Dengue Fever

Dengue fever is a  caused by the. Symptoms typically begin three to fourteen days after infection. This may include a high, , , and , and a characteristic. Recovery generally takes two to seven days. In a small proportion of cases, the disease develops into severe dengue, also known as dengue hemorrhagic fever, resulting in, and  leakage, or into dengue shock syndrome, where  occurs.

Dengue is spread by several species of female es of the ', principally '. The virus has five types; infection with one type usually gives lifelong to that type, but only short-term immunity to the others. Subsequent infection with a different type increases the risk of severe complications. A number of tests are available to confirm the diagnosis including detecting to the virus or its.

A has been approved and is commercially available in a number of countries. The vaccine, however, is only recommended in those who have been previously infected. Other methods of prevention include reducing mosquito habitat and limiting exposure to bites. This may be done by getting rid of or covering standing water and wearing clothing that covers much of the body. Treatment of acute dengue is supportive and includes giving fluid either by mouth or for mild or moderate disease. For more severe cases, may be required. About half a million people require hospital admission every year. (acetaminophen) is recommended instead of s (NSAIDs) for and  in dengue due to an increased risk of bleeding from NSAID use.

Dengue has become a global problem since the and is  in more than 110 countries, mainly in  and. Each year between 50 and 528 million people are infected and approximately 10,000 to 20,000 die. The earliest descriptions of an outbreak date from 1779. Its viral cause and spread were understood by the early 20th century. Apart from eliminating the mosquitos, work is ongoing for medication targeted directly at the virus. It is classified as a.

Signs and symptoms
Typically, people infected with dengue virus are (80%) or have only mild symptoms such as an uncomplicated fever. Others have more severe illness (5%), and in a small proportion it is life-threatening. The (time between exposure and onset of symptoms) ranges from 3 to 14 days, but most often it is 4 to 7 days. Therefore, travelers returning from endemic areas are unlikely to have dengue if fever or other symptoms start more than 14 days after arriving home. Children often experience symptoms similar to those of the and  (vomiting and diarrhea) and have a greater risk of severe complications, though initial symptoms are generally mild but include high fever.

Clinical course
The characteristic symptoms of dengue are sudden-onset fever, headache (typically located behind the eyes), muscle and joint pains, and a rash. The alternative name for dengue, "breakbone fever", comes from the associated muscle and joint pains. The course of infection is divided into three phases: febrile, critical, and recovery.

The febrile phase involves high fever, potentially over 40 C, and is associated with generalized pain and a headache; this usually lasts two to seven days. Nausea and vomiting may also occur. A rash occurs in 50–80% of those with symptoms in the first or second day of symptoms as, or later in the course of illness (days 4–7), as a rash. A rash described as "islands of white in a sea of red" has also been observed. Some e (small red spots that do not disappear when the skin is pressed, which are caused by broken ) can appear at this point, as may some mild bleeding from the s of the mouth and nose. The fever itself is classically or saddleback in nature, breaking and then returning for one or two days.

In some people, the disease proceeds to a critical phase as fever resolves. During this period, there is leakage of plasma from the blood vessels, typically lasting one to two days. This may result in fluid accumulation in the and  as well as  and. There may also be organ dysfunction and severe, typically from the. (dengue shock syndrome) and hemorrhage (dengue hemorrhagic fever) occur in less than 5% of all cases of dengue; however, those who have previously been infected with other s of dengue virus ("secondary infection") are at an increased risk. This critical phase, while rare, occurs relatively more commonly in children and young adults.

The recovery phase occurs next, with resorption of the leaked fluid into the bloodstream. This usually lasts two to three days. The improvement is often striking, and can be accompanied with severe ing and a. Another rash may occur with either a or a  appearance, which is followed by peeling of the skin. During this stage, a state may occur; if it, it may cause a  or. A feeling of may last for weeks in adults.

