Yellow fever and dengue: a threat to Europe?

Review articles
Yellow fever and dengue: a threat to Europe?
P Reiter (paul.reiter@pasteur.fr)1
1. Insects and Infectious Disease Unit, Institut Pasteur, Paris, France
Citation style for this article:
Citation style for this article: Reiter P. Yellow fever and dengue: a threat to Europe?. Euro Surveill. 2010;15(10):pii=19509. Available online: http://www.
eurosurveillance.org/ViewArticle.aspx?ArticleId=19509
This article has been published on 11 March 2010
The introduction and rapidly expanding range of Aedes
Aedes aegypti, the primary urban vector for both
albopictus in Europe is an iconic example of the grow-
viruses, was once established as far north in Europe
ing risk of the globalisation of vectors and vector-
as Brest and Odessa (Figure 1). It disappeared from
borne diseases. The history of yellow fever and dengue
the entire Mediterranean region in the mid-20th cen-
in temperate regions confirms that transmission of
tury, for reasons that are not clear. Ae. albopictus, gen-
both diseases could recur, particularly if Ae. aegypti,
erally regarded as a less important vector of dengue
a more effective vector, were to be re-introduced. The
[7], is also capable of transmitting yellow fever. It was
article is a broad overview of the natural history and
introduced to Europe in the 1970s, is well established
epidemiology of both diseases in the context of these
in at least twelve countries (Figure 2) [8], and is likely
risks.
to spread northwards, perhaps as far as Scandinavia.
Background
The number of persons who visit countries endemic for
There is logic in dealing with yellow fever and dengue
dengue and yellow fever is continually rising [11,12]. It
together, for they have much in common:
is therefore cogent to consider whether introduction
of these viruses is likely to lead to autochthonous and
• Both are caused by viruses of the family
even endemic transmission in Europe.
Flaviviridae, genus Flavivirus.
• Both viruses are strictly primatophilic – they only
Transmission
infect primates, including man.
Five factors are key to the epidemiology of vector-borne
• In their original habitat, both are zoonotic infec-
diseases: the ecology and behaviour of the host, the
tions transmitted by forest-dwelling mosquitoes.
ecology and behaviour of the vectors, and the degree
• Both can cause haemorrhagic illness in humans,
of immunity in the population. A holistic view of this
often with fatal consequences.
complexity is key to assessing the likelihood of trans-
• Both owe their importance as human pathogens to
mission in Europe [13].
two forest mosquitoes that have become closely
associated with the peridomestic environment.
Origin of the viruses
• The viruses and their urban vectors owe their
There is little doubt that the yellow fever virus (YFV)
worldwide distribution to transportation of goods
originated in Africa, and that viruses circulating in the
and people.
New World are of African origin. Curiously, yellow fever
• Both diseases have a history of transmission in
has never been recorded in Asia, although Ae. aegypti
temperate regions, including Europe.
is widespread there.
According to the World Health Organization, there are
There are four antigenically distinct DENV serotypes
currently 200,000 worldwide cases and 30,000 deaths
that cause very similar disease in humans. It is widely
from yellow fever per year, 90% of them in Africa [1],
accepted that all four are of Asian origin [14], although
and as many as 50 million cases of dengue [2].
DENV-2 is enzootic in Africa [15].
Epidemics of yellow fever, sometimes catastrophic,
Zoonotic vectors and hosts
were once common in North America as far north as
In the Old World, the sylvatic vectors of yellow fever
New York and Boston (Table), and in European ports
and dengue are canopy-dwelling mosquitoes of the
as far north as Cardiff and Dublin [3]. Large epidemics
genus Aedes and three subgenera, Stegomyia, Finlaya,
of dengue occurred in the same regions from the 18th
and Diceromyia, that feed exclusively on monkeys. In
century onwards. A massive epidemic, estimated at
the Americas, the principal zoonotic vectors of yellow
one million cases, with at least 1,000 deaths, occurred
fever are Sabethes and Haemogogus species; both are
in Greece in 1927-28 [4,5]
also strictly primatophilic [3].
