HEPATITIS VIRUSES




 
 
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Logo image © Jeffrey Nelson, Rush University, Chicago, Illinois  and The MicrobeLibrary
I am grateful to Peniel Dimberu (Yale University) for corrections to this page
 Figure 1A
Hepatitis A virus
CDC		Several diseases of the liver, collectively known as hepatitis, are caused by viruses. The viruses involved, five of which have been reasonably well characterized, come from a wide range of virus families. Hepatitis A virus is a picornavirus, a small single strand RNA virus; hepatitis B virus belongs to the hepadnavirus family of double stranded DNA viruses; hepatitis C virus is a flavivirus, a single stand RNA virus; hepatitis E, also an RNA virus, is similar to a calicivirus. Hepatitis D which is also known as Delta agent is a circular RNA that is more similar to a plant a viroid than a complete virus. For a summary of the hepatitis viruses, see Table1.
 
 Figure 1B
An electron micrograph of the Hepatitis A virus (HAV)
 CDC - Betty Partin		HEPATITIS A VIRUSThis picornavirus (figure 1) is the causative agent of infectious hepatitis. Picornaviruses have a single strand, 3’-polyadenylated, positive sense RNA genome surrounded by a naked (unenveloped) icosahedral capsid that is around 28 nm in diameter (figure 2). At the 5’ end of the RNA strand is a viral protein called VPg. There is only one serotype of HAV.
 
 Figure 2
Hepatitis A virus - a picornavirus
Replication
The virus binds to a receptor that is found on the surface of hepatocytes and a few other cells. HAV cellular receptor 1 (havcr-1) has an ectodomain that contains an N-terminal cysteine-rich immunoglobulin-like region, followed by a mucin-like region that extends the immunoglobulin-like region well above the cell surface. The immunoglobulin-like region is required for binding of HAV. The virus spends its entire life in the cytoplasm where it replicates using a virus-encoded RNA-dependent RNA polymerase. For further information on picornavirus replication see Virology Section Chapter Four.
 Figure 3A
Transmission electron micrograph of hepatitis B virions, also known as Dane particles
CDC/Dr. Erskine Palmer Figure 3B
Hepatitis B virus © Dr Linda Stannard, University of Cape Town, South Africa. Used with permission
 Figure 3C
Hepatitis B virus 
CDC		HEPATITIS B VIRUSHuman hepatitis B virus (figure 3) is the prototype virus of the hepadnavirus family and causes serum hepatitis. HBV has a diameter of about 40nm. It infects humans and chimpanzees but there are closely related members of this family that infect other mammals and birds. HBV is a DNA virus and is enveloped. The DNA is only partly double stranded and forms a circle of around 3,200 bases. Although surrounded by a host cell-derived envelope, HBV is remarkably stable to organic solvents. It is also heat- and pH-resistant. The genome is associated with the P (polymerase) protein and this complex is, in turn, surrounded by the core antigens (HBcAg and HBeAg). These two proteins have most of their sequence in common and most of the HBeAg is secreted since it is processed differently from the HBcAg and thus not assembled into progeny virus. Embedded in the surface lipid bilayer is the surface antigen (HBsAg). The HBsAg (Australia antigen) is made up of three glycoproteins that are encoded by the same gene. The proteins are translated in the same reading frame but start at a different AUG start codon; thus, all have the same C-terminus. The largest protein is the L protein (42kd) and contained within this is the M glycoprotein. The S glycoprotein (27kD) is contained within the M protein. The HBsAg protein is also secreted into the patient’s serum where it can be seen as spherical (mostly self-associated S protein) or filamentous particles (also mostly S protein but with some L and M). The former are smaller than the true virus but the filaments can be quite large (several hundred nanometers). This large amount of free HBsAg accounts for the inability to detect antibodies against the protein early during infection (the so-called "window" between the presence HBsAg (indicative of the presence of virus) and the presence of anti-HBsAg).
The glycoproteins on the virus surface contain antigenic determinants that are group specific and type specific. Using these determinants, epidemiologists identify eight subtypes of HBV. HBV virions are also known as Dane particles.
 Figure 3D Hepatitis B virus. Dane particle and incomplete particles that are found in patient's serum Figure 3E
Hepatitis B virus structure © Dr Linda Stannard, University of Cape Town, South Africa. Used with permission
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Figure 4A
Hepatitis B replication


