Dengue fever.doc

7/27/2019 Dengue fever.doc

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Dengue fever (UK /de/ or US /di/), also known as breakbone fever, is an infectious tropical diseasecaused by the dengue virus. Symptoms include fever, headache,muscle andjoint pains, and a characteristic skin

rash that is similar to measles. In a small proportion of cases the disease develops into the life-threatening dengue

hemorrhagic fever, resulting in bleeding, low levels of blood platelets and blood plasma leakage, or into dengueshock syndrome, where dangerously low blood pressure occurs.

Dengue is transmitted by several species ofmosquito within the genusAedes, principallyA. aegypti. The virus hasfour different types; infection with one type usually gives lifelong immunity to that type, but only short-term

immunity to the others. Subsequent infection with a different type increases the risk of severe complications. As

there is no commercially available vaccine, prevention is sought by reducing the habitat and the number of

mosquitoes and limiting exposure to bites.

Treatment of acute dengue is supportive, using either oral or intravenous rehydration for mild or moderate disease,

and intravenous fluids andblood transfusion for more severe cases. The incidence of dengue fever has increased

dramatically since the 1960s, with around 50100 million people infected yearly. Early descriptions of the condition

date from 1779, and its viral cause and the transmission were elucidated in the early 20th century. Dengue has

become a global problem since the Second World War and is endemic in more than 110 countries. Apart from

eliminating the mosquitoes, work is ongoing on a vaccine, as well as medication targeted directly at the virus.

sign and symptoms

Cause

Virology

Main article: Dengue virus

A TEMmicrographshowing dengue virusvirions (the cluster of dark dots near the center)
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Dengue fever virus (DENV) is an RNA virusof the family Flaviviridae; genusFlavivirus. Other members of the

same genus include yellow fever virus, West Nile virus, St. Louis encephalitis virus, Japanese encephalitis virus,

tick-borne encephalitis virus, Kyasanur forest disease virus, and Omsk hemorrhagic fever virus.[12] Most are

transmitted byarthropods(mosquitoes orticks), and are therefore also referred to as arboviruses(arthropod-borne

viruses).[12]

The dengue virus genome (genetic material) contains about 11,000 nucleotide bases, which code for the threedifferent types of protein molecules (C, prM and E) that form the virus particle and seven other types of protein

molecules (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5) that are only found in infected host cells and are required

for replication of the virus.[13][14]There are four strains of the virus, which are called serotypes, and these are referred

to as DENV-1, DENV-2, DENV-3 and DENV-4. [2] The distinctions between the serotypes is based on the their

antigenicity.[15]

Transmission

The mosquitoAedes aegyptifeeding on a human host

Dengue virus is primarily transmitted byAedes mosquitoes, particularlyA. aegypti.[2]

These mosquitoes usually livebetween thelatitudesof 35 North and 35 South below anelevation of 1,000 metres (3,300 ft).[2] They typically bite

during the day, particularly in the early morning and in the evening, [16][17]but they are able to bite and thus spread

infection at any time of day all during the year.[18] OtherAedes species that transmit the disease include A.albopictus,A. polynesiensis andA. scutellaris.[2]Humans are the primaryhostof the virus,[2][12]but it also circulates

in nonhumanprimates.[19] An infection can be acquired via a single bite. [20] A female mosquito that takes a blood

meal from a person infected with dengue fever, during the initial 210 day febrile period, becomes itself infected

with the virus in the cells lining its gut. [21]About 810 days later, the virus spreads to other tissues including the

mosquito'ssalivary glands and is subsequently released into its saliva. The virus seems to have no detrimental effect

on the mosquito, which remains infected for life. Aedes aegypti prefers to lay its eggs in artificial water containers,

to live in close proximity to humans, and to feed on people rather than othervertebrates.[22]

Dengue can also be transmitted via infectedblood products and through organ donation.[23][24] In countries such as

Singapore, where dengue is endemic, the risk is estimated to be between 1.6 and 6 per 10,000 transfusions.[25]

Vertical transmission (from mother to child) during pregnancy or at birth has been reported. [26] Other person-to-

person modes of transmission have also been reported, but are very unusual.[9] The genetic variation in dengue

viruses is region specific, suggestive that establishment into new territories is relatively infrequent, despite dengue

emerging in new regions in recent decades.[7]