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Sylvatic transmission to humans
Sylvatic infections are acquired when humans enter
Whatever the reason, given the absence of wild pri-
woodland where there is zoonotic transmission. In
mates, it is unlikely that any vector species native to
recent years, a number of unvaccinated tourists have
Europe is able to transmit these viruses.
died of yellow fever after visiting enzootic areas [16,17].
Peridomestic transmission
Vector-host specificity
Neither YFV nor DENV would have major importance as
Host specificity is a characteristic of many vectors; it
human pathogens in the absence of two mosquito spe-
is conceivable that it improves the chances of locating
cies, Ae. (Stegomyia) aegypti and Ae. (S.) albopictus,
hosts. This may be particularly useful in the sylvatic
both of which have become closely associated with the
environment, where bands of monkeys roam between
peridomestic environment. Infected humans return-
established sleeping sites.
ing from an enzootic area may initiate transmission to
The specificity of DENV and YFV to primatophilic vec-
humans in human settlements if either of these spe-
tors may have evolved to exploit this relationship,
cies is present (although to date, no yellow fever infec-
and/or to surmount barriers to infection in the insect.
tions have been attributed to Ae. albopictus).
Table
Major epidemics of yellow fever in North America, north of Mexico
Year
Year
1668
New York, Philadelphia and other settlements
1803
Boston, Philadelphia
1690
Charleston
1804
Philadelphia
1691
Boston
1805
Philadelphia
1693
Charleston, Philadelphia, Boston
1807
Charleston
1694
Philadelphia, New York, Boston
1811
New Orleans, Florida, New Jersey
1699
Charleston, Philadelphia
1817
New Orleans, Charleston, Baltimore
1702
New York
1819
New Orleans, Charleston, Baltimore, Philadelphia, New York
1703
Charleston
1820
New Orleans, Philadelphia
New Orleans, Mississippi Valley, Alabama, Charleston,
1728
Charleston
1821
Baltimore, Philadelphia, New York, Boston
1732
Charleston
1822
New Orleans, New York
1734
Charleston, Philadelphia, New York, Albany, Boston
1823
Key West
1737
Virginia
1824
New Orleans, Charleston
1739
Charleston
1825
Mobile, Natchez, Washington
1741
Virginia, Philadelphia, New York
1827
New Orleans, Mobile
1743
Virginia, New York
1828
New Orleans, Memphis
1745
Charleston, New York
1829
Key West, Mobile, Natchez
1747
New Haven
1837
New Orleans, Mobile, Natchez
1748
Charleston
1839
Galveston, Mobile, Charleston
1751
Philadelphia, New York
1841
Key West, New Orleans
1762
Philadelphia
1843
Galveston, Mobile, Mississippi Valley, Charleston
1778
Philadelphia
1847
New Orleans, Mobile, Natchez
1780
Philadelphia
1852
Charleston
1783
Baltimore
1853
New Orleans
1791
Philadelphia, New York
1854
New Orleans, Mobile, Alabama, Charleston
1792
Charleston
1855
Mississippi Valley, Norfolk
1793
Philadelphia
1856
New Orleans, Charleston
1794
Philadelphia
1858
Charleston
1795
Philadelphia
1867
Key West, Galveston, New Orleans, Mobile, Philadelphia
1796
Philadelphia
1870
New York
1797
Philadelphia
1873
New Orleans, Mississippi Valley, Alabama, Memphis
1798
Philadelphia
1876
Charleston
1799
Philadelphia
1877
Port Royal SC
New Orleans, Memphis, Mississippi Valley to St Louis, Chat-
1800
Philadelphia
1878
tanooga, many other cities
1801
Norfolk, New York, Massachussetts
1879
Memphis
1802
Philadelphia
1905
New Orleans
Reproduced from [6] with permission from Environmental Health Perspectives.