 Figure 4B
Genome replication in retroviruses

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Figure 4C
Genome replication in hepadnaviruses
Replication
HBV has a very curious way of replicating itself since (figure 4A), although it is a DNA virus, it uses a RNA proviral intermediate that has to be copied back to DNA. The copying of RNA to DNA is not a normal function of an uninfected cell but is found in retroviruses that also have an RNA genome and a DNA intermediate that gets integrated into host cell chromosomes. For the purpose of copying RNA to DNA, retroviruses and HBV have a virally-encoded DNA polymerase (P) called reverse transcriptase.After the HBV has attached to the cell surface receptor (which has yet to be identified but may be a member of the ovalbumin family of serine protease inhibitors), the viral membrane fuses with the cell membrane releasing the core into the cytoplasm. The core proteins dissociate from the partially double stranded DNA. DNA polymerase now completes the DNA so that it is completely double stranded. This is done by the virally-encoded polymerase in the cytoplasm that is one of the core proteins (whereas the cell’s DNA polymerase is in the nucleus). The double stranded DNA enters the nucleus and the ends are ligated by host enzymes so that the virus is in the form of a circular episome. The viral DNA associates with host nuclear histones and is transcribed by cellular RNA polymerase II into mRNAs. In contrast to the situation with retroviruses, however, the DNA form of HBV is usually not integrated into cellular DNA; rather it is found as an independent episome. This is because, unlike retroviruses, hepadnaviruses have no integrase activity. However, integrated parts of the HBV genome are found in the chromosomes of many hepatocellular carcinoma patients.
Four mRNAs are made from the HBV genome. The host cell RNA polymerase interacts with four promoters but transcription always ceases at the same polyadenylation site so that the overlapping mRNAs have a common 3’ terminus. One of these mRNAs is slightly longer than the DNA sequence because of the polyadenylation at one end and a repeated region. This is the full length c-RNA that will be the template for the genome. The full length messenger RNA codes for the polymerase and core HBcAg and HBeAg proteins. The latter are very similar because they are translated in the same reading frame from two different start codons. Two smaller mRNAs (2.4 and 2.1 bases) which overlap code for the surface glycoproteins. There is also a small mRNA of 700 bases that codes for a protein that is a protein kinase and is a transactivator of transcription.
In the cytoplasm, the full-length (3,500 base) positive strand c-RNA is encapsidated by core proteins. Inside the core, the RNA is transcribed to minus strand DNA by the same DNA polymerase (reverse transcriptase) that completed the double stranded DNA  and, at the same time, the RNA is degraded by a ribonuclease H that is also part of the reverse transcriptase. Unlike the reverse transcriptase of the retroviruses, the HBV reverse transcription reaction does not require a tRNA primer. Rather, the polymerase itself acts as a primer and remains covalently attached to the 5’ end of the negative strand DNA. A host cell chaperone protein, heat shock protein 90, is also necessary. The chaperone associates with the reverse transcriptase allowing it to fold into an active conformation.
The virus now buds through the endoplasmic reticulum and/or Golgi Body membranes (or perhaps a novel pre-Golgi compartment) of the host cell from which it acquires HBsAg. At this stage or later, the minus stand of DNA is partly transcribed into a plus strand. When the viral DNA polymerase is used to transcribe RNA to DNA, it is acting as a reverse transcriptase similar to that found in retroviruses; in fact, HBV DNA polymerase and retroviral reverse transcriptase are very similar, and may have evolved from a common ancestor.
Virus particles that contain RNA or DNA at various stages of replication can be found in the bloodstream suggesting that nucleic acid replication is not tightly controlled with the passage out of the cell. In addition, empty envelopes containing the envelope proteins embedded in a lipid bilayer are continuously being shed.

RNA polymerase problemThere is a distinct problem posed by using host cell RNA polymerase II to transcribe a DNA viral genome to an RNA form (See section on retroviruses). The normal function of RNA polymerase II is to transcribe a gene into messenger RNA for subsequent translation into protein. In the mRNA, all that is required is the information to make the protein. In the DNA gene, additional information is present that is needed to make the RNA. This extra information (that is not transcribed into RNA) includes the promoter (the site at which the RNA polymerase binds), the enhancers that are up- and down- stream of the region transcribed to mRNA and the polyadenylation site. Thus, a messenger RNA is smaller than the DNA gene, even if there are no introns.

Retroviruses overcome the loss of promoter/enhancer information as a result of using RNA polymerase II transcription by carrying internal copies of the promoter and enhance regions (these are the U3 and U5 sequences respectively). They duplicate their internal U3 promoter sequence and transpose it to the opposite end when the DNA is transcribed from RNA. Similarly, the enhancers and other 3’ information are stored internally (as U5) and transposed to the other end. These events give rise to the long terminal repeats (LTRs) that are only found in the DNA form of the virus. When the RNA polymerase recognizes the promoter in the U3 region, it finds the transcription initiation site at the border between the U3 and R and starts transcribing at the beginning of the R region. This leads to a faithful copy of the original RNA as the terminal U3 and U5 are lost (figure 4B).

The same problem occurs in hepadnaviruses which also have a DNA form of their genome that is copied to RNA by host cell RNA polymerase II before copying the RNA back to DNA using reverse transcriptase. However, the mechanism is different; in this case, the DNA form of the virus is smaller than the RNA form, quite the opposite of what occurs in the retroviruses.

The hepadnaviruses are small DNA viruses and, in contrast to the retroviruses, it is the DNA that is packaged into the viral particle. This DNA is copied to RNA in the infected cell by RNA polymerase II and the resulting RNA is copied back to DNA by reverse transcriptase in the maturing virus particle.

In the viral particle, the DNA is only partially double stranded. The negative strand is complete, though not ligated into a circle. There are free 5’ (with an attached reverse transcriptase protein molecule) and 3’ ends. The DNA is in the form of a relaxed circle because it is hybridized to a partial copy of the positive strand. The DNA contains two direct repeats (DR1 and DR2). DR1 is close to the 5’ end of the negative strand and DR2 is close to the 5’ end of the partial positive strand.

On entering the nucleus, the negative strand is ligated to form a covalently closed circle. This is then copied by host RNA polymerase II. The polymerase starts about 6 bases to the left (in figure 4Ci-2) of the DR1 and proceeds (clockwise in figure 4Ci-2) around the circle past both the initiation site and the DR1 and stops at the termination/poly A site (light blue) that is a little further downstream. The RNA becomes polyadenylated. The RNA copy is therefore larger than the covalently closed circular DNA (compare the situation in retroviruses) because the DR1 region has been duplicated and poly A has been added.

This RNA moves to the cytoplasm where encapsidation by viral proteins occurs. There is an encapsidation signal at the 5’ end of the RNA and thus only one RNA molecule is found in each virion (compare the situation in retroviruses). Now, in the virus particle itself, the RNA is copied to DNA using reverse transcriptase. All DNA polymerases need a primer and in the case of the retroviruses this is a host cell tRNA that is packed in the virion. In the hepadnaviruses, the polymerase is packaged in the virion as it is in the retroviruses, though there are fewer polymerase proteins per virus particle in the hepadnaviruses. The reverse transcriptase is itself the primer for the synthesis of the negative DNA strand and it remains attached to the 5’ end of the DNA via a tyrosine residue.