Predisposition

Severe disease is more common in babies and young children, and in contrast to many other infections it is more

common in children that are relatively well nourished. [5] Otherrisk factors for severe disease include female sex,

highbody mass index,[7]andviral load.[27] While each serotype can cause the full spectrum of disease, [13]virus strain

is a risk factor.[7]Infection with one serotype is thought to produce lifelong immunity to that type, but only short

term protection against the other three.[2][9] The risk of severe disease from secondary infection increases if someone

previously exposed to serotype DENV-1 contracts serotype DENV-2 or DENV-3, or if someone previously exposedto DENV-3 acquires DENV-2.[14] Dengue can be life-threatening in people with chronic diseasessuch asdiabetes

and asthma.[14]

Polymorphisms (normal variations) in particular genes have been linked with an increased risk of severe dengue

complications. Examples include the genes coding for the proteins known as TNF, mannan-binding lectin,[1]

CTLA4, TGF,[13] DC-SIGN, PLCE1, and particular forms of human leukocyte antigen from gene variations of

HLA-B.[7][14]A common genetic abnormality in Africans, known as glucose-6-phosphate dehydrogenase deficiency,
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appears to increase the risk.[27] Polymorphisms in the genes for the vitamin D receptor and FcR seem to offer

protection against severe disease in secondary dengue infection.[14]

Mechanism

When a mosquito carrying dengue virus bites a person, the virus enters the skin together with the mosquito's saliva.

It binds to and enterswhite blood cells, and reproduces inside the cells while they move throughout the body. Thewhite blood cells respond by producing a number of signaling proteins, such as cytokinesand interferons, which are

responsible for many of the symptoms, such as the fever, the flu-like symptoms and the severe pains. In severe

infection, the virus production inside the body is greatly increased, and many more organs (such as the liverand the

bone marrow) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body

cavities due to capillary permeability. As a result, less blood circulates in the blood vessels, and the blood pressure

becomes so low that it cannot supply sufficient blood to vital organs. Furthermore, dysfunction of the bone marrowdue to infection of thestromal cells leads to reduced numbers of platelets, which are necessary for effective blood

clotting; this increases the risk of bleeding, the other major complication of dengue fever. [27]

Viral replication

Once inside the skin, dengue virus binds to Langerhans cells (a population of dendritic cells in the skin that

identifies pathogens).[27] The virusenters the cellsthrough binding between viral proteins and membrane proteinsonthe Langerhans cell, specifically the C-type lectins called DC-SIGN,mannose receptorand CLEC5A.[13] DC-SIGN,a non-specific receptor for foreign material on dendritic cells, seems to be the main point of entry. [14] The dendritic

cell moves to the nearestlymph node. Meanwhile, the virus genome is translated in membrane-bound vesicles on the

cell'sendoplasmic reticulum, where the cell's protein synthesis apparatus produces new viral proteins that replicate

the viral RNA and begin to form viral particles. Immature virus particles are transported to the Golgi apparatus, the

part of the cell where some of the proteins receive necessary sugar chains (glycoproteins). The now mature new

viruses bud on the surface of the infected cell and are released by exocytosis. They are then able to enter other white

blood cells, such asmonocytesand macrophages.[13]

The initial reaction of infected cells is to produce interferon, a cytokinethat raises a number of defenses against viral

infection through theinnate immune system by augmenting the production of a large group of proteins mediated by

the JAK-STAT pathway. Some serotypes of dengue virus appear to have mechanisms to slow down this process.

Interferon also activates the adaptive immune system, which leads to the generation of antibodies against the virusas well as T cells that directly attack any cell infected with the virus.[13]Various antibodies are generated; some bind

closely to the viral proteins and target them forphagocytosis (ingestion byspecialized cells and destruction), but

some bind the virus less well and appear instead to deliver the virus into a part of the phagocytes where it is not

destroyed but is able to replicate further.[13]

Severe disease

It is not entirely clear why secondary infection with a different strain of dengue virus places people at risk of dengue

hemorrhagic fever and dengue shock syndrome. The most widely accepted hypothesis is that of antibody-dependent

enhancement (ADE). The exact mechanism behind ADE is unclear. It may be caused by poor binding of non-

neutralizing antibodies and delivery into the wrong compartment of white blood cells that have ingested the virus for

destruction.[13][14] There is a suspicion that ADE is not the only mechanism underlying severe dengue-related

complications,[1]and various lines of research have implied a role for T cells and soluble factors such as cytokinesand the complement system.[27]

