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Surveillance of global dengue distributionJane Messina, Oliver Brady, Simon Hay, Jeremy Farrar & James Whitehorn 1. What is the present global dengue distribution & burden Dengue is found in 128 countries and is ubiquitous throughout the tropics, with
regional and local spatial variations in risk [1]. There is a disproportionate burden
of infection borne by Asian countries, which account for 70% of the world’s total
burden, recently estimated at 96 mil ion apparent infections [2]. Half of this is
attributable to India. The Americas account for approximately half of the remain­
ing burden (14%); this is primarily attributable to cases from Brazil and Mexico.
While Africa was previously considered at low risk from dengue, more recent esti­
mates suggest its burden is comparable with that of the Americas, with significant
under reporting and misdiagnosis as other symptomatical y similar il nesses. While
Oceania is also at high risk from dengue, its relative contribution to the global
burden is low (<2%). Dengue also appears to be spreading on multiple frontiers,
with recent incursions into the southern states of the USA, continental Europe and
southern Argentina. Many of the socioeconomic and environmental changes that
accompany global development are favorable to the transmission of dengue and
thus augur for its continued expansion [3].
Messina, Brady, Hay, Farrar & Whitehorn “connectivity also has 2. What are the main factors that lation of dengue virus types, the epidemiological Dengue is transmitted by Aedes aegypti and Aedes albopictus, so the absolute distribution of these vectors defines its global limits. The spread of A. albopictus in particular is facilitat­ ing the global spread of dengue into new areas. Meteor ological factors affect the
lifecycle and survival of Aedes populations, therefore determining their abundance
within the limits of their distribution. Specifical y, precipita tion is important because
Aedes requires water­fil ed containers for laying eggs, while temperature affects
vector growth and behavior as well as dengue virus (DENV) incubation within the
vector [4–6]. When combined with the population dynamics of the DENV in hu­
man populations and a myriad of human–environment interactions, these factors
affect the duration of dengue establishment and viral diversity (often correlated),
therefore resulting in spatial y heterogeneous patterns of local risk. At the global
scale, patterns in climatic variables such as precipitation and temperature have thus
been resolved as important predictors of risk for dengue [2]. Socioeconomic and
demo graphic factors (e.g., urban extents) are also very important when assessing
global patterns of dengue risk, since A. aegypti and A. albopictus are adapted to
human­modified environments [2]. Large cities in tropical zones therefore suffer a
disproportionately high share of the total global dengue burden. Increasing global
connectivity also has probable implications for rises in the global cocirculation of
DENV types, the epidemiological consequences of which are poorly understood.
3. What is the current status of dengue surveillance systems In most dengue­endemic areas, disease reporting is mandatory, but the level of severity at which the disease gets reported varies regional y. In South and Central America, most endemic countries report an inclusive range of dengue classifications (clinical/laboratory­diagnosed dengue fever, dengue hemorrhagic fever, dengue deaths) weekly by province. These data may be supplemented by vector surveil ance in urban areas, such as the Brazilian Levantamento Rapido de Indice para Aedes aegypti (LIRAa) system, which monitors A. aegypti abundance at the pupal and larval stages during household surveys. Many countries in south and southeast Asia Surveillance of global dengue distribution currently only report the more severe forms of numbers that get reported to the WHO is consider- The majority of reporting is government hos­ pital inpatient based, although patients’ ad­ dresses may be recorded in some instances for surveil ance purposes (e.g., Singapore). In countries such as India, where many
patients seek private healthcare or are treated mostly as out patients, there may
be significant gaps in dengue surveil ance [1]. Furthermore, no dengue­endemic
country conducts regular surveil ance of inapparent infections. The accuracy of
the case numbers that then get reported to the WHO is also considerably variable
across space and time.
4. What should be the priorities for improving dengue surveillance? Routine dengue surveil ance should ideal y be composed of human cases of the
disease, laboratory­based surveil ance and vector surveil ance in an integrated
system [7]. Reporting of human cases should have both consistent passive and
enhanced sentinel components. In sentinel sites, all febrile il ness cases should be
tested for the presence of anti­DENV IgM antibodies and clinical capacities should
be augmented. Any detection of positive dengue cases should trigger site­specific
entomological surveil ance and control responses.
Peaks in dengue mortality often occur during outbreaks that cause healthcare
infrastructures to be overwhelmed. Major problems still need to be solved in the
definition of an outbreak, its early detection and, most importantly, the set of re­
sulting administrative responses at the vector control and healthcare levels. Much
of the highly variable practice in this area is founded upon a poor evidence base