The DNA initiates on a hydroxyl group of the tyrosine using, as a template, a region near the 5’ end of the RNA (fig 4Ci-3). The polymerase copies through the DR1 near the 5’ end of the RNA and terminates at the end of the RNA molecule. Next, a template exchange occurs in which the nascent negative strand DNA moves to the DR1 near the 3’ end (fig 4Ci-4). Why this is necessary is obscure since the initiation could have occurred near the 3’ DR1. From the 3’ DR1, the DNA is extended accompanied by RNase H digestion of the template RNA strand. Synthesis stops when the 5’ end of the RNA is reached (figure 4Ci-4). The negative strand is now terminally redundant. The RNA is not completely destroyed and the last 15 or so nucleotides remain (figure 4Cii-5) to serve as a primer for the second (positive) DNA strand synthesis. This is translocated to the DR2 at the 5’ end of the first DNA stand (figure 4Cii-6). Extension continues to the 5’ end of the first DNA strand. There now occurs a switch of template in which the DR1 at the 5’ end of the negative strand is replaced by the DR1 at the 3’ end so circularizing the template (figure 4Cii-7). The reverse transcriptase now copies around the circle for a variable distance to form the DNA that is found in mature virus particles.
 
CarcinogenesisIt is clear that individuals who are HBsAg positive are at a much higher risk of hepatocellular carcinoma than those who are negative. In patients with chronic hepatitis, there is destruction of hepatocytes as a result of the immune response to the virus. This results in regeneration (by cell division) of liver cells that may ultimately cause the cancer. Although the virus does not integrate during the course of normal replication, parts of the HBV genome are found integrated into the DNA of hepatocellular carcinoma patients. This may result in the activation of a cellular proto-oncogene in much the same way as occurs in some retrovirus-caused cancers; in fact, in most cases of woodchuck hepatocellular carcinoma (a widely used model system), viral DNA is found close to the myc or a similar proto-oncogene. Hepatocellular carcinoma takes many years to develop and this may reflect the rarity of integration in the absence of an integrase enzyme. The tumor that does develop is thus likely to be clone of a single cell where this process has occurred.
An HBV protein called protein X is known to activate the src kinase and this may also underlie HBV carcinogenesis. This protein may also interact with p53, one of the cell's tumor suppressor genes.
 Figure 5
Hepatitis C structure Figure 6
Flavivirus polyprotein processing		HEPATITIS C VIRUSHepatitis C is a flavivirus (of which yellow fever is the prototype) that causes non-A, non-B hepatitis. Flaviviruses (figure 5) are icosahedral, positive strand RNA viruses and gain an envelope from their host cell. The virus particle is about 30 to 60nm across. The genome of 9,600 bases codes for ten proteins. In many ways, the flaviviruses are similar to picornaviruses with the prominent exception that they are enveloped. The viral RNA does not have a 5’ cap or 3’ poly A tract. Translation of the viral RNA is mediated by the internal ribosome entry site (IRES).
There is one protein product from one open reading frame. The hepatitis C virus polyprotein is cleaved by both a virally-encoded protease activity and a cellular protease. The nascent protein contains a signal sequence that results in the translating ribosome attaching to the cytoplasmic surface of the endoplasmic reticulum. The envelope protein (E) thus crosses and embeds in the membrane and the signal sequence is removed by a cellular signal protease.  This results in the remainder of the protein, the core protein, becoming cytoplasmic. It is cut by two viral proteases. The C-terminal domain of NS2 is a cysteine protease and cleaves at the NS2/NS3 junction. Another protease (NS3/4A serine protease) cleaves the remaining junctions.
Thus, the core protein is cut into NS1, NS2, NS3 and NS4 proteins. NS2 and NS4 are then cut again (to give NS2a, NS2b, NS4a and NS4b) 
HCV binds to either the CD81 antigen or low density lipoprotein (LDL) receptor on hepatocytes via its E2 glycoprotein. There is also some evidence that it may bind to glycosaminoglycans.
 Figure 7
Hepatitis Delta agent CDC		HEPATITIS DELTA AGENTHepatitis D (figure 7) is a highly defective virus since it cannot produce infective virions without the help of a co-infecting helper virus. This helper virus is hepatitis B virus that supplies the HBsAg surface protein. In budding out of the cell, HDV acquires a membrane containing HBsAg. HDV is similar to a plant viroid in that it has a small circular RNA genome (1,700 bases) but unlike the plant viroids, the RNA encodes a protein called the delta antigen. This complexes with the RNA. The RNA is single stranded negative sense and is a covalently closed circle. Because of a large amount of base pairing, the RNA takes on a rod-like structure (figure 8).
 
 Figure 8
Hepatitis Delta agent - structure Figure 9
Hepatitis delta agent. Three RNA forms. Adapted from Wagner and Hewitt.: Basic Virology. Blackwell Publishing		HDV can only form an infectious particle if the cell in which it replicates is co-infected with HBV since the latter provides the surface HBsAg which is required for reinfection of another cell. The HBsAg of HDV binds to the same surface receptor as HBV and the virus fuses with the cell membrane. The tropism of HDV is therefore the same as HBV. The RNA genome is coated with delta antigen, the only protein encoded by the RNA. The delta antigen, which is exposed when the envelope is lost, has a nuclear localization signal that targets the genome to the nucleus. Here the genome is copied by host cell RNA polymerase II, the enzyme that normally makes mRNA. RNA polymerase II is used by some other viruses to copy their genomes, for example, the retroviruses, but in that case the polymerase copies DNA to RNA (which is the normal function of the enzyme in the uninfected cell). In HDV replication, the polymerase is copying RNA to RNA. The negative sense genomic RNA is copied to a positive strand that is also circular. The genomic RNA can also be transcribed into a linear 5’ capped and 3’ polyadenylated mRNA which is smaller than the genomic RNA and contains the small open reading frame from which the delta antigen is translated; or it can be generated from the circular positive sense genomic-sized RNA by an autocatalytic process that cleaves the RNA. Thus, the RNA is acting as a ribozyme, that is a catalytic RNA (figure 9).Delta antigen, translated from the mRNA has two forms that differ in size by 19 amino acids (195 compared to 214 residues). The formation of the large delta antigen happens by a rather strange mechanism in which a host cell enzyme called double stranded RNA-activated adenosine deaminase converts a UAG (stop) codon into a UGG that allows translation to proceed to the next stop codon. The small delta antigen is involved in the replication of the genome but the larger form suppresses replication. This leads to the promotion of viral particle assembly.
 Figure 10
Hepatitis E virus CDC		HEPATITIS E VIRUSThis virus (figure 10), which causes enteric non-A, non-B hepatitis, seems to be related to the Caliciviruses but its classification is undecided since the genome organization is not the same as that of the Caliciviridae. In sequence, HEV is more similar to rubella which is a Togavirus than to any Calicivirus. HEV is a small (approximately 34nm), round, icosahedral, positive strand RNA virus that does not have an envelope. It has a rather smooth surface but not as smooth a HAV. The genome has a poly A tract and is capped at the 5’ end. There are three open reading frames that overlap; each is in a different coding frame. Based on sequence motifs, open reading frame 1 (ORF1) appears to have several enzymic activities. These may be involved in RNA capping, proteolysis and an RNA-dependent RNA polymerase activity. ORF2 is the structural protein and may be glycosylated. It appears to have a signal sequence suggesting that its encoded protein may enter the endoplasmic reticulum. The third ORF codes for a phosphoprotein of unknown function that interacts with the host cell’s cytoskeleton. Not much is known about HEV replication but it is likely that the positive strand RNA is copied to a negative strand intermediate by a viral polymerase
 HEPATITIS G VIRUSHepatitis G virus is a flavivirus, like HCV to which it is closely related. It is associated with some cases of acute or chronic non-A, non-B, non-C, non-D, non-E hepatitis. Although it seems common in human blood, it may not he a significant cause of hepatitis in humans.
 