Severe disease is marked by the problems of capillary permeability (an allowance of fluid and protein normally

contained within blood to pass) and disorderedblood clotting.[6][7] These changes appear associated with a disordered

state of the endothelial glycocalyx, which acts as amolecular filterof blood components.[7] Leaky capillaries (and

the critical phase) are thought to be caused by an immune system response. [7] Other processes of interest include

infected cells that become necroticwhich affect both coagulation and fibrinolysis (the opposing systems of bloodclotting and clot degradation)and low platelets in the blood, also a factor in normal clotting.[27]
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Diagnosis

The diagnosis of dengue is typically made clinically, on the basis of reported symptoms and physical examination;

this applies especially in endemic areas. [1]However, early disease can be difficult to differentiate from other viral

infections.[5] A probable diagnosis is based on the findings of fever plus two of the following: nauseaand vomiting,

rash, generalized pains, low white blood cell count, positive tourniquet test, or any warning sign (see table) in

someone who lives in an endemicarea.[28] Warning signs typically occur before the onset of severe dengue. [8] The

tourniquet test, which is particularly useful in settings where no laboratory investigations are readily available,involves the application of a blood pressure cuff at between the diastolic and systolic pressure for five minutes,

followed by the counting of anypetechialhemorrhages; a higher number makes a diagnosis of dengue more likelywith the cut off being more than 10 to 20 per 2.5 cm2 (1 inch2).[8][29][30]

The diagnosis should be considered in anyone who develops a fever within two weeks of being in the tropics or

subtropics.[7] It can be difficult to distinguish dengue fever and chikungunya, a similar viral infection that shares

many symptoms and occurs in similar parts of the world to dengue. [9]Often, investigations are performed to exclude

other conditions that cause similar symptoms, such as malaria,leptospirosis,viral hemorrhagic fever,typhoid fever,

meningococcal disease, measles, andinfluenza.[5][31]

The earliest change detectable on laboratory investigations is a low white blood cell count, which may then be

followed bylow plateletsand metabolic acidosis.[5]A moderately elevated level ofaminotransferase (ASTand ALT)

from the liver is commonly associated with low platelets and white blood cells. [7] In severe disease, plasma leakage

results in hemoconcentration (as indicated by a rising hematocrit) and hypoalbuminemia.[5] Pleural effusions or

ascites can be detected by physical examination when large, [5] but the demonstration of fluid on ultrasound mayassist in the early identification of dengue shock syndrome.[1][5] The use of ultrasound is limited by lack of

availability in many settings.[1] Dengue shock syndrome is present ifpulse pressure drops to 20 mm Hg along with

peripheral vascular collapse.[7] Peripheral vascular collapse is determined in children via delayed capillary refill,rapid heart rate, or cold extremities.

Laboratory tests

When laboratory tests for dengue fever become positive where day zero is the start of symptoms, 1st refers to in

those with a primary infection, and 2nd refers to in those with a secondary infection.[7]

The diagnosis of dengue fever may be confirmed by microbiological laboratory testing. [28][34] This can be done byvirus isolation in cell cultures,nucleic acid detection byPCR, viralantigen detection (such as forNS1) or specific

antibodies (serology).[14][31]Virus isolation and nucleic acid detection are more accurate than antigen detection, but

these tests are not widely available due to their greater cost .[31] Detection of NS1 during the febrile phase of a

primary infection may be greater than 90% however is only 6080% in subsequent infections.[7]All tests may be

negative in the early stages of the disease. [5][14]PCR and viral antigen detection are more accurate in the first seven

days.[7]In 2012 a PCR test was introduced that can run on equipment used to diagnose influenza; this is likely to

improve access to PCR-based diagnosis.[35]
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These laboratory tests are only of diagnostic value during the acute phase of the illness with the exception of

serology. Tests for dengue virus-specific antibodies, types IgG andIgM, can be useful in confirming a diagnosis in

the later stages of the infection. Both IgG and IgM are produced after 57 days. The highest levels (titres) of IgM are

detected following a primary infection, but IgM is also produced in reinfection. IgM becomes undetectable 3090

days after a primary infection, but earlier following re-infections. IgG, by contrast, remains detectable for over 60years and, in the absence of symptoms, is a useful indicator of past infection. After a primary infection IgG reaches

peak levels in the blood after 1421 days. In subsequent re-infections, levels peak earlier and the titres are usuallyhigher. Both IgG and IgM provide protective immunity to the infecting serotype of the virus. [9][14][36]The laboratory

test for IgG and IgM antibodies can cross-react with other flaviviruses and may result in a false positive after recent

infections or vaccinations with yellow fever virus or Japanese encephalitis. [7] The detection of IgG alone is not

considered diagnostic unless blood samples are collected 14 days apart and a greater than fourfold increase in levels

of specific IgG is detected. In a person with symptoms, the detection of IgM is considered diagnostic.[36]

