Dengue fever also known as breakbone fever, is an acute febrile infectious disease caused by the dengue virus. Typical symptoms include headache, a petechial rash, and muscle and joint pains; in a small proportion the disease progresses to life-threatening complications such as dengue hemorrhagic fever (which may lead to severe hemorrhage) and dengue shock syndrome (where a very low blood pressure can cause organ dysfunction).
Dengue is usually transmitted by the mosquito Aedes aegypti, and rarely Aedes albopictus. The virus has four different serotypes, and an infection with one usually gives lifelong immunity to it, but only short-term immunity to the others. There is currently no available vaccine, but outbreaks can be prevented by reducing the habitat and 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 blood transfusions for more severe cases. Rates of infection have increased dramatically over the last 50 years with around 50–100 million people infected yearly. A global disease, dengue is currently endemic in more than 110 countries with 2.5 billion people living in areas where it is prevalent. 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.

Classification
The World Health Organization's 2009 classification divides dengue fever into two groups: uncomplicated and severe. This replaces the 1997 WHO classification, which was simplified as it was found to be too restrictive, but the older classification is still widely used. The 1997 classification divided dengue into undifferentiated fever, dengue fever, and dengue hemorrhagic fever.

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), 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. Grades III and IV are referred to as "dengue shock syndrome".

Signs and symptoms
Schematic depiction of the symptoms of dengue fever.
Infections from dengue virus range from asymptomatic, to a simple fever, to life threatening. The incubation period (time between exposure and onset of symptoms) is 4–10 days. Most infections are very mild, and many probably experience no symptoms at all. Children often experience symptoms similar to those of the common cold and gastroenteritis (vomiting and diarrhea). In travellers returning from endemic areas with fever or other symptoms, dengue is unlikely if symptoms start more than 14 days after returning.

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 nickname "break-bone fever" comes from the associated muscle and joints pains. The course of infection is classically divided into three phases: febrile, critical, and recovery.
The febrile phase involves high fevers, frequently over 40 °C (104 °F) and associated with generalized pain and a headache; this usually lasts 2–7 days. Flushed skin and some petechia (point-like hemorrhages in the skin) may occur at this point as may some mild bleeding from mucous membranes of the mouth and nose.
The critical phase, if it occurs, follows the resolution of the high fevers and typically lasts one to two days. During this phase there may be significant fluid accumulation in the thoracic 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. During this phase, organ dysfunction and severe bleeding (typically from the gastrointestinal tract) may occur. Shock and hemorrhage occurs in less than 5% of all cases of dengue with those who have previously been infected with other serotypes of dengue at increased risk.

The recovery phase occurs next if the person survives with resorption of the leaked fluid. This resorption usually occurs over two to three days. The improvement is often striking, but there may be severe itching and a slow heart rate. It is during this stage that a fluid overload state may present with symptoms of cerebral edema such as an altered level of consciousness or seizures.

Associated problems
Dengue may occasional affect a number of other body systems. This may be either in isolation or along with the classic dengue symptoms. A decreased level of consciousness may occur in 0.5—6% of severe cases. This is thought to be due to encephalopathy (brain dysfunction) resulting from either disruption in the function of other organs (such as hepatic encephalopathy in li ver involvement), or encephalitis (direct infection of the brain by the virus).

A number of other neurological disorders has been reported in the context of dengue, such as transverse myelitis and Guillain-Barré syndrome. Myocarditis (heart dysfunction due to infection of the heart muscle) and acute liver failure are among the rarer complications of dengue.

Cause
Transmission
The mosquito Aedes aegypti feeding off a human host Dengue virus is primarily transmitted by Aedes mosquitoes, particularly A. aegypti. These mosquitoes usually live between the latitudes of 35 degrees North and 35 degrees South below an elevation of 1,000 metres (3,300 ft). They bite primarily during the day. Other mosquito species—A. albopictus, A polynesiensis and several A. scutellaris—may also transmit the disease. Humans are the primary host of the virus. However it may also circulate in nonhuman primates. An infection may be acquired via a single bite. After taking a blood meal from an infected person, the virus infects the cells lining the mosquito's 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 has a preference for feeding off them rather than other vertebrates.

Dengue may also be transmitted via infected blood products and through organ donation. In countries such as Singapore, where dengue is endemic, the risk is estimated to be between 1.6 and 6 per 10,000 transfusions. Vertical transmission (from mother to child) during pregnancy or at birth has been observed.

Virology
Dengue fever virus (DENV) is a single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus. Its genome (genetic material) is about 11000 bases that codes for three structural proteins (C, prM and E) and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5), with short non-coding regions on both the 5' and 3' ends. There are four serotypes of the virus. All four serotypes can cause the full spectrum of disease. Infection with one serotype is believed to produce lifelong immunity it and short term protection from other serotypes.

The severe complications on secondary infection seem to occur particularly if someone previously exposed to DENV-1 then contracts DENV-2 or DENV-3, or if someone previously exposed to DENV-3 then acquires DENV-2.