 
Table 1
 Hepatitis AHepatitis BHepatitis CHepatitis DeltaHepatitis E
Virus familyPicornavirusHepadnavirusFlavivirusCircular RNA similar to plant viroidSimilar to Calicivirus
Nucleic acidRNA (+ sense)DNA (partially double strand)RNA (+ sense)RNA (- sense)RNA (+ sense)
Disease causedInfectious hepatitisSerum hepatitisNon-A, non-B hepatitis Enteric non-A, non-B hepatitis
Size~ 28nm~40nm30 - 60nm~ 40nm30 - 35 nm
EnvelopeNoYesYesYesNo

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From Wikipedia, the free encyclopedia Jump to: navigation, search For other uses, see Dengue fever (disambiguation). Dengue fever Classification and external resources The typical rash seen in dengue fever ICD-10 A90. ICD-9 061 DiseasesDB 3564 MedlinePlus 001374 eMedicine med/528 MeSH C02.782.417.214 Dengue fever (UK: /ˈdɛŋɡeɪ/, US: /ˈdɛŋɡiː/), also known as breakbone fever, is an infectious tropical disease caused by the dengue virus. Symptoms include fever, headache, muscle and joint pains, and a characteristic morbilliform skin rash. In a small proportion of cases the disease develops to the life-threatening dengue hemorrhagic fever (bleeding, low levels of blood platelets and blood plasma leakage) and dengue shock syndrome (circulatory failure). Dengue is transmitted by several species of mosquito within the Aedes genus, principally A. aegypti. The virus has four 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 is believed to increase the risk of severe complications. As there is no 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 and blood transfusion for more severe cases. The incidence of dengue fever has increased dramatically over the last 50 years, with around 50–100 million people infected yearly. Dengue is currently endemic in more than 110 countries. 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 worldwide problem since the Second World War. Contents [hide] 1 Signs and symptoms 1.1 Clinical course 1.2 Associated problems 2 Cause 2.1 Virology 2.2 Transmission 2.3 Predisposition 3 Mechanism 3.1 Viral reproduction 3.2 Severe disease 4 Diagnosis 4.1 General 4.2 Classification 4.3 Virology and serology 5 Prevention 6 Management 7 Epidemiology 8 History 8.1 Etymology 8.2 Discovery 9 Research 10 Notes 11 References 12 External links Signs and symptoms Schematic depiction of the symptoms of dengue fever People infected with dengue virus are commonly asymptomatic or only have mild symptoms such as an uncomplicated fever.[1][2] Others have more severe illness, and in a small proportion it is life-threatening.[1] The incubation period (time between exposure and onset of symptoms) ranges from 3–14 days, but most often it is 4–7 days.[3] This means that travellers returning from endemic areas are unlikely to have dengue if fever or other symptoms start more than 14 days after arriving home.[4] Children often experience symptoms similar to those of the common cold and gastroenteritis (vomiting and diarrhea),[5] but are more susceptible to the severe complications.[4] Clinical course The characteristic symptoms of dengue are: a sudden-onset fever, headache (typically behind the eyes), muscle and joint pains, and a rash. The alternative name for dengue, "break-bone fever", comes from the associated muscle and joints pains.[1][6] The course of infection is divided into three phases: febrile, critical, and recovery.[7] The febrile phase involves high fevers, frequently over 40 °C (104 °F) and is associated with generalized pain and a headache; this usually lasts two to seven days.[6][7] Flushed skin and some small red spots called petechiae, which are caused by broken capillaries, may occur at this point,[7] as may some mild bleeding from mucous membranes of the mouth and nose.[4][6] The critical phase, if it occurs, follows the resolution of the high fever and typically lasts one to two days.[7] During this phase there may be significant fluid accumulation in the chest and abdominal cavity due to increased capillary permeability and leakage. This leads to depletion of fluid from the circulation and decreased blood supply to vital organs.[7] During this phase, organ dysfunction and severe bleeding (typically from the gastrointestinal tract) may occur.[4][7] Shock and hemorrhage occur in less than 5% of all cases of dengue,[4] however those who have previously been infected with other serotypes of dengue virus ("secondary infection") have an increased risk.[4][8] The recovery phase occurs next, with resorption of the leaked fluid into the bloodstream.[7] This usually lasts two to three days.[4] The improvement is often striking, but there may be severe itching and a slow heart rate.[4][7] It is during this stage that a fluid overload state may occur, which if it affects the brain may reduce the level of consciousness or cause seizures.[4] Associated problems Dengue may occasionally affect several other body systems.[7] This may be either in isolation or along with the classic dengue symptoms.[5] A decreased level of consciousness occurs in 0.5–6% of severe cases. This may be caused by infection of the brain by the virus or indirectly due to impairment of vital organs, for example, the liver.[5][9] Other neurological disorders have been reported in the context of dengue, such as transverse myelitis and Guillain-Barré syndrome.[5] Infection of the heart and acute liver failure are among the rarer complications of dengue.[4][7] Cause Virology Main article: Dengue virus A TEM micrograph showing dengue virus virions (the cluster of dark dots near the center) Dengue fever virus (DENV) is an RNA virus of the family Flaviviridae; genus Flavivirus. Other members of the same family 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.[9] Most are transmitted by arthropods (mosquitoes or ticks), and are therefore also referred to as arboviruses (arthropod-borne viruses).[9] The dengue virus genome (genetic material) contains about 11,000 nucleotide bases, which code for the three different types of protein molecules that form the virus particle (C, prM and E) 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.[8][10] 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] All four serotypes can cause the full spectrum of disease.