a child watches as a worker fumigates to prevent …dengue reborn widespread resurgence of a...

Dengue RebornWidespread Resurgence

of a Resilient Vector

A child watches as a worker fumigates to preventdengue fever and other mosquito-borne diseases,Old Havana, Cuba, January 2008.

A 382 Environmental Health Perspectives • VOLUME 116 | NUMBER 9 | September 2008

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Focus | Dengue Reborn

Dengue—a viral disease that can refer to both dengue fever and

the more severe dengue hemorrhagic fever (DHF)—swept away

records again this past spring as it raged across Brazil, infecting

more than 160,000 people and killing more than 100. The reports were similar

to those out of Southeast Asia in the summer of 2007, South America the

previous spring, and India the fall before that. Although it may not be the

most devastating of the mosquito-borne diseases—malaria strikes 10 times

more people and yellow fever kills more of its victims—dengue has become a

major public health concern for two reasons: the speed with which it is spreading

and the escalating seriousness of its complications.

In the nineteenth century, dengue fever was a mild illness found in the tropics.

Deaths were rare, and years passed between major epidemics. But since the

mid-twentieth century, the range of the dengue virus has steadily broadened.

In the last 50 years, its worldwide incidence has increased 30-fold, and various

estimates posit that anywhere from one-third to nearly one-half of the world’s

population are now at risk of becoming infected.

Aedes aegypti, the primary vector for dengue, has become perfectly adaptedto the urban environment. In the wake of discontinued eradication efforts,Ae. aegypti has reinfested nearly every region from which it was eliminated.

Moreover, today’s dengue infection is notwhat it once was. DHF, a complication ofdengue infection that was not recognizeduntil the 1950s (although cases probablyoccurred as early as 1870 in India), nowappears in many dengue epidemics. In addi-tion to the fever, rash, headache, and muscleand joint pain of classic dengue fever (whichearned dengue its nickname of “breakbonefever”), DHF sometimes causes hemorrhag-ing that can lead to shock and even death.Epidemic DHF is now a leading cause ofhospitalization and death among children in

several Southeast Asian countries. World-wide, of the 50 million dengue infectionsestimated by the World Health Organ-ization (WHO) each year, there are 500,000cases of DHF and 22,000 deaths, mainlyamong children.

Once considered mainly an Asian dis-ease, dengue fever and DHF now alsopermeate the tropical Americas. Between1995 and 2001, the number of dengue casesin the Americas doubled, according to theWHO. By 2007, the annual incidence therereached nearly 900,000 cases, with morethan 25,000 people suffering DHF.

The dengue virus comes in four dis-tinct serotypes. Individuals who becomeinfected with one serotype obtain lifelongimmunity against that serotype but notagainst the other three—and there is goodevidence that a previous dengue infectionincreases the odds of developing DHFupon infection with a different serotype.“Somehow, having that prior infectionenhances invasion of target cells by newdengue [serotypes],” explains LauraHarrington, a medical entomologist atCornell University.

Dengue experts agree on many of thecauses of the disease’s spread, includingdemographic changes and interruptions invector control efforts. But some controversyhas surfaced over whether climate change—often cited as a factor in broadening diseasevector habitats—has had or will have any-thing to do with the virus’s expansion. “It’stoo early to predict what effects global warm-ing will have, if any,” says David Morens,senior scientific advisor at the NationalInstitute of Allergy and Infectious Diseases(NIAID) in Bethesda, Maryland. “But it’scertainly something to be concerned about.”

Re-emergence of a DiseaseSeveral factors have assisted in the spread ofdengue around the world. Aedes aegypti, themosquito that is the chief carrier of thedengue virus, originated in Africa butmigrated to other continents via the slavetrade in the 1500s and 1600s, says DuaneGubler, director of the Asia-Pacific Instituteof Tropical Medicine and InfectiousDiseases at the University of Hawaii atManoa in Honolulu. “As urban port citiesdeveloped, [the Ae. aegypti] mosquitobecame established and became highly

adapted to humans,” he says. Accord-ingly, as the tropical developing worldhas become increasingly urbanizedover the past few decades, Ae. aegyptihave proliferated.

Whereas Ae. aegypti originallybred in small natural water bodiessuch as tree holes or rock pools, it nowbreeds successfully in water that accu-mulates in discarded trash such as bot-tles, plastic and cellophane packaging,and tires, as well as in domestic waterstorage containers that are common inplaces where people do not have easyaccess to a regular supply of cleanwater. Ae. aegypti also prefers to liveinside buildings rather than outside.Finally, this mosquito prefers to feedon humans, meaning viral transmis-sion is not diluted by the mosquitofeeding on other animals as well. Ae.aegypti therefore is “perfectly adaptedto the urban environment,” saysGubler.