that must also be rapidly improved [8].
In any location, it is important to understand the age­structured ratio of all dengue infections, as this provides for a richer understanding of the local epidemiology of Messina, Brady, Hay, Farrar & Whitehorn the disease. This will be required if we are to estimate and measure the impact of
control and ultimately vaccination. Ideal y, this would involve national programs of
annual age­stratified seroprevalence surveys; however, these are likely to be finan­
cial y prohibitive [3]. More feasible would be sentinel surveil ance of cohorts in a
representative sample of environments. These would also help to greatly improve
national and global burden estimates.
5. What are the reasons for the disappointing results of the Sanofi Pasteur dengue candidate? What is the probable timeframe for the incorporation of an efficacious vaccine into immunization programs? The Sanofi Pasteur (Lyon, France) candidate is a live attenuated tetravalent den­
gue–yellow fever 17D virus vaccine. The Phase IIB efficacy study conducted in
Thai schoolchildren showed a surprisingly low overall efficacy of 30.2% [9].
Given the enormous burden of dengue and the fact this was the leading den­
gue vaccine candidate, these were very disappointing results for global public
health.
The reasons for these results are not completely clear. One of the major difficul­
ties with dengue vaccine development is our incomplete understanding of den­
gue pathogenesis and, in particular, our lack of knowledge of what the correlates
of dengue immunity are and how best to measure them [10]. However, we do
know that infection with one DENV serotype induces lifelong immunity against
that serotype and short­lasting crossreactive immunity against the other sero­
types. The investigators propose that the DENV2 incorporated into the yel ow
fever chimera may not have been able to induce protective antibodies against the
DENV2 circulating in Thailand at the time of the study [9]. Others have suggested
that a failure to induce balanced viremias or immune responses across the four
serotypes of DENV may have been partial y responsible for the low efficacy ob­
served [11]. In addition, the results of this trial have pointed towards the potential
limitations of using primate dengue vaccine chal enge models to inform us of efficacy in humans [12]. It is possible a dengue human
“trials of the Sanofi candi- chalenge model may play an important role in vaccine development [13].
we are many years from a commercially available It remains to be seen whether the Sanofi vaccine candidate offers protection against Surveillance of global dengue distribution severe disease, and ongoing Phase III trials may demonstrate this. There are
other vaccine candidates in earlier stages of development [14]. Most of the
candi dates in early stages of clinical development are also tetravalent live atten­
uated vaccines, although some others in preclinical development have adopted
different designs. While it is exciting that there are numerous potential vaccine
candidates at various stages of development, it is important to remember that
the vaccine development process is lengthy [15]. Should the Phase III trials of the
Sanofi candidate prove disappointing, we are many years away from a commer­
cially available vaccine. The challenge of funding vaccine development remains
– traditionally this has been the remit of commercial entities but the global
importance of dengue may justify increased noncommercial funding. Once an
efficacious dengue vaccine has been developed, individual countries must make
economic justifications for its introduction and incorporation into immunization
programs. It is likely that countries with a high burden of dengue cases will be
the first to introduce a dengue vaccine into their immunization programmes. In
addition, there is likely to be a market for a dengue vaccine for travelers and
the military.
While a dengue vaccine is highly desirable for global health, it is essential that other components of dengue control are not neglected, for example individual clinical management and vector control.
6. What are the major factors contributing to the continued spread The global burden of dengue is large, with recent work suggesting there are an
estimated 390 mil ion infections each year [2]. This figure is three­times higher
than the WHO’s previous estimates of the global dengue burden. One of the
key factors in both the spread and intensification of dengue is the spread of
efficient disease vectors, in particular the highly domesticated and urbanized
mosquito A. aegypti [16,17]. This spread has been augmented by the current lack
of effective vector control measures. A. ae­
gypti is thought to have emerged from Africa
during the slave trade and spread into Asia
as a result of trade expansion. Dengue out­ breaks in Africa, such as that seen in Cape Verde in 2009, may well reflect increased trade between Asia and Africa [18]. In the
Messina, Brady, Hay, Farrar & Whitehorn last 50 years, A. aegypti has spread throughout the tropical world, reflecting
increased globalization with increased international trade and huge population
movements [19]. Another potential dengue vector, A. albopictus, has extended
its global range dramatical y in recent years, including spread into Europe and
North America [20]. However, as A. albopictus is not the primary dengue vector,
it is not clear how much its expansion has contributed to the global spread of