Prevention

A 1920s photograph of efforts to disperse standing water and thus decrease mosquito populations

There are no approved vaccines for the dengue virus.[1] Prevention thus depends on control of and protection from

the bites of the mosquito that transmits it.[16][37] The World Health Organization recommends an Integrated VectorControl program consisting of five elements:[16]

1. Advocacy, social mobilization and legislation to ensure that public health bodies and communities are

strengthened;

2. Collaboration between the health and other sectors (public and private);

3. An integrated approach to disease control to maximize use of resources;

4. Evidence-based decision making to ensure any interventions are targeted appropriately; and

5. Capacity-building to ensure an adequate response to the local situation.

The primary method of controllingA. aegypti is by eliminating its habitats.[16]This is done by emptying containers

of water or by adding insecticides or biological control agents to these areas,[16] although spraying with

organophosphate orpyrethroid insecticides is not thought to be effective. [3] Reducing open collections of water

through environmental modification is the preferred method of control, given the concerns of negative health effect

from insecticides and greater logistical difficulties with control agents. [16] People can prevent mosquito bites by

wearing clothing that fully covers the skin, using mosquito nettingwhile resting, and/or the application of insect

repellent (DEETbeing the most effective).[20]

Management

There are no specific antiviral drugsfor dengue, however maintaining proper fluid balance is important.[7]

Treatmentdepends on the symptoms, varying from oral rehydration therapy at home with close follow-up, to hospital

admission with administration ofintravenous fluidsand/orblood transfusion.[38]A decision for hospital admission is

typically based on the presence of the "warning signs" listed in the table above, especially in those with preexisting

health conditions.[5]

Intravenous hydration is usually only needed for one or two days. [38] The rate of fluid administration is titrated to a

urinary output of 0.51 mL/kg/h, stable vital signs and normalization of hematocrit.[5] Invasive medical procedures

such asnasogastric intubation, intramuscular injections and arterial punctures are avoided, in view of the bleeding
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risk.[5]Paracetamol (acetaminophen) is used for fever and discomfort while NSAIDs such as ibuprofen and aspirin

are avoided as they might aggravate the risk of bleeding.[38] Blood transfusion is initiated early in patients presenting

with unstable vital signs in the face of a decreasing hematocrit, rather than waiting for the hemoglobin concentration

to decrease to some predetermined "transfusion trigger" level. [39] Packed red blood cells or whole blood are

recommended, whileplatelets and fresh frozen plasma are usually not.[39]

During the recovery phase intravenous fluids are discontinued to prevent a state offluid overload.[5]

If fluid overloadoccurs and vital signs are stable, stopping further fluid may be all that is needed. [39] If a person is outside of the

critical phase, a loop diuretic such as furosemide may be used to eliminate excess fluid from the circulation.[39]

Epidemiology

See also:Dengue fever outbreaks

Dengue distribution in 2006.

Epidemic dengue andA. aegypti

A. aegypti, without epidemic dengue

Most people with dengue recover without any ongoing problems.[28] The mortality is 15% without treatment,[5] andless than 1% with adequate treatment;[28] however severe disease carries a mortality of 26%.[5]Dengue isendemicin

more than 110 countries.[5] It infects 50 to 390 million people worldwide a year, leading to half a million

hospitalizations,[1][40] and approximately 25,000 deaths.[6] For the decade of the 2000s, 12 countries in Southeast Asia

were estimated to have about 3,000,000 infections and 6,000 deaths annually.[41]

The most common viral disease transmitted by arthropods, [13] dengue has a disease burden estimated to be 1600

disability-adjusted life years per million population, which is similar to tuberculosis, another childhood and tropicaldisease.[14] As a tropical disease dengue was deemed in 1998 second in importance to malaria, [5] though the World

Health Organization counts dengue as one of seventeenneglected tropical diseases.[42]