[8] Infection with one serotype is believed to produce lifelong immunity to that serotype but only short term protection against the others.[2][6] The severe complications on secondary infection seem to occur particularly if someone previously exposed to serotype DENV-1 then contracts serotype DENV-2 or serotype DENV-3, or if someone previously exposed to type DENV-3 then acquires DENV-2.[10] Transmission The mosquito Aedes aegypti feeding off a human host Dengue virus is primarily transmitted by Aedes mosquitoes, particularly A. aegypti.[2] These mosquitoes usually live between the latitudes of 35° North and 35° South below an elevation of 1,000 metres (3,300 ft).[2] They bite primarily during the day.[11] Other mosquito species—Aedes albopictus, A. polynesiensis and several A. scutellaris—may also transmit the disease.[2] Humans are the primary host of the virus,[2][9] but it may also circulate in nonhuman primates.[12] An infection may be acquired via a single bite.[13] A mosquito that takes a blood meal from a person infected with dengue fever becomes itself infected with the virus in the cells lining its gut. About 8–10 days later, the virus spreads to other tissues including the mosquito's salivary 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 and tends to live in close proximity to humans, and prefers to feed off people rather than other vertebrates.[14] Dengue may also be transmitted via infected blood products and through organ donation.[15][16] In countries such as Singapore, where dengue is endemic, the risk is estimated to be between 1.6 and 6 per 10,000 transfusions.[17] Vertical transmission (from mother to child) during pregnancy or at birth has been observed.[13] Other person-to-person modes of transmission have been reported, but are very unusual.[6] 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.[4] Women are more at risk than men.[10] Dengue may be life-threatening in people with chronic diseases such as diabetes and asthma.[10] It is thought that polymorphisms (normal variations) in particular genes may increase the risk of severe dengue complications. Examples include the genes coding for the proteins known as TNFα, mannan-binding lectin,[1] CTLA4, TGFβ,[8] DC-SIGN, and particular forms of human leukocyte antigen.[10] A common genetic abnormality in Africans, known as glucose-6-phosphate dehydrogenase deficiency, appears to increase the risk.[18] Polymorphisms in the genes for the vitamin D receptor and FcγR seem to offer protection.[10] Mechanism When a mosquito carrying DENV bites a person, the virus enters the skin together with the mosquito's saliva. It binds to and enters white blood cells, and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing a number of signalling proteins (such as interferon) that 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 liver and the bone marrow) can be affected, and fluid from the bloodstream leaks through the wall of small blood vessels into body cavities. 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 marrow 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.[18] Viral reproduction After entering the skin, DENV binds to Langerhans cells (a population of dendritic cells in the skin that identifies pathogens).[18] The virus enters the cells through binding between viral proteins and membrane proteins on the Langerhans cell, specifically the C-type lectins called DC-SIGN, mannose receptor and CLEC5A.[8] DC-SIGN, a non-specific receptor for foreign material on dendritic cells, seems to be the main one.[10] The dendritic cell moves to the nearest lymph node. Meanwhile, the virus genome is replicated in membrane-bound vesicles on the cell's endoplasmic reticulum, where the cell's protein synthesis apparatus produces new viral proteins, and the viral RNA is copied. Immature virus particles are transported to the Golgi apparatus, the part of the cell where the 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 enter other white blood cells (such as monocytes and macrophages).[8] The initial reaction of infected cells is to produce the interferon, a cytokine that raises a number of defenses against viral infection through the innate immune system by augmenting the production of a large group of proteins (mediated by the JAK-STAT pathway). Some serotypes of DENV 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 virus as well as T cells that directly attack any cell infected with the virus.[8] Various antibodies are generated; some bind closely to the viral proteins and target them for phagocytosis (ingestion by specialized 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.[8] Severe disease Further information: Antibody-dependent enhancement It is not entirely clear why secondary infection with a different strain of DENV 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.[8][10] 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 cytokines and the complement system).[18] Severe disease is marked by two problems: dysfunction of endothelium (the cells that line blood vessels) and disordered blood clotting.[5] Endothelial dysfunction leads to the leakage of fluid from the blood vessels into the chest and abdominal cavities, while coagulation disorder is responsible for the bleeding complications. Higher levels of virus in the blood and involvement of other organs (such as the bone marrow and the liver) are associated with more severe disease. Cells in the affected organs die, leading to the release of cytokines and activation of both coagulation and fibrinolysis (the opposing systems of blood clotting and clot degradation). These alterations together lead to both endothelial dysfunction and coagulation disorder.[18] Diagnosis General Warning signs[19] Abdominal pain Ongoing vomiting Liver enlargement Mucosal bleeding High hematocrit with low platelets Lethargy The diagnosis of dengue is typically made clinically, on the basis of reported symptoms and physical examination; this applies especially in endemic areas.[1] Early disease can however be difficult to differentiate from other viral infections.[4] A probable diagnosis is based on the findings of fever plus two of the following: nausea and vomiting, rash, generalized pains, low white blood cell count, positive tourniquet test, or any warning sign (see table) in someone who lives in an endemic area.