During World War II, Japaneseand Allied military movements spreadviruses throughout Southeast Asia. Inthe aftermath of the war, “for the firsttime, several serotypes were comingtogether,” Harrington says, as peoplebegan to travel across the world morefrequently. Subsequent economicboom and rapid urbanization inSoutheast Asia led to conditions idealfor epidemics—cramped l iv ing

quarters, low-quality housing, and poormanagement of water, sewage, and wastesystems. Dengue’s progression from tropicalnuisance to life-threatening epidemicreached a tipping point in the 1950s, whenDHF was first reported in the Philippinesand Thailand.

Meanwhile, on the other side of theglobe, dengue had been largely eliminated inthe Americas, mainly thanks to attempts tocontrol urban yellow fever in the 1950s and1960s. The Pan American Health Organi-zat ion (PAHO), an international publichealth agency, initiated a campaign to rid

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In the wake of rapid urbanization and heightened global travel since World War II, the numberof both dengue cases and countries reporting infection has climbed precipitously.

Source: WHO; http://www.who.int/csr/disease/dengue/impact/en/index.html

Dengue since 1955: more cases, more places

Central and South American, Caribbean,and southern U.S. regions of Ae. aegypti,which also transmits yellow fever virus. Bygoing after Ae. aegypti aggressively with theinsecticide DDT and systematically elimi-nating its breeding areas, the campaignlargely eradicated the vector from Centraland South America, although not theCaribbean and southern United States, saysGubler. In the course of eradicating yellowfever, the efforts also squashed dengue trans-mission in the region.

DDT was banned in the United States in1972. Coincidentally, says Gubler, Ae. aegyptieradication efforts were deemed successfuland therefore largely abandoned, withresources redirected to otherpressing issues of the day suchas President Richard Nixon’s“War on Cancer.” Since then,Ae. aegypti has returned tonearly every region fromwhich it was eliminated. “Wehave allowed Aedes aegypti toreinfest most if not all of theu rban a r e a s o f t r op i c a lAmerica,” says Gubler.

In 1981 a serotype ofdengue imported from south-east Asia caused an outbreak ofDHF in Cuba—the first DHFepidemic in the Americas.Since then, all four serotypeshave spread throughout theAmericas, causing DHF out-breaks and becoming endemicin many countries.

Increased global move-ment of people and cargo viaair travel have undoubtedlyassisted dengue’s growth, saysHarrington. It is this move-ment that now allows mul-tiple serotypes of dengue toencounter each other frequently, leading tothe complications of DHF. And in theAmericas, the reinvasion of Ae. aegypti afterthe lapse of eradication campaigns also con-tributed to dengue’s resurgence, Harringtonsays. “For those of us who work in dengueresearch, I think there’s a fairly strong con-sensus about what the major factors are [indengue’s spread],” she says.

The Climate Change QuestionOne factor, however, remains debatable:the effect of climate change on the dissemi-nation of dengue. Like many vector-bornediseases, dengue fever shows a clear weather-related pattern: rainfall and temperaturesaffect both the spread of mosquito vectorsand the likelihood that they will transmit

virus from one human to another. In a coolclimate, the virus takes so long to replicateinside the mosquito that most likely themosquito would die before it actually has achance to transmit the virus to another per-son, says senior research fellow Simon Halesof the University of Otago, New Zealand.“There’s a consensus that climate is one ofthe necessary factors that has to be right fordengue to be able to be transmitted,” Halessays. “Whether or not climate change willaffect the spread of dengue is probablymore contentious.”

Several studies have predicted that globalclimate change could increase the likelihoodof dengue epidemics. In the 14 September

2002 issue of The Lancet, Hales and hiscolleagues published an empirical model ofworldwide dengue distribution in whichthey reported that annual average vaporpressure (a measure of humidity) was thesingle climate factor that best predicteddengue fever distribution. They also usedtheir model to predict likely effects ofhumidity on dengue distribution. If humiditywere to remain at 1990 levels into the nextcentury, a projected 3.5 billion people wouldbe at risk of dengue infection in 2085, butassuming humidity increases as projected bythe Intergovernmental Panel on ClimateChange, the authors estimate that in fact5.2 billion could be at risk.