The incidence of dengue increased 30 fold between 1960 and 2010.[43] This increase is believed to be due to a

combination of urbanization, population growth, increased international travel, and global warming.[1] The

geographical distribution is around the equator with 70% of the total 2.5 billion people living in endemic areas fromAsia and the Pacific.[43] In the United States, the rate of dengue infection among those who return from an endemic

area with a fever is 38%,[20] and it is the second most common infection after malaria to be diagnosed in this group.[9]

Like most arboviruses, dengue virus is maintained in nature in cycles that involve preferred blood-sucking vectors

and vertebrate hosts.[44] The viruses are maintained in the forests of Southeast Asia and Africa by transmission from

femaleAedes mosquitoesof species other thanA. aegyptito her offspring and to lower primates.[44]In towns and

cities, the virus is primarily transmitted by the highly domesticated A. aegypti. In rural settings the virus is

transmitted to humans byA. aegypti and other species ofAedes such asA. albopictus.[44] Both these species have had

expanding ranges in the second half of the 20th century.[7] In all settings the infected lower primates or humans

greatly increase the number of circulating dengue viruses, in a process called amplification. [44]Infections are most

commonly acquired in the urban environment.[45] In recent decades, the expansion of villages, towns and cities in

endemic areas, and the increased mobility of people has increased the number of epidemics and circulating viruses.Dengue fever, which was once confined to Southeast Asia, has now spread to Southern China, countries in the

Pacific Ocean and America,[45] and might pose a threat to Europe.[3]

History

The first record of a case of probable dengue fever is in a Chinese medical encyclopedia from the Jin Dynasty (265

420 AD) which referred to a "water poison" associated with flying insects. [46][47] The primary vector, A. aegypti,spread out of Africa in the 15th to 19th centuries due in part to increased globalization secondary to the slave trade.
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[7] There have been descriptions of epidemics in the 17th century, but the most plausible early reports of dengue

epidemics are from 1779 and 1780, when an epidemic swept across Asia, Africa and North America. [47] From that

time until 1940, epidemics were infrequent.[47]

In 1906, transmission by the Aedes mosquitoes was confirmed, and in 1907 dengue was the second disease (after

yellow fever) that was shown to be caused by a virus. [48]Further investigations by John Burton Clelandand Joseph

Franklin Silercompleted the basic understanding of dengue transmission.[48]

The marked spread of dengue during and after theSecond World Warhas been attributed to ecologic disruption. The

same trends also led to the spread of different serotypes of the disease to new areas, and to the emergence of dengue

hemorrhagic fever. This severe form of the disease was first reported in the Philippinesin 1953; by the 1970s, it had

become a major cause ofchild mortalityand had emerged in the Pacific and the Americas. [47]Dengue hemorrhagic

fever and dengue shock syndrome were first noted in Central and South America in 1981, as DENV-2 wascontracted by people who had previously been infected with DENV-1 several years earlier.[12]

Etymology

The origins of the Spanish word dengue are not certain, but it is possibly derived from dinga in theSwahili phrase

Ka-dinga pepo, which describes the disease as being caused by an evil spirit.[46] Slaves in the West Indies having

contracted dengue were said to have the posture and gait of a dandy, and the disease was known as "dandy fever".[49][50]

The term "breakbone fever" was applied by physician and United States Founding FatherBenjamin Rush, in a 1789

report of the 1780 epidemic in Philadelphia. In the report title he uses the more formal term "bilious remitting

fever".[51] The term dengue fever came into general use only after 1828.[50] Other historical terms include "breakheart

fever" and "la dengue".[50]Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine",

"Thai", or "Singapore hemorrhagic fever".[50]

Research

Public health officers releasingP. reticulatafry into an artificial lake in theLago Nortedistrict ofBraslia, Brazil, as

part of a vector control effort.

Research efforts to prevent and treat dengue include various means of vector control, [52] vaccine development, and

antiviral drugs.[37]

With regards to vector control, a number of novel methods have been used to reduce mosquito numbers with somesuccess including the placement of the guppy (Poecilia reticulata) orcopepodsin standing water to eat the mosquito

larvae.[52] Attempts are ongoing to infect the mosquito population with bacteria of the Wolbachia genus, which

makes the mosquitoes partially resistant to dengue virus. [7][53]There are also trials with genetically modified male

A. aegypti that after release into the wild mate with females, and their offspring unable to fly.[54]

There are ongoing programs working on a dengue vaccine to cover all four serotypes.[37]One of the concerns is that

a vaccine could increase the risk of severe disease through antibody-dependent enhancement (ADE).[55]