[19] Warning signs typically occur before the onset of severe dengue.[7] The tourniquet test, which is particularly useful in settings where no laboratory investigations are readily available, involves the application of a blood pressure cuff for five minutes, followed by the counting of any petechial hemorrhages; a higher number makes a diagnosis of dengue more likely.[7] It may 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.[6] Often, investigations are performed to exclude other conditions that cause similar symptoms, such as malaria, leptospirosis, typhoid fever, and meningococcal disease.[4] The earliest change detectable on laboratory investigations is a low white blood cell count, which may then be followed by low platelets and metabolic acidosis.[4] In severe disease, plasma leakage may result in hemoconcentration (as indicated by a rising hematocrit) and hypoalbuminemia.[4] Pleural effusions or ascites may be detected by physical examination when large,[4] but the demonstration of fluid on ultrasound may assist in the early identification of dengue shock syndrome.[1][4] The use of ultrasound is limited by lack of availability in many settings.[1] Classification The World Health Organization's 2009 classification divides dengue fever into two groups: uncomplicated and severe.[1][19] This replaces the 1997 WHO classification, which needed to be simplified as it had been found to be too restrictive, but the older classification is still widely used.[19] The 1997 classification divided dengue into undifferentiated fever, dengue fever, and dengue hemorrhagic fever.[4][20] Dengue hemorrhagic fever was subdivided further into four grades (grade I–IV). Grade I is the presence only of easy bruising or a positive "tourniquet test" (see below) in someone with fever, grade II is the presence of spontaneous bleeding into the skin and elsewhere, grade III is the clinical evidence of shock, and grade IV is shock so severe that blood pressure and pulse cannot be detected.[20] Grades III and IV are referred to as "dengue shock syndrome".[19][20] Virology and serology Dengue fever may also be diagnosed by microbiological laboratory testing.[19] This can be done by virus isolation in cell cultures, nucleic acid detection by PCR, viral antigen detection or specific antibodies (serology).[10][21] Virus isolation and nucleic acid detection are more accurate than antigen detection, but these tests are not widely available due to their greater cost.[21] All tests may be negative in the early stages of the disease.[4][10] Apart from serology, laboratory tests are only of diagnostic value during the acute phase of the illness. Tests for dengue virus-specific antibodies, types IgG and IgM, can be useful in confirming a diagnosis in the later stages of the infection. Both IgG and IgM are produced after 5–7 days. The highest levels (titres) of IgM are detected following a primary infection, but IgM is also produced in secondary and tertiary infections. The IgM becomes undetectable 30–90 days after a primary infection, but earlier following re-infections. IgG, by contrast, remains detectable for over 60 years and, in the absence of symptoms, is a useful indicator of past infection. After a primary infection the IgG reaches peak levels in the blood after 14–21 days. In subsequent re-infections, levels peak earlier and the titres are usually higher. Both IgG and IgM provide protective immunity to the infecting serotype of the virus. In the laboratory test the IgG and the IgM antibodies can cross-react with other flaviviruses, such as yellow fever virus, which can make the interpretation of the serology difficult.[6][10][22] 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.[22] Prevention A 1920s photograph of efforts to disperse standing water and thus decrease mosquito populations There are currently 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.[11][23] The World Health Organization recommends an Integrated Vector Control program consisting of five elements: (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.[11] The primary method of controlling A. aegypti is by eliminating its habitats.[11] This may be done by emptying containers of water or by adding insecticides or biological control agents to these areas.[11] 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.[11] People may prevent mosquito bites by wearing clothing that fully covers the skin and/or the application of insect repellent (DEET being the most effective).[13] Management There are no specific treatments for the dengue fever virus.[1] Treatment depends on the symptoms, varying from oral rehydration therapy at home with close follow-up, to hospital admission with administration of intravenous fluids and/or blood transfusion.[24] 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.[4] Intravenous hydration is usually only needed for one or two days.[24] The rate of fluid administration is titrated to a urinary output of 0.5–1 mL/kg/hr, stable vital signs and normalization of hematocrit.[4] Invasive medical procedures such as nasogastric intubation, intramuscular injections and arterial punctures are avoided, in view of the bleeding risk.[4] Acetaminophen may be used for fever and discomfort while NSAIDs such as ibuprofen and aspirin are avoided as they might aggravate the risk of bleeding.[24] 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.[25] Packed red blood cells or whole blood are recommended, while platelets and fresh frozen plasma are usually not.[25] During the recovery phase intravenous fluids are discontinued to prevent a state of fluid overload.[4] If fluid overload occurs and vital signs are stable, stopping further fluid may be all that is needed.[25] 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.[25] Epidemiology See also: Dengue fever outbreaks Dengue distribution in 2006. Red: Epidemic dengue and Ae. aegypti Aqua: Just Ae. aegypti. Most people with dengue recover without any ongoing problems.[19] The mortality is 1–5% without treatment,[4] and less than 1% with adequate treatment.[19] Severe disease carries a mortality of 26%.[4] Dengue is believed to infect 50 to 100 million people worldwide a year with half a million life-threatening infections requiring hospitalization,[1] resulting in approximately 12,500–25,000 deaths.