Associated problems
Dengue can occasionally affect several other, either in isolation or along with the classic dengue symptoms. A decreased level of consciousness occurs in 0.5–6% of severe cases, which is attributable either to or indirectly as a result of impairment of vital organs, for example, the.

Other neurological disorders have been reported in the context of dengue, such as and. and are among the rarer complications.

A pregnant woman who develops dengue may be at a higher risk of as well as  and.

Virology
Dengue fever virus (DENV) is an of the family '; genus '. Other members of the same genus include, , , , , , , and. Most are transmitted by s (mosquitos or s), and are therefore also referred to as es (arthropod-borne viruses).

The dengue virus (genetic material) contains about 11,000 s, which  for the three different types of protein molecules (C, prM and E) that form the  and seven other non-structural protein molecules (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5) that are found in infected host cells only and are required for replication of the virus. There are five strains of the virus, called s, of which the first four are referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The fifth type was announced in 2013. The distinctions between the serotypes are based on their.

Transmission
Dengue virus is primarily transmitted by ' mosquitos, particularly '. These mosquitos usually live between the s of 35° North and 35° South below an of 1000 m. They typically bite during the early morning and in the evening, but they may bite and thus spread infection at any time of day. Other Aedes species that transmit the disease include ', ' and . Humans are the primary of the virus, but it also circulates in nonhuman s. An infection can be acquired via a single bite. A female mosquito that takes a blood meal from a person infected with dengue fever, during the initial 2- to 10-day febrile period, 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 s 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 is particularly involved, as it prefers to lay its eggs in artificial water containers, to live in close proximity to humans, and to feed on people rather than other s.

Dengue can also be transmitted via infected and through. In countries such as, where dengue is endemic, the risk is estimated to be between 1.6 and 6 per 10,000. (from mother to child) during pregnancy or at birth has been reported. Other person-to-person modes of transmission, including sexual transmission, have also been reported, but are very unusual. 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.

Predisposition
Severe disease is more common in babies and young children, and in contrast to many other infections, it is more common in children who are relatively well nourished. Other s for severe disease include female sex, high, and. While each serotype can cause the full spectrum of disease, virus strain is a risk factor. Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three. 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 exposed to DENV-3 acquires DENV-2. Dengue can be life-threatening in people with s such as and.

(normal variations) in particular s have been linked with an increased risk of severe dengue complications. Examples include the genes coding for the proteins, , , , , , and particular of  from gene variations of. A common genetic abnormality, especially in Africans, known as, appears to increase the risk. Polymorphisms in the genes for the and  seem to offer protection against severe disease in secondary dengue infection.

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 enters s, and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing a number of signaling proteins, such as and, 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 and the ) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to. 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 due to infection of the s 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.

Viral replication
Once inside the skin, dengue virus binds to s (a population of s in the skin that identifies pathogens). The virus through binding between viral proteins and s on the Langerhans cell, specifically the s called DC-SIGN,  and. DC-SIGN, a non-specific receptor for foreign material on dendritic cells, seems to be the main point of entry. The dendritic cell moves to the nearest. Meanwhile, the virus genome is translated in membrane-bound vesicles on the cell's, 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, the part of the cell where some of the proteins receive necessary sugar chains (s). The now mature new viruses are released by. They are then able to enter other white blood cells, such as s and s.

The initial reaction of infected cells is to produce, a that raises a number of defenses against viral infection through the  by augmenting the production of a large group of proteins mediated by the. Some serotypes of dengue virus appear to have mechanisms to slow down this process. Interferon also activates the, which leads to the generation of against the virus as well as s that directly attack any cell infected with the virus. Various antibodies are generated; some bind closely to the viral proteins and target them for (ingestion by  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.

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 (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. There is a suspicion that ADE is not the only mechanism underlying severe dengue-related complications, and various lines of research have implied a role for T cells and soluble factors such as cytokines and the.