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. Women are more at risk than men. Dengue may be life-threatening in people with chronic diseases such as diabetes and asthma.
It is thought that polymorphisms (normal variations) in particular genes may increase the risk of severe dengue complications. Examples include the genes coding for TNFα, mannan-binding lectin, CTLA4, TGFβ, DC-SIGN, and particular alleles of human leukocyte antigen. Glucose-6-phosphate dehydrogenase deficiency, a common genetic abnormality in Africans, appears to increase the risk. Polymorphisms in the genes for the vitamin D receptor and FcγR seem to offer protection.

Mechanism
When a mosquito carrying DENV bites a person, the virus enters the skin with the mosquito's saliva. It encounters and binds to a number of different cells in the skin, such as keratinocytes and Langerhans cells (a population of dendritic cells in the skin that identifies pathogens). Entry into cells is by binding of viral proteins to membrane proteins, such as the C-type lectins DC-SIGN, mannose receptor and CLEC5A. DC-SIGN, a non-specific receptor for foreign material on dendritic cells, seems to be the main one. The virus then enters the cells, and 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 from the endoplasmic reticulum to the Golgi apparatus, where the viral glycoproteins are modified. Mature new viruses bud on the surface of the infected cell and are released by exocytosis. They then enter other white blood cells (such as monocytes and macrophages)
The initial reaction of infected cells is to produce the cytokine interferon, which 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. 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 duplicate further.
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 phagocytes. There is a suspicion that ADE is not the only mechanism underlying severe dengue-related complications, and a role for low-avidity T cells and soluble factors (such as cytokines and the complement system) is implied by various lines of research.
Severe disease is marked by two problems: dysfunction of endothelium (the cells that line blood vessels) and disordered coagulation (blood clotting).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.

Diagnosis
General

The diagnosis of dengue is typically made clinically, on the basis of reported symptoms and physical examination; this applies especially in endemic areas. Early disease can however be difficult to differentiate from other viral infections. 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 in someone who lives in an endemic area. Warning signs typically occur before the onset of severe dengue. 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. Often, investigations are performed to exclude other conditions that cause similar symptoms, such as malaria, leptospirosis, typhoid fever, and meningococcal disease.
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. Plasma leakage may result in hemoconcentration (as indicated by a rising hematocrit) and hypoalbuminemia. Pleural effusions or ascites may be detected on clinical examination when large,  but the demonstration of fluid on ultrasound may assist in the early identification of dengue shock syndrome.   The use of ultrasound is limited by lack of availability in many settings.

Virology and serology
Dengue fever may also be diagnosed by microbiological laboratory testing.  This can be done by virus isolation in cell cultures, nucleic acid detection by PCR, viral antigen detection or specific antibodies (serology).   Virus isolation and nucleic acid detection are more accurate than antigen detection, but these tests are not widely available due to their greater cost.  All tests may be negative in the early stages of the disease.  
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.   The detection of IgG alone is not considered diagnostic unless blood samples are collected 14 days apart and a greater than four-fold increase in levels of specific IgG is detected. In a person with symptoms, the detection of IgM is considered diagnostic.

Prevention
There are currently no approved vaccines for the dengue virus.  Prevention thus depends on control of and protection from the bites of the mosquito that transmits it.   The World Health Organization recommends a 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.
The primary method of controlling A. aegypti is by eliminating its habitats.  This may be done by emptying containers of water or by adding insecticides or biological control agents to these areas.  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.  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).  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.
There are ongoing programs working on a dengue vaccine to cover all four serotypes.  One of the concerns is that a vaccine may increase the risk of severe disease through antibody-dependent enhancement.  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.  A number of vaccines are currently undergoing testing.    It is hoped that the first products will be commercially available by 2015.

Management
There are no specific treatments for the dengue fever virus.  Treatment depends on the symptoms, and may vary from advice to drink plenty of fluids such as oral rehydration solution at home with close follow up, to admission to hospital for carefully titrated isotonic intravenous fluids and/or blood transfusions.  A decision for hospital admission is typically based on the presence or absence of the "warning signs" listed above, and the presence of preexisting health conditions.
Intravenous fluids if used are usually only needed for one or two days.  Fluids are titrated to a urinary output of 0.5–1 mL/kg/hr, stable vital signs and normalization of hematocrit.  Procedures that increase bleeding risk such as nasogastric tubes, intramuscular injections and arterial punctures are avoided.  Acetaminophen may be used for fever and discomfort while NSAIDs such as ibuprofen or aspirin are avoided due to an increased bleeding risk.  The need for blood tranfusions is based on the presence of unstable vital signs and a decreasing haematocrit rather than the usual haematocrit of less than 30% used in sepsis.  Packed red blood cells or whole blood are recommended, while platelets and fresh frozen plasma are usually not.
During the recovery phase intravenous fluids are discontinued to prevent a state of fluid overload.  If fluid overload occurs and vitals are stable stopping further fluid may be all that is needed.  If a person is outside of the critical phase, the loop diuretic furosemide may be used to eliminate excess fluid from the circulation.