[5][26] The burden of disease from dengue is estimated to be similar to other childhood and tropical diseases, such as tuberculosis, at 1600 disability-adjusted life years per million population.[10] It is the most common viral disease transmitted by arthropods.[8] As a tropical disease it is deemed only second in importance to malaria.[4] It is endemic in more than 110 countries.[4] The World Health Organization counts dengue as one of sixteen neglected tropical diseases.[27] The incidence of dengue increased 30 fold between 1960 and 2010.[28] 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 from Asia and the Pacific.[28] In the United States, the rate of dengue infection among those who return from an endemic area with a fever is 2.9–8.0%,[13] and it is the second most common infection after malaria to be diagnosed in this group.[6] Until 2003, dengue was classified as a potential bioterrorism agent, but subsequent reports removed this classification as it was deemed too difficult to transfer and only caused hemorrhagic fever in a relatively small proportion of people.[29] History Etymology The origins of the word "dengue" are not clear, but one theory is that it is derived from the Swahili phrase Ka-dinga pepo, which describes the disease as being caused by an evil spirit.[30] The Swahili word dinga may possibly have its origin in the Spanish word dengue, meaning fastidious or careful, which would describe the gait of a person suffering the bone pain of dengue fever.[31] However, it is possible that the use of the Spanish word derived from the similar-sounding Swahili.[30] 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".[32][33] The term "break-bone fever" was first applied by physician and Founding Father Benjamin Rush, in a 1789 report of the 1780 epidemic in Philadelphia. In the report he uses primarily the more formal term "bilious remitting fever".[29][34] The term dengue fever came into general use only after 1828.[33] Other historical terms include "breakheart fever" and "la dengue".[33] Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine", "Thai", or "Singapore hemorrhagic fever".[33] Discovery 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.[30][35] 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 Asia, Africa and North America.[35] From that time until 1940, epidemics were infrequent.[35] 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.[36] Further investigations by John Burton Cleland and Joseph Franklin Siler completed the basic understanding of dengue transmission.[36] The marked rise of spread of dengue during and after the Second World War has been attributed to ecologic disruption. The same trends also led to the spread of different serotypes of the disease to different areas, and the emergence of dengue hemorrhagic fever, which was first reported in the Philippines in 1953. In the 1970s, it became a major cause of child mortality. Around the same time it emerged in the Pacific and the Americas.[35] Dengue hemorrhagic fever and dengue shock syndrome were first noted in Middle and Southern America in 1981, as DENV-2 was contracted by people who had previously been infected with DENV-1 several years earlier.[9] Research Current research efforts to prevent and treat dengue have included different means of vector control,[37] vaccine development, and antiviral drugs.[23] With regards to vector control, a number of novel methods have been used to reduce mosquito numbers with some success including the placement of the fish Poecilia reticulata or copepods in standing water to eat the mosquito larva.[37] There are ongoing programs working on a dengue vaccine to cover all four serotypes.[23] One of the concerns is that a vaccine may increase the risk of severe disease through antibody-dependent enhancement.[38] The ideal vaccine 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.[38] A number of vaccines are currently undergoing testing.[10][29][38] It is hoped that the first products will be commercially available by 2015.[23] 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 might be used to treat attacks of dengue fever and prevent severe complications.[39][40] Discovery of the structure of the viral proteins may aid the development of effective drugs.[40] There are several plausible targets. The first approach is inhibition of the viral RNA-dependent RNA polymerase (coded by NS5), which copies the viral genetic material, with nucleoside analogs. Secondly, it may be possible to develop specific inhibitors of the viral protease (coded by NS3), which splices viral proteins.[41] 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.[39] Notes ^ a b c d e f g h i j k l m Whitehorn J, Farrar J (2010). "Dengue". Br. Med. Bull. 95: 161–73. doi:10.1093/bmb/ldq019. PMID 20616106. ^ a b c d e f g WHO (2009), pp. 14–16 ^ Gubler (2010), p. 379 ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa Ranjit S, Kissoon N (July 2010). "Dengue hemorrhagic fever and shock syndromes". Pediatr. Crit. Care Med. 12 (1): 90–100. doi:10.1097/PCC.0b013e3181e911a7. PMID 20639791. ^ a b c d e f Varatharaj A (2010). "Encephalitis in the clinical spectrum of dengue infection". Neurol. India 58 (4): 585–91. doi:10.4103/0028-3886.68655. PMID 20739797. ^ a b c d e f g h Chen LH, Wilson ME (October 2010). "Dengue and chikungunya infections in travelers". Curr. Opin. Infect. Dis. 23 (5): 438–44. doi:10.1097/QCO.0b013e32833c1d16. PMID 20581669. ^ a b c d e f g h i j k l WHO (2009), pp. 25–27 ^ a b c d e f g h i j Rodenhuis-Zybert IA, Wilschut J, Smit JM (August 2010). "Dengue virus life cycle: viral and host factors modulating infectivity". Cell. Mol. Life Sci. 67 (16): 2773–86. doi:10.1007/s00018-010-0357-z. PMID 20372965. ^ a b c d e Gould EA, Solomon T (February 2008). "Pathogenic flaviviruses". The Lancet 371 (9611): 500–9. doi:10.1016/S0140-6736(08)60238-X. PMID 18262042. ^ a b c d e f g h i j k l m Guzman MG, Halstead SB, Artsob H, et al. (December 2010). "Dengue: a continuing global threat". Nat. Rev. Microbiol. 