the disease. In addition, the rapid and, at times, uncontrol ed expansion of urban
centers in Asia, Latin America and increasingly in Africa has supported the pro­
liferation of vector breeding sites [19]. The proliferation of domesticated disease
vectors combined with large non immune populations have led to explosive dis­
ease outbreaks and the establishment of dengue endemicity. The intensification
of dengue is dependent on transmission intensity and time since disease estab­
lishment. It is inferred by increasing diversity and stability of DENV serotypes in a
given geographic location.
7. What are the goals of the WHO 2012–2020 global strategy for Dengue is an increasing global public health concern. Dengue causes individual
patient suffering, places immense strain on struggling health systems and re­
sults in a significant economic burden. The WHO global strategy seeks to address
these problems by reducing the burden of dengue [21]. Specifical y, the strategy
aims to reduce the mortality and morbidity from dengue by 50 and 25%, respec­
tively, using 2010 WHO estimates as a baseline by using and building on existing
knowledge.
Earlier and better case detection and improved individual case management will hopefully result in the desired mortality reduction. To reduce morbidity, the strategy suggests developing outbreak detection tools and supporting im­proved integrated vector control measures. The achievement of these aims will require appropriate research and implementation of relevant evidence­based activities.
While we ful y support the aims of the WHO global strategy, one concern is that
the 2010 WHO dengue estimates are thought to be significant underestimates of
the global disease burden [2]. Improved case detection will result in more realistic
disease estimates but will make achieving the specific objectives of the global
strategy impossible.
Surveillance of global dengue distribution and improved individual patient management will Early case detection and improved individu­ al patient management will result in reduc­ tions of both mortality and morbidity. The dengue field could build on the platform of enhanced surveillance adopted for influenza
after the 2009 pandemic resulting in earlier outbreak detection and improved
patient management [8,22]. Reassuringly, in experienced settings, the mor­
tality from dengue is very low. Treatment is supportive and in severe cases
requires careful fluid resuscitation and, in cases of hemorrhage, administration
of blood products [16]. As the period of significant plasma leak is transient, it
is common in inexperienced settings to give too much fluid, with the danger
of overloading the patient. The 2009 WHO dengue guidelines classify dengue
into ‘dengue’ and ‘severe dengue’, and place emphasis on various warning
signs that may indicate a patient progressing to more severe disease [7]. While
there has been significant debate about the merits of the new disease clas­
sification, the guidelines are designed to make management of patients with
dengue easier and recognition of patients with potentially more severe disease
more efficient [23]. Thus the implementation of the new guidelines has the
potential to reduce dengue mortality and morbidity. At the moment, there are
no specific therapeutics that can be used in dengue, although both antiviral
and immuno modulatory drugs have been trialled [24–26]. The develop ment of
a safe therapeutic agent that can reduce the duration of illness and the risk
of progressing to severe disease would be a major advance in our efforts to
control dengue.
Successful prevention strategies have enormous potential to result in signifi­
cant reductions in dengue mortality and morbidity. An efficacious vaccine is
of course highly desirable but, as discussed above, is still years away. Vector
control strategies have previously had limited success in controlling dengue,
but exciting new advances may change this. For example, infection of mos­
quitoes with fruit fly strains of symbiont Wolbachia bacteria appears to reduce
mosquito lifespan and interfere with pathogen replication [27,28]. Releases of
Wolbachia­infected A. aegypti have been commenced in Australia and parts
of southeast Asia. The impact of this imaginative approach to dengue control
remains to be seen.
Messina, Brady, Hay, Farrar & Whitehorn ployment, consultancies, honoraria, stock ownership or options, expert organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed the production of this manuscript.
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Dengue: transmission, diagnosis and surveillance

Biomarkers for dengue: prospects and challenges

Dengue diagnosis: commercially available kits and laboratory support

Lessons learned from dengue: focus on Taiwan

Intraepidemic increases in dengue disease severity: applying lessons

Prospects for controlling dengue spread: vaccines and vector control

Multiple choice ­questions: answers

Clinical & biochemical parameters

Markers of endothelial activation

Identifying novel biomarkers & future directions

Immune response in dengue infections

Antibody detection (IgM & IgG)

Combined use of serological tests

Clinical features & epidemiology of dengue in Taiwan

Insights into dengue pathogenesis from Taiwan

Future directions: biomarkers research in Taiwan

Dengue in travelers with special needs

Future perspective & take-home message

Studies on the 1997 Cuban outbreak

Disease severity increases in Nicaragua & Taiwan

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