2
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Dengue is endemic in many urban and rural popula-
Figure 1
tions throughout the tropics. ‘Virgin soil’ epidemics in
Historical distribution of Aedes aegypti
large cities are often explosive. In 1988, for example,
there were an estimated 420,000 cases in four months
in the coastal city of Guayaquil, Ecuador [18]
The large urban outbreaks of yellow fever that were
common until the early 20th century remain a real
and constant danger in enzootic countries that do not
enforce routine vaccination. Moreover, it is reasonable
to assume that areas that are prone to dengue trans-
mission are equally prone to yellow fever, so areas
without history of the latter, including those in south-
east Asia, may well be at risk.
Dark grey areas: maximum range distribution of Ae. aegypti, black
lines: January 10°C isotherm in the northern hemisphere; mid grey
Vectors
lines: the July 10°C isotherm in the southern hemisphere.
The yellow fever mosquito, Aedes aegypti
The distribution limit broadly fits the 10°C isotherm in the southern
Ae. aegypti is the quintessential urban vector of yellow
hemisphere, but far less so in the northern hemisphere.
Source: adapted from a map published by Christophers [9].
fever and dengue. It is a remarkable species because
Figure 2
Current (2009) distribution of Aedes albopictus in Europe by administrative unit
Orange: overwintering expanding populations; purple: populations only observed indoors (in glass houses); green: not detected in past 5
years; pale yellow: no recent data on mosquito fauna; blue: no information on any mosquito studies; white: not included in this study.
Source: [10].
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the ‘domesticated’ form is rarely found more than 100
for they are not resistant to freezing. Thus there is no
m from human habitation and feeds almost exclusively
obvious climatic reason why the species, were it to
on human blood. Nevertheless, like its forest ances-
be re-introduced, could not survive in most areas in
tor, it remains day-active with a preference for heavy
Europe.
shade. It freely enters homes and other buildings and
spends much of its time hidden in dark places, often
Aedes albopictus
among clothing, a stable microclimate with few preda-
In its original range, Ae. albopictus was present from
tors. Its human host is abundant and lives under the
Beijing and northern Japan to tropical Asia [25]. In
same roof, an arrangement that minimises the hazards
1983, however, the mosquito was found in Memphis,
of questing for a blood meal. It lays eggs in man-made
Tennessee [26], and, two years later, a survey revealed
objects that contain water, from discarded tires and
that it was widely distributed, often common, in the
buckets to the saucers under flowerpots and water-
southern United States. Investigation revealed a glo-
storage barrels. In short, humans are the perfect host:
bal trade in used tyres that were frequently infested
they provide safe shelter, plentiful food and abundant
with eggs and larvae of the species [27]. Japan was the
sites for procreation. Indeed, in most cities of the trop-
principal exporter, and a study of winter diapause at
ics, homes are so close together and breeding sites so
various latitudes in Asia confirmed that the day-length
abundant that they can be regarded as a single factory
that triggered diapause was identical in the southern
for mosquitoes in an urban jungle. In the past three
United States and in southern Japan [28]. The mosquito
decades, attempts to reduce populations of the spe-
is now widespread in the United States, and is a major
cies have rarely been successful and never sustained
nuisance species as far north as Nebraska and Illinois,
[19,20].
where winter snowfall can be well above 200 cm, aver-
age January night-time temperatures are -10ºC, and
The Asian Tiger mosquito, Aedes albopictus
temperatures as low as -33ºC have been recorded. It
Ae. albopictus is often abundant in the peridomestic
is also established in Mexico and all the countries of
environment, particularly in areas with plentiful veg-
Central and South America except Chile. In Africa it is
etation. However, in addition to humans, it feeds freely
well established in Nigeria, Gabon, Equatorial Guinea
on animals and birds, and so can exist far from human
and Cameroon [29,30], and in Europe it has been
habitation. Since non-primates are not susceptible to
reported from 16 countries [8]. Recent infestations in
the viruses, such blood meals do not contribute to the
the Netherlands have been traced to imports of ‘lucky
transmission cycle, and for this reason, Ae. albopictus
bamboo’ from sub-tropical China [31], but these mos-
has generally been regarded as a secondary vector [7].
quitoes do not appear to have survived the winter, per-
Nevertheless, dengue epidemics have been recorded in
haps because they have no winter diapause.
places where Ae. albopictus is the only vector [21], and
in recent years, the species has proved highly effective
Clinical features
in urban transmission of another African sylvatic virus,
Yellow fever
chikungunya virus [22,23].