8 (12 Suppl): S7–S16. doi:10.1038/nrmicro2460. PMID 21079655. ^ a b c d e f WHO (2009), pp. 59–60 ^ "Vector-Borne Viral Infections". World Health Organization. Retrieved 17 January 2011. ^ a b c d Center for Disease Control and Prevention. "Chapter 5 – Dengue Fever (DF) and Dengue Hemorrhagic Fever (DHF)". 2010 Yellow Book. Retrieved 2010-12-23. ^ Gubler (2010), pp. 377–78 ^ Wilder-Smith A, Chen LH, Massad E, Wilson ME (January 2009). "Threat of dengue to blood safety in dengue-endemic countries". Emerg. Infect. Dis. 15 (1): 8–11. doi:10.3201/eid1501.071097. PMC 2660677. PMID 19116042. ^ Stramer SL, Hollinger FB, Katz LM, et al. (August 2009). "Emerging infectious disease agents and their potential threat to transfusion safety". Transfusion 49 Suppl 2: 1S–29S. doi:10.1111/j.1537-2995.2009.02279.x. PMID 19686562. ^ Teo D, Ng LC, Lam S (April 2009). "Is dengue a threat to the blood supply?". Transfus Med 19 (2): 66–77. doi:10.1111/j.1365-3148.2009.00916.x. PMC 2713854. PMID 19392949. ^ a b c d e Martina BE, Koraka P, Osterhaus AD (October 2009). "Dengue virus pathogenesis: an integrated view". Clin. Microbiol. Rev. 22 (4): 564–81. doi:10.1128/CMR.00035-09. PMC 2772360. PMID 19822889. ^ a b c d e f g h WHO (2009), pp. 10–11 ^ a b c WHO (1997). "Chapter 2: clinical diagnosis". Dengue haemorrhagic fever: diagnosis, treatment, prevention and control (2nd ed.). Geneva: World Health Organization.. pp. 12–23. ISBN 9241545003. ^ a b WHO (2009), pp. 90–95 ^ a b Gubler (2010), p. 380 ^ a b c d WHO (2009), p. 137 ^ a b c WHO (2009), pp. 32–37 ^ a b c d WHO (2009), pp. 40–43 ^ WHO media centre (March 2009). "Dengue and dengue haemorrhagic fever". World Health Organization. Retrieved 2010-12-27. ^ Neglected Tropical Diseases. "Diseases covered by NTD Department". World Health Organization. Retrieved 2010-12-27. ^ a b WHO (2009), p. 3 ^ a b c Barrett AD, Stanberry LR (2009). Vaccines for biodefense and emerging and neglected diseases. San Diego: Academic. pp. 287–323. ISBN 0-12-369408-6. ^ a b c Anonymous (2006). "Etymologia: dengue". Emerg. Infec. Dis. 12 (6): 893. ^ Harper D (2001). "Etymology: dengue". Online Etymology Dictionary. Retrieved 2008-10-05. ^ Anonymous (1998-06-15). "Definition of Dandy fever". MedicineNet.com. Retrieved 2010-12-25. ^ a b c d Halstead SB (2008). Dengue (Tropical Medicine: Science and Practice). River Edge, N.J: Imperial College Press. pp. 1–10. ISBN 1-84816-228-6. ^ Rush AB (1789). "An account of the bilious remitting fever, as it appeared in Philadelphia in the summer and autumn of the year 1780". Medical enquiries and observations. Philadelphia, Pa.: Prichard and Hall. pp. 104–117. ^ a b c d Gubler DJ (July 1998). "Dengue and dengue hemorrhagic fever". Clin. Microbiol. Rev. 11 (3): 480–96. PMC 88892. PMID 9665979. ^ a b Henchal EA, Putnak JR (October 1990). "The dengue viruses". Clin. Microbiol. Rev. 3 (4): 376–96. PMC 358169. PMID 2224837. ^ a b WHO (2009), p. 71 ^ a b c Webster DP, Farrar J, Rowland-Jones S (November 2009). "Progress towards a dengue vaccine". Lancet Infect Dis 9 (11): 678–87. doi:10.1016/S1473-3099(09)70254-3. PMID 19850226. ^ a b Sampath A, Padmanabhan R (January 2009). "Molecular targets for flavivirus drug discovery". Antiviral Res. 81 (1): 6–15. doi:10.1016/j.antiviral.2008.08.004. PMC 2647018. PMID 18796313. ^ a b Noble CG, Chen YL, Dong H, et al. (March 2010). "Strategies for development of Dengue virus inhibitors". Antiviral Res. 85 (3): 450–62. doi:10.1016/j.antiviral.2009.12.011. PMID 20060421. ^ Tomlinson SM, Malmstrom RD, Watowich SJ (June 2009). "New approaches to structure-based discovery of dengue protease inhibitors". Infectious Disorders Drug Targets 9 (3): 327–43. PMID 19519486. References Gubler DJ (2010). "Dengue viruses". In Mahy BWJ, Van Regenmortel MHV. Desk Encyclopedia of Human and Medical Virology. Boston: Academic Press. ISBN 0-12-375147-0. WHO (2009). Dengue Guidelines for Diagnosis, Treatment, Prevention and Control. World Health Organization. ISBN 9241547871. External links Find more about Dengue fever on Wikipedia's sister projects: Definitions from Wiktionary Images and media from Commons Learning resources from Wikiversity News stories from Wikinews Quotations from Wikiquote Source texts from Wikisource Textbooks from Wikibooks Dengue fever at the Open Directory Project "Dengue". WHO. Retrieved 2010-12-24. "Dengue". US Centers for Disease Control and Prevention. Retrieved 2010-12-24. "Dengue fever". UK Health Protection Agency. Retrieved 2010-12-24. [hide]v · d · eZoonotic viral diseases (A80–B34, 042–079) Arthropod/ (arbovirus) Mosquito Bunyaviridae Arbovirus encephalitis: La Crosse encephalitis (LCV) · California encephalitis (CEV) Viral hemorrhagic fever: Rift Valley fever (RVFV) Flaviviridae Arbovirus encephalitis: Japanese encephalitis (JEV) · Australian encephalitis (MVEV, KUNV) · St. Louis encephalitis (SLEV) · West Nile fever (WNV) Viral hemorrhagic fever: Dengue fever (DV) other: Yellow fever (YFV) · Zika fever Togaviridae Arbovirus encephalitis: Eastern equine encephalomyelitis (EEEV) · Western equine encephalomyelitis (WEEV) · Venezuelan equine encephalomyelitis (VEEV) other: Chikungunya (CV) · O'Nyong-nyong fever (OV) · Ross River fever (RRV) Tick Bunyaviridae Viral hemorrhagic fever: Crimean-Congo hemorrhagic fever (CCHFV) Flaviviridae Arbovirus encephalitis: Tick-borne encephalitis (TBEV) · Powassan encephalitis (PV) · Deer tick virus encephalitis (DTV) Viral hemorrhagic fever: Omsk hemorrhagic fever (OHFV) · Kyasanur forest disease (KFDV/Alkhurma virus)) · Langat virus (LGTV) Reoviridae Colorado tick fever (CTFV) Mammal Rodent (Robovirus) Arenaviridae Viral hemorrhagic fever: Lassa fever (LV) · Venezuelan hemorrhagic fever (Guanarito virus) · Argentine hemorrhagic fever (Junin virus) · Bolivian hemorrhagic fever (Machupo virus) · Lujo virus Bunyaviridae Puumala virus · Andes virus · Sin Nombre virus · Hantavirus (HV) Bat Filoviridae VHF: Ebola hemorrhagic fever · Marburg hemorrhagic fever Rhabdoviridae Australian bat lyssavirus · Mokola virus · Duvenhage virus · Lagos bat virus · Chandipura virus(sandfly) Bornaviridae Menangle · Henipavirus · Borna disease (Borna disease virus) Multiple Rhabdoviridae Rabies (RV) M: VIR virs(prot)/clss cutn/syst (hppv/hiva, infl/zost/zoon)/epon drugJ(dnaa, rnaa, rtva, vacc) Retrieved from "http://en.wikipedia.org/wiki/Dengue_fever"

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