Other work has reported correlationsbetween dengue and climate variables such

as El Niño, temperature, rainfall, and cloudcover. In March 2008, the United NationsIntergovernmental Panel on ClimateChange released its Fourth Assessment Reporton Climate Change Impacts: Impacts,Adaptation and Vulnerability, concludingthat climate change could increase the num-ber of people at risk of dengue infection.

But some dengue researchers feel that acase for a connection between dengue inci-dence and climate change has yet to bemade. Global warming might influencedengue transmission “to the extent that itinfluences how water is managed and han-dled,” says Harrington, but temperatureincreases are probably not important for the

virus’s expansion. “If you really sit down andlook at the science, . . . there are no real harddata to show that [climate change is] havingan effect,” she says.

There’s no argument that global warm-ing is occurring, says Gubler, but as for thesuggestion that it has played any role in theexpansion of dengue, “It’s all hype. A lot ofpublic health officials and a lot of policymakers use global warming as a cop-out, anexcuse for not controlling a disease that isvery preventable.”

In a plenary session at the May 2008annual meeting of the American Institute ofBiological Sciences, Gubler urged that policymakers not focus on climate change butresume addressing the chief known drivers ofdengue’s spread—namely, population


Environmental Health Perspectives • VOLUME 116 | NUMBER 9 | September 2008 A 385

A systematic eradication program largely eliminated Ae. aegypti in the Americas by the 1970s. But oncethe program was discontinued, the vector came back stronger than ever.

Source: Arias JR. 2002. Dengue: how are we doing? Washington, DC: Pan American Health Organization.

Ae. aegypti infestation before, during, and after concerted eradication efforts in the Americas

1930s 1970 2002

growth, urbanization, and modern trans-portation. Importantly, he said, “we needpolitical will. With political will, we may getthe economic support that we need to do theresearch to develop effective prevention andcontrol strategies.”

But even as there is no documentationthat climate change is influencing the spreadof dengue, Hales counters there also is noproof regarding many other factors claimedresponsible for increased dengue—such asurbanization, population increase, andheightened travel—and that no published

studies have attempted to assess the relativeimportance of these factors in comparison totemperature trends. It is not controversial,he adds, that dengue is highly temperature-sensitive, citing work published by DouglasM. Watts and colleagues in the January1987 issue of The American Journal ofTropical Medicine and Hygiene showing thattemperature-induced variations in how effi-ciently Ae. aegypti transmits the dengue virusmay be “a significant determinant” in theannual cyclic pattern of DHF epidemics inBangkok.

As for whether dengue is very pre-ventable, Hales points to the example ofSingapore, where dengue persists despitethe best efforts of this wealthy country withits well-developed public health infrastruc-ture and vector control. Hales concedes thatit’s too soon to say for sure whether climatechange is promoting the spread of dengue,but that “other things being equal, wewould expect [the disease] to spread withprojected climate change.” If Earth warmsas expected, “then a larger area of the planet’ssurface will be climatically suitable for

dengue,” he says.Global transport has

helped another dengue vec-tor spread to new territory.An article in the September1987 issue of the Journal ofthe American MosquitoControl Association notedthat the Asian tiger mos-quito, Aedes albopictus,spread worldwide throughthe international trade inused tires. Over the past 25years, the relatively cold-hardy Ae. albopictus hasinvaded many U.S. states,and rising average tempera-tures raise the possibilitythat the vector could moveeven further north.

Ae. albopictus is occa-s iona l l y an impor tantdengue vector in rural andsuburban areas in SoutheastAsia, says Philip McCall, amedical entomologist atthe Liverpool School ofTropical Medicine, UnitedKingdom, and it was alsobehind Hawaii’s 2001 out-break of 122 cases on theisland of Maui. But Gublersays i t i s a mistake toassume that dengue epi-demics wil l necessari lyresult from the spread ofAe. albopictus. Althoughthis mosquito has beenshown to be a highly effi-cient carrier in controlledexperiments, it is far less soin real-world situations, heexplains, mainly because itfeeds on both humans andnonhuman animals, and itprefers rural environmentsto urban settings. If Ae.albopictus populations wereto displace Ae. aegypti, then



0.0-0.1 0.1-0.2 0.2-0.3 0.3-0.4 0.4-0.5

0.5-0.6 0.6-0.7 0.7-0.8 0.8-0.9 0.9-1.0

A

B

Scientists recently modeled the estimated baseline population at risk for dengue infection in 1990 (A) andin 2085 (B) using climate data for 1961–1990 and projections for humidity change—a function of climatechange—for 2080–2100. Ranges above indicate percentage of the population at risk: 0–10%, 10–20%, etc.However, many scientists do not agree that climate change will appreciably alter the risk of dengue.

