel less
frequently than adults.
In conclusion, we developed a model using most
recent global dengue estimates and robust data on air
travel volume to quantify the potential risk for dengue
virus importations into Italy. We found substantial risk,
peaking in the third quarter of the year, increasing over
time, and predicted to more than triple by 2020 compared with 2005. Despite the high number of importations of both “apparent” and “inapparent” dengue
infections, to date, no dengue outbreak has occurred in
Italy. The main reason may be the absence of A. aegypti,
the primary vector for dengue. However, potentially
A. aegypti could be introduced to Italy at any time,
given that conducive climate conditions exist for vector proliferation and dengue-epidemic potential.7 This
could then lead to a similarly major outbreak as the
one observed in Madeira in 2012 after the introduction of the primary vector to this island. Furthermore,
the dengue vector A. albopictus is already widely spread
in Italy. However, the threshold of imported dengue
importations necessary for A. albopictus to result in
major transmission of dengue is still unknown. Although
the extent of dengue importation into Italy is much
higher than that of chikungunya, an importation of
chikungunya resulted in autochthonous transmission
in the year 2007, but this has not yet been observed
for dengue.4,34 This is most likely because A. albopictus is more susceptible to chikungunya viruses compared
with dengue viruses.49 Further research is needed to
determine the threshold levels for A. albopictus populations and the number of infected humans to cause
autochthonous transmission of dengue in Southern
Europe.
Particularly in areas and time periods of heightened risk such as Rome during late summer months,
ongoing vector surveillance and strengthened dengue
surveillance are the recommended strategies to prevent
dengue transmission in Europe as a result of increasing imported dengue infections. Our study supports the
need for more modeling efforts based on interconnectivity between dengue-endemic countries and naïve but
susceptible countries in Europe and elsewhere to predict and quantify the potential risk of imported dengue
infections and later the potential for local transmission
as a result of importations.
J Travel Med 2015; 22: 186–193
Quam et al.
Acknowledgments
The study was financially supported by the European Union’s Seventh Framework Programme
(FP7/2007-2013) under the grant agreement
282589—DengueTools.29 This work was undertaken
within the Umeå Centre for Global Health Research at
Umeå University, with support from FAS, the Swedish
Council for Working Life and Social Research (Grant
no. 2006-1512). The funders had no role in study
design, data collection and analysis, decision to publish,
or preparation of the manuscript.
Declaration of Interests
The authors state that they have no conflicts of interest
to declare.
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