The idealvaccine is safe, effective after one or two injections, covers all serotypes, does not contribute to ADE, is easily

transported and stored, and is both affordable and cost-effective. [55] As of 2012, a number of vaccines wereundergoing testing.[17][55]The most developed is based on a weakened combination of the yellow fever virus and each

of the four dengue serotypes.[17][56] It is hoped that the first products will be commercially available by 2015.[37]

Apart from attempts to control the spread of the Aedes mosquito and work to develop a vaccine against dengue,

there are ongoing efforts to develop antiviral drugs that would be used to treat attacks of dengue fever and prevent

severe complications.[57][58] Discovery of the structure of the viral proteins may aid the development of effective

drugs.[58] There are several plausible targets. The first approach is inhibition of the viral RNA-dependent RNA
http://en.wikipedia.org/wiki/Dengue_fever#cite_note-NEJM2012-7http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Gubler98-47http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Gubler98-47http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Henchal-48http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Henchal-48http://en.wikipedia.org/wiki/John_Burton_Clelandhttp://en.wikipedia.org/wiki/John_Burton_Clelandhttp://en.wikipedia.org/wiki/Joseph_Franklin_Silerhttp://en.wikipedia.org/wiki/Joseph_Franklin_Silerhttp://en.wikipedia.org/wiki/Joseph_Franklin_Silerhttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-Henchal-48http://en.wikipedia.org/wiki/World_War_IIhttp://en.wikipedia.org/wiki/World_War_IIhttp://en.wikipedia.org/wiki/Philippineshttp://en.wikipedia.org/wiki/Philippineshttp://en.wikipedia.org/wiki/Child_mortalityhttp://en.wikipedia.org/wiki/Child_mortalityhttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-Gubler98-47http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Gubler98-47http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Gould-12http://en.wikipedia.org/wiki/Swahili_languagehttp://en.wikipedia.org/wiki/Swahili_languagehttp://en.wikipedia.org/wiki/Evil_spirithttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-EID06-46http://en.wikipedia.org/wiki/Dengue_fever#cite_note-EID06-46http://en.wikipedia.org/wiki/Dandyhttp://en.wikipedia.org/wiki/Dandyhttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-49http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Hal08-50http://en.wikipedia.org/wiki/Founding_Fathers_of_the_United_Stateshttp://en.wikipedia.org/wiki/Benjamin_Rushhttp://en.wikipedia.org/wiki/Philadelphiahttp://en.wikipedia.org/wiki/Philadelphiahttp://en.wikipedia.org/wiki/Philadelphiahttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-Barrett09-51http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Hal08-50http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Hal08-50http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Hal08-50http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Hal08-50http://en.wikipedia.org/wiki/Spawn_(biology)http://en.wikipedia.org/wiki/Spawn_(biology)http://en.wikipedia.org/wiki/Artificial_lakehttp://en.wikipedia.org/wiki/Lago_Nortehttp://en.wikipedia.org/wiki/Lago_Nortehttp://en.wikipedia.org/wiki/Lago_Nortehttp://en.wikipedia.org/wiki/Bras%C3%ADliahttp://en.wikipedia.org/wiki/Bras%C3%ADliahttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp71-52http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp137-37http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp137-37http://en.wikipedia.org/wiki/Poecilia_reticulatahttp://en.wikipedia.org/wiki/Copepodshttp://en.wikipedia.org/wiki/Copepodshttp://en.wikipedia.org/wiki/Copepodshttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp71-52http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp71-52http://en.wikipedia.org/wiki/Wolbachiahttp://en.wikipedia.org/wiki/Wolbachiahttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-NEJM2012-7http://en.wikipedia.org/wiki/Dengue_fever#cite_note-53http://en.wikipedia.org/wiki/Dengue_fever#cite_note-53http://en.wikipedia.org/wiki/Dengue_fever#cite_note-54http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp137-37http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp137-37http://en.wikipedia.org/wiki/Antibody-dependent_enhancementhttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-Webster-55http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Webster-55http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHO2012-17http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHO2012-17http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Webster-55http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Webster-55http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHO2012-17http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHO2012-17http://en.wikipedia.org/wiki/Dengue_fever#cite_note-56http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp137-37http://en.wikipedia.org/wiki/Antiviral_drughttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-Sampath-57http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Noble-58http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Noble-58http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Noble-58http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Noble-58http://en.wikipedia.org/wiki/RNA-dependent_RNA_polymerasehttp://en.wikipedia.org/wiki/File:Equipes_usam_t%C3%A9cnicas_de_combate_%C3%A0_dengue_em_Bras%C3%ADlia.jpghttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-NEJM2012-7http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Gubler98-47http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Gubler98-47http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Henchal-48http://en.wikipedia.org/wiki/John_Burton_Clelandhttp://en.wikipedia.org/wiki/Joseph_Franklin_Silerhttp://en.wikipedia.org/wiki/Joseph_Franklin_Silerhttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-Henchal-48http://en.wikipedia.org/wiki/World_War_IIhttp://en.wikipedia.org/wiki/Philippineshttp://en.wikipedia.org/wiki/Child_mortalityhttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-Gubler98-47http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Gould-12http://en.wikipedia.org/wiki/Swahili_languagehttp://en.wikipedia.org/wiki/Evil_spirithttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-EID06-46http://en.wikipedia.org/wiki/Dandyhttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-49http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Hal08-50http://en.wikipedia.org/wiki/Founding_Fathers_of_the_United_Stateshttp://en.wikipedia.org/wiki/Benjamin_Rushhttp://en.wikipedia.org/wiki/Philadelphiahttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-Barrett09-51http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Hal08-50http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Hal08-50http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Hal08-50http://en.wikipedia.org/wiki/Spawn_(biology)http://en.wikipedia.org/wiki/Artificial_lakehttp://en.wikipedia.org/wiki/Lago_Nortehttp://en.wikipedia.org/wiki/Bras%C3%ADliahttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp71-52http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp137-37http://en.wikipedia.org/wiki/Poecilia_reticulatahttp://en.wikipedia.org/wiki/Copepodshttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp71-52http://en.wikipedia.org/wiki/Wolbachiahttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-NEJM2012-7http://en.wikipedia.org/wiki/Dengue_fever#cite_note-53http://en.wikipedia.org/wiki/Dengue_fever#cite_note-54http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp137-37http://en.wikipedia.org/wiki/Antibody-dependent_enhancementhttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-Webster-55http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Webster-55http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHO2012-17http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Webster-55http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHO2012-17http://en.wikipedia.org/wiki/Dengue_fever#cite_note-56http://en.wikipedia.org/wiki/Dengue_fever#cite_note-WHOp137-37http://en.wikipedia.org/wiki/Antiviral_drughttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-Sampath-57http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Noble-58http://en.wikipedia.org/wiki/Dengue_fever#cite_note-Noble-58http://en.wikipedia.org/wiki/RNA-dependent_RNA_polymerase