Source: Hales S, et al. 2002. Potential effect of population and climate changes on global distribution ofdengue fever: an empirical model. Lancet 360:830–834.

Will climate change affect the spread of dengue in coming years?

that could actually lead to reduced risk ofdengue transmission, Gubler says.

A Disease of PovertyDengue is a disease of poverty, Hales says.“In the places where it’s really rife, typicallyurban shantytowns, people have got verypoor services,” he explains. “Waste is pilingup in the street. There’s no running water,so people have to collect water in vessels,which then breed mosquitoes. The peoplehave got terrible housing, so they’re not ableto protect themselves from getting bitten.And they’re living in very close proximity.It’s the perfect recipe for a huge epidemic.”

Even if today’s temperate latitudes didbecome more suitable for dengue transmis-sion, Gubler says, most of those regions aremore developed and have good enoughhousing and water supply that dengue epi-demics would remain unlikely. The standardof living in the United States will likely pre-vent any major dengue epidemics. “TheUnited States is not going to have major epi-demics of vector-borne diseases unless weallow our public health system to deterioratecompletely,” Gubler says.

But professor Peter Hotez of The SabinVaccine Institute and George WashingtonUniversity worries about the effect of dengueand other diseases he calls “neglected infec-tions of poverty” on the poorest people inthe United States. “There’s always been thisreservoir of people at risk, and my concern isthat, because they’re poor and voiceless, weignore them,” he says.

Although dengue is endemic in PuertoRico (where it has caused epidemics sincethe 1960s), it is absent from most of thecontinental United States, except in travelersreturning from tropical locales. However,the disease appears occasionally along theU.S.–Mexico border, Hotez says. Along theborder, reported incidence is much higher inthe Mexican states than the U.S. ones, prob-ably because of different living standards—window screens, air conditioning, and effec-tive sanitation may help keep dengue at bayon the U.S. side, Hotez says.

However, a study published in theOctober 2007 issue of Emerging InfectiousDiseases found that dengue incidence wassurprisingly high in the border town ofBrownsville, Texas. The researchers foundevidence of past dengue infection in 40% ofBrownsville residents. People with lowincome, no air conditioning, and poor streetdrainage were most likely to have sufferedinfection.

In a review published 25 June 2008 inPLoS Neglected Tropical Diseases, Hotez esti-mated as many as 200,000 U.S. cases of

dengue fever occur each year, “but the esti-mates are pretty wide-ranging,” he says.There have so far been few reports of DHFin the United States. However, Hotez pointsout that DHF outbreaks have happened asclose as Cuba; therefore, he says, “so there’severy reason to believe that it could happenin the United States.”

Many of the people at risk of dengueinfection in the United States are membersof minority groups, Hotez says—something

that also applies to other infections thatmany people think of as “tropical” disease.Besides dengue, low-income Hispaniccommunities near the Mexican border arealso at risk of Chagas disease, cutaneousleishmaniasis, and cysticercosis, an infectioncaused by ingesting tapeworm eggs, which isnow a leading cause of epilepsy and seizuresin areas around the U.S.–Mexico border.Many of these infections have been aroundfor a while, Hotez says; however, “We’ve just


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Dengue is transmitted by mosquitoes that have become perfectly adapted to the urbanenvironment. Areas where there is poor sanitation and overcrowding (such as Rio deJaneiro, Brazil, above and below) are ripe for epidemics. According to the BrazilianMinistry of Health, Rio was the site of about half the dengue cases in an epidemic thatswept this country in spring 2008.

ignored and neglected them because we tendnot to pay attention to the plight of the poorand underrepresented minorities.”

Hotez suspects that people living inother areas prone to neglected infections—especially the post-Katrina Gulf Coast andelsewhere in the Mississippi River delta—areat some risk of dengue, but few data havebeen collected. “It’s not clear how manycases of dengue infection there are each yearin the United States,” he says. “We’re notdoing aggressive surveillance.”

Curbing Dengue’sExpansion Researchers are coming atdengue from a variety ofangles to try to curb thevirus’s spread. There areno available vaccines orantivirals for dengueinfection, leaving mos-quito control as the onlycurrent method for pre-vention and control.