As with most viral diseases, yellow fever can present
with a wide spectrum of symptoms, from mild to fatal.
Globalisation of vectors and viruses
In clinical cases, there is generally a sudden onset of
Aedes aegypti
fever with severe headache, arthralgias, and myalgia.
Ae. aegypti and yellow fever arrived in the New World
The striking yellowing of the eyes and skin, caused by
together, as passengers in the slave trade. Slave
hepatic dysfunction, may appear on the third day and
ships generally made the passage from Africa to the
indicates a poor prognosis. The fever often follows a
Americas in four to six weeks. The virus was enzootic
‘saddleback’ curve, with a brief drop in temperature
in regions where the slave caravans captured local
and symptoms after the third day, followed by a return
inhabitants, and urban transmission was rife in the
with increased severity that can lead to spontaneous
ports of dispatch. The casks used for shipboard stor-
haemorrhage (‘coffee ground’ vomit), delirium, renal
age of water must have been prolific breeding sites for
failure, coma and death. Fatality rates of clinical cases
the mosquito, and the slaves were an abundant source
can be as high as 80% [3], on a par with Ebola, Marburg
of blood. With the slaves and the mosquito came the
and other haemorrhagic viral infections.
virus, and it was not uncommon for ships to arrive
in port with large numbers of dying persons aboard,
Dengue
hence the yellow flag of quarantine.
As many as 80% of all dengue infections are asymp-
tomatic. Among clinical cases, early stages are similar
In the United States, the species has been recorded
to those of yellow fever, although with excruciating
from 21 states (Alabama, Arkansas, Florida, District of
arthralgia and myalgia, hence the term ‘break-bone
Colombia, Georgia, Illinois, Indiana, Kansas, Kentucky,
fever’. Fever and other symptoms rarely last more
Louisiana, Maryland, Missouri, Mississippi, New York,
than seven days, but convalescence can be prolonged
North Carolina, Ohio, Oklahoma, South Carolina,
and debilitating. The later stages of the illness often
Tennessee, Texas, and Virginia) [24]. In many of these,
include a widespread rash [32].
winter temperatures below -20°C are not unusual.
Presumably the mosquitoes survive in sheltered sites,
4
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A portion of dengue cases, usually less than 5%, can be
that coverage is inadequate, and there is a real and
severe and a fraction of these may be fatal [33]. Severe
present danger of a major urban epidemic. Moreover,
dengue, commonly referred to as dengue haemorrhagic
there is good reason to believe that the 2.5 billion peo-
fever/dengue shock syndrome (DHF/DSS) to distinguish
ple who live in regions at risk of dengue infection are
it from ‘classic’ dengue, is associated with spontane-
also at risk of yellow fever; if so, then, given the lax
ous haemorrhage and an increase of vascular perme-
attitude towards vaccination of travellers in most coun-
ability that can lead to life-threatening hypovolemic
tries, the danger of a catastrophic epidemic beyond
shock. The causes of this condition have been debated
regions generally associated with transmission is also
for decades, but remain unresolved [34-36]. A widely
real, and this could include parts of Europe infested
held but hotly contested hypothesis is that after infec-
with Ae. albopictus. If such an event were to occur, cur-
tion with one serotype, secondary infections by one or
rent stocks of vaccine would probably be inadequate to
more of the others can precipitate the syndrome by a
respond to worldwide demand.