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polymerase (coded by NS5), which copies the viral genetic material, with nucleoside analogs. Secondly, it may be

possible to develop specificinhibitors of the viralprotease (coded by NS3), which splices viral proteins.[59]Finally, it

may be possible to develop entry inhibitors, which stop the virus entering cells, or inhibitors of the 5 capping

process, which is required for viral replication.[57]
http://en.wikipedia.org/wiki/RNA-dependent_RNA_polymerasehttp://en.wikipedia.org/wiki/Nucleoside_analoghttp://en.wikipedia.org/wiki/Protease_inhibitor_(pharmacology)http://en.wikipedia.org/wiki/Protease_inhibitor_(pharmacology)http://en.wikipedia.org/wiki/Proteasehttp://en.wikipedia.org/wiki/Proteasehttp://en.wikipedia.org/wiki/Protein_splicinghttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-pmid19519486-59http://en.wikipedia.org/wiki/Dengue_fever#cite_note-pmid19519486-59http://en.wikipedia.org/wiki/Entry_inhibitorhttp://en.wikipedia.org/wiki/Entry_inhibitorhttp://en.wikipedia.org/wiki/Five_prime_caphttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-Sampath-57http://en.wikipedia.org/wiki/RNA-dependent_RNA_polymerasehttp://en.wikipedia.org/wiki/Nucleoside_analoghttp://en.wikipedia.org/wiki/Protease_inhibitor_(pharmacology)http://en.wikipedia.org/wiki/Proteasehttp://en.wikipedia.org/wiki/Protein_splicinghttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-pmid19519486-59http://en.wikipedia.org/wiki/Entry_inhibitorhttp://en.wikipedia.org/wiki/Five_prime_caphttp://en.wikipedia.org/wiki/Dengue_fever#cite_note-Sampath-57

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