“Ultimately, we needa vaccine for dengue,”says Harrington. “That’sprobably the only waythat we’re going to be ableto have a s igni f icantimpact.” Dengue vaccinedevelopment has provenchallenging, largely becauseof the four different virusserotypes in circulation.Because DHF usuallyoccurs when an individualalready has immunity against one dengueserotype, researchers fear that vaccines thatfail to provide equal immunity against allfour serotypes may actually predisposepeople to hemorrhagic complications if theyencounter a novel serotype after being vacci-nated. “That has really slowed the develop-ment of the dengue vaccine,” Hotez says.

Currently, researchers at the Korea-basedPediatric Dengue Vaccine Initiative, chairedby Gubler and funded by the Bill &Melinda Gates Foundation, are facilitatingthe development of several different tech-nologies to overcome those obstacles, forexample, by helping some companies withclinical trials, establishing field sites, andworking with developing countries to createthe infrastructure to manage eventual vac-cine distribution.

As part of the Grand Challenges inGlobal Health program, also funded in partby the Gates Foundation, researchers arecreating mosquitoes that are geneticallyincapable of transmitting the dengue virus.

About a dozen scientists worldwide aretackling different facets of the project, saysHarrington, whose laboratory is assessingwhether the transgenic strains are likely tooutcompete Ae. aegypti for resources andmates in the wild. “If you could dreamabout something that could really make animpact, this would be it,” she says.

For now, dengue control still relies heav-ily on controlling the mosquito that trans-mits it. McCall and his colleagues have beenrunning studies in Latin America andSoutheast Asia to judge the effectiveness of

household-based insecticide-treated materials(such as window curtains) and domesticwater container covers as foils to the mos-quito carriers and dengue transmission.Also, scientists from Vietnam and Australiareported in the January 2005 issue of TheAmerican Journal of Tropical Medicine andHygiene that cultivating a natural predatorof Aedes mosquitoes, the tiny crustaceanMesocyclops, in water storage containers vir-tually eliminated Ae. aegypti populations. “Iwas amazed,” McCall says. “I’m often skep-tical about biological control, but inVietnam, when used in combination withclean-up and education campaigns, thisseems to have been spectacularly successful.”

Research continues on all fronts, addingto the collective knowledge about denguetransmission and, in some cases, challeng-ing long-held assumptions. A mathematicalmodel published by Suwich Thammapaloand colleagues in the 12 February 2008issue of Proceedings of the NationalAcademy of Sciences showed that decreasing

dengue transmission may sometimes causean increase in cases of DHF. The model’spredictions were boosted by epidemiologicdata from Thailand that were later pub-lished 16 July 2008 in PLoS NeglectedTropical Diseases. The authors of bothpapers speculate that the effect may arisefrom a brief, transient cross-protection thatpeople experience when infected with oneserotype of dengue. At very high levels ofdengue transmission, people could thenhave immunity to all four serotypes of thevirus. If transmission is reduced moderately,

th i s c ro s s - immuni tywould also be reduced.The results are contro-versial, McCall says, “butmany in the field believeit to be the case.”

Not everyone agrees,however, and Harring-ton summarizes some ofthe concerns about thep a p e r . T h e a u t h o r sbased their conclusionso n t h e r e l a t i o n s h i pbetween dengue infec-tion and transmission asa function of mosquitoabundance as measuredusing the Breteau index,which reflects the num-ber of water containerswith mosquito larvae in100 randomly selectedhouses in a community.But the Breteau index isa poor estimate of mos-

quito abundance, she says, and it rarelyindicates what species i s abundant .Moreover, it does not provide a largeenough sample size to be powerful andmeaningful.

“This type of work is a prime example ofscientists working in isolation,” she says. “Ithighlights the need for cross-collaborativework on models for dengue ecology and epi-demiology where biologically meaningfulmodels can be developed.”

According to Hales, some of the mostpromising solutions may not directlyinvolve mosquito eradication and may havelittle to do with technology. “What people[at risk] need is a decent environment inwhich to live,” he says. “If we had a denguevaccine, most likely those people wouldn’tbe able to afford it anyway. I’m not sayingdon’t look for a vaccine, but that’s probablynot a short-term answer for the problemfor these people.”

Melissa Lee Phillips


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A worker fumigates a house in Old Havana, Cuba, January 2008. Control of mos-quitoes with pesticides is one of the few methods currently available to rein indengue. Systematic habitat destruction also has proved effective in the past.

a child watches as a worker fumigates to prevent …dengue reborn widespread resurgence of a...

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