process referred to as antibody-dependent enhance-
ment, but the occurrence of severe dengue in epidem-
Dengue
ics of primary infection, such as the Greek epidemic
No vaccine against dengue is available, but attenuated
and a recent epidemic in Cape Verde [37], contradicts
virus vaccines and second-generation recombinant
this hypothesis. An associated controversy is the valid-
vaccines are in active development [42]. A large-scale
ity of graded sets of criteria to categorise severity that
trial (phase IIb) of a chimeric tetravalent vaccine [43]
are recommended by the World Health Organization,
has been under way since February 2009 [44]. If suc-
and these have been revised several times in recent
cessful, then a vaccine might be licenced within five
years [38]. Both issues are of prime importance for the
years.
management and treatment of patients.
Vector control
It is a common misconception that DHF/DSS first
At the beginning of the 20th century, urban yellow fever
appeared in the 1950s in south-east Asia. It is certainly
was eliminated from many countries by energetic cam-
true that the syndrome became a serious public health
paigns to eliminate Ae. aegypti breeding sites. After
problem in that period, but it was not a new phenome-
the Second World War, focal application of the syn-
non: significant mortality associated with haemorrhagic
thetic pesticide dichlorodiphenyltrichloroethane (DDT)
symptoms had been described in the earliest epidemic
to infested containers and their surroundings was an
of dengue-like disease on record, in Philadelphia in
outstanding success; according to the Pan American
1789, as well as in later epidemics in East Africa and in
Health Organization, the species was eradicated from
Australia [14,39]. Moreover, as already mentioned, at
22 countries in the Americas [45]. The reason for the
least 1,000 people died in the Greek epidemic in 1927-
efficacy of this method has only recently become
28. In the years after the Second World War, however,
apparent: ‘skip-oviposition’ (the deposition of small
rapid expansion of densely populated urban areas,
numbers of eggs in many different sites) made it highly
coupled with enormous infestations of Ae. aegypti, led
probable that they would encounter treated sites [19].
to a massive increase in the prevalence and incidence
No substitute for DDT is currently available, so many
of the disease in south-east Asia, so a plausible expla-
authorities resort to spraying insecticidal aerosols
nation for the emergence of this ‘new’ syndrome is that
(ultra-low-volume) of organophosphates or pyrethroids
escalating numbers of classic infections simply led to
from hand-held machines, road vehicles or aircraft.
an increased awareness of the relatively rare manifes-
Unfortunately, the method is expensive and gener-
tations – the ‘iceberg effect’.
ally ineffective, at least against Ae. aegypti, because
the species spends much of its time indoors at sites
Treatment
that are inaccessible to the aerosol [20,46]. Moreover,
There is no specific treatment for yellow fever or den-
even if a large number of mosquitoes were to be elimi-
gue virus infections; supportive therapy is the only
nated by this treatment, the impact on adult mosquito
option, although there is active research into antiviral
populations would probably be too short for an effec-
drugs against these diseases [40]. For dengue fevers,
tive impact on transmission [47]. Although the World
intravenous fluids are used to counter haemoconcen-
Health Organization recommends that health authori-
tration, and platelet transfusions in the event of severe
ties evaluate the technique under local circumstances
thrombocytopaenia [41]. Strict avoidance of anticoagu-
[6], their principal strategy is community-based source
lants, including aspirin, is important.
reduction, the elimination of breeding sites by the com-
munity. Unfortunately, there is no evidence that this
Prevention
approach has been successful in any part of the world.
Vaccination
Yellow fever
Control of Ae. albopictus is probably even more diffi-
A safe, effective yellow fever vaccine, based on a live
cult than for Ae. aegypti, given its ability to breed away
attenuated strain, has been available for more than half
from human habitation, but insecticidal aerosols may
a century, and mass vaccination is a highly effective
be more effective for Ae. albopictus because the mos-
approach to prevent urban transmission, but the inci-
quito tends to rest outdoors.
dence of the disease, particularly in Africa, confirms
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The future in Europe
Dengue is essentially an urban disease because of
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