Epidemiology
Most people with dengue recover without any ongoing problems.  The mortality is 1–5% without treatment,  and less than 1% with adequate treatment.  Severe disease carries a mortality of 26%.  Dengue is believe to infect 50 to 100 million people worldwide a year with 1/2 million life-threatening infections requiring hospitalization,  resulting in approximately 12,500-25,000 deaths.  
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.  It is the most common viral disease transmitted by arthropods.  As a tropical disease it is deemed only second in importance to malaria.  While once exclusively a tropical disease it has become global, and is endemic in more than 110 countries.  The World Health Organization counts dengue as one of sixteen neglected tropical diseases.
The incidence of dengue increased 30 fold between 1960 and 2010.  This increase is believed to be due to a combination of urbanization, population growth, increased international travel, and global warming.  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.  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%.
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.

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.  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.  Alternatively, the use of the Spanish word may derive from the similar-sounding Swahili.  Slaves in the West Indies who contracted dengue were said to have the posture and gait of a dandy, and the disease was known as "dandy fever".  
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".   The term dengue fever only came into general use after 1828.  Other historical terms include "breakheart fever" and "la dengue".  Terms for severe disease include: infectious thrombocytopenic purpura and Philippine, Thai, or Singapore hemorrhagic fever.

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.   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.  From that time until 1940, epidemics were infrequent.
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 a virus.  Further investigations by John Burton Cleland and Joseph Franklin Siler completed the basic understanding of dengue transmission.
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, and the epidemic has been spreading since then.

Dengue virus (DENV) in one of four serotypes is the cause of dengue fever. It is a mosquito-borne single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus. All four serotypes can cause the full spectrum of disease. Its genome is about 11000 bases that codes for three structural proteins, capsid protein C, membrane protein M, envelope protein E; seven nonstructural proteins, NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5; and short non-coding regions on both the 5' and 3' ends. Further classification of each serotype into genotypes often relates to the region where particular strains are commonly found or were first found.

Life cycle
The primary life cycle of the dengue virus involves humans and mosquitoes. There is also another cycle in Africa. which involves non human primates.

Structure
E protein
The DENV E (envelope) protein, found on the viral surface, is important in the initial attachment of the viral particle to the host cell. Several molecules which interact with the viral E protein (ICAM3-grabbing non-integrin., CD209  Rab 5 , GRP 78 , and The Mannose Receptor)have been shown to be important factors mediating attachment and viral entry.

prM/M protein
The DENV prM (membrane) protein, which is important in the formation and maturation of the viral particle, consists of seven antiparallel β-strands stabilized by three disulphide bonds. The glycoprotein shell of the mature DENV virion consists of 180 copies each of the E protein and M protein. The immature virion starts out with the E and prM proteins forming 90 heterodimers that give a spiky exterior to the viral particle. This immature viral particle buds into the endoplasmic reticulum and eventually travels via the secretory pathway to the golgi apparatus. As the virion passes through the trans-Golgi Network (TGN) it is exposed to low pH. This acidic environment causes a conformational change in the E protein which disassociates it from the prM protein and causes it to form E homodimers. These homodimers lay flat against the viral surface giving the maturing virion a smooth appearance. During this maturation pr peptide is cleaved from the M peptide by the host protease, furin. The M protein then acts as a transmembrane protein under the E-protein shell of the mature virion. The pr peptide stays associated with the E protein until the viral particle is released into the extracellular environment. This pr peptide acts like a cap, covering the hydrophobic fusion loop of the E protein until the viral particle has exited the cell.

NS3 protein
The DENV NS3 is a serine protease, as well as an RNA helicase and RTPase/NTPase. The protease domain consists of six β-strands arranged into two β-barrels formed by residues 1-180 of the protein. The catalytic triad (His-51, Asp-75 and Ser-135), is found between these two β-barrels, and its activity is dependent on the presence of the NS2B cofactor. This cofactor wraps around the NS3 protease domain and becomes part of the active site. The remaining NS3 residues (180-618), form the three subdomains of the DENV helicase. A six-stranded parallel β-sheet surrounded by four α-helices make up subdomains I and II, and subdomain III is composed of 4 α-helices surrounded by three shorter α-helices and two antiparallel β-strands.[10]

NS5 protein
The DENV NS5 protein is a 900 residue peptide with a methyltransferase domain at its N-terminal end (residues 1-296) and a RNA-dependent RNA polymerase (RdRp) at its C-terminal end (residues 320–900). The methyltransferase domain consists of an α/β/β sandwich flanked by N-and C-terminal subdomains. The DENV RdRp is similar to other RdRps containing palm, finger, and thumb subdomains and a GDD motif for incorporating nucleotides.[10]

The reason that some people suffer from more severe forms of dengue, such as dengue hemorrhagic fever, is multifactorial. Different strains of viruses interacting with people with different immune backgrounds lead to a complex interaction. Among the possible causes are cross-serotypic immune response, through a mechanism known as antibody-dependent enhancement, which happens when a person who has been previously infected with dengue gets infected for the second, third or fourth time. The previous antibodies to the old strain of dengue virus now interfere with the immune response to the current strain, leading paradoxically to more virus entry and uptake