Severe disease is marked by the problems of capillary permeability (an allowance of fluid and protein normally contained within blood to pass) and disordered. These changes appear associated with a disordered state of the endothelial, which acts as a of blood components. Leaky capillaries (and the critical phase) are thought to be caused by an immune system response. Other processes of interest include infected cells that become —which affect both coagulation and (the opposing systems of blood clotting and clot degradation)—and low platelets in the blood, also a factor in normal clotting.

Diagnosis
The diagnosis of dengue is typically made clinically, on the basis of reported symptoms and ; this applies especially in endemic areas. However, early disease can be difficult to differentiate from other. A probable diagnosis is based on the findings of fever plus two of the following: and vomiting, rash, generalized pains,, positive , or any warning sign (see table) in someone who lives in an  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 at between the  and systolic pressure for five minutes, followed by the counting of any  hemorrhages; a higher number makes a diagnosis of dengue more likely with the cut off being more than 10 to 20 per 1 inch2 (6.25 cm2).

The diagnosis should be considered in anyone who develops a fever within two weeks of being in the or. It can be difficult to distinguish dengue fever and, a similar viral infection that shares many symptoms and occurs in similar parts of the world to dengue. Often, investigations are performed to exclude other conditions that cause similar symptoms, such as, , , , , , and. also has similar symptoms as dengue.

The earliest change detectable on laboratory investigations is a low white blood cell count, which may then be followed by and. A moderately elevated level of ( and ) from the liver is commonly associated with low platelets and white blood cells. In severe disease, plasma leakage results in (as indicated by a rising ) and. s or can be detected by physical examination when large, but the demonstration of fluid on  may assist in the early identification of dengue shock syndrome. The use of ultrasound is limited by lack of availability in many settings. Dengue shock syndrome is present if drops to ≤ 20 mm Hg along with peripheral vascular collapse. Peripheral vascular collapse is determined in children via delayed, rapid heart rate, or cold extremities. While warning signs are an important aspect for early detection of potential serious disease, the evidence for any specific clinical or laboratory marker is weak.

Classification
The 's 2009 classification divides dengue fever into two groups: uncomplicated and severe. This replaces the 1997 WHO classification, which needed to be simplified as it had been found to be too restrictive, though the older classification is still widely used including by the World Health Organization's Regional Office for South-East Asia. Severe dengue is defined as that associated with severe bleeding, severe organ dysfunction, or severe plasma leakage while all other cases are uncomplicated. The 1997 classification divided dengue into undifferentiated fever, dengue fever, and dengue hemorrhagic fever. Dengue hemorrhagic fever was subdivided further into grades I–IV. Grade I is the presence only of easy bruising or a positive tourniquet test 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 cannot be detected. Grades III and IV are referred to as "dengue shock syndrome".

Laboratory tests
The diagnosis of dengue fever may be confirmed by microbiological laboratory testing. This can be done by virus isolation in s, by, viral  detection (such as for ) or specific  (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. Detection of NS1 during the febrile phase of a primary infection may be greater than 90% sensitive however is only 60–80% in subsequent infections. All tests may be negative in the early stages of the disease. PCR and viral antigen detection are more accurate in the first seven days. 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.

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 and, 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 (s) of IgM are detected following a primary infection, but IgM is also produced in reinfection. 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, 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 testing for IgG and IgM antibodies there may be cross-reactivity with other flaviviruses which may result in a false positive after recent infections or vaccinations with yellow fever virus or Japanese encephalitis. 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.

Prevention
Prevention depends on control of and protection from the bites of the mosquito that transmits it. 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.

The primary method of controlling A. aegypti is by eliminating its s. This is done by getting rid of open sources of water, or if this is not possible, by adding s or to these areas. Generalized spraying with or  insecticides, while sometimes done, is not thought to be effective. Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effects from insecticides and greater logistical difficulties with control agents. People can prevent mosquito bites by wearing clothing that fully covers the skin, using ting while resting, and/or the application of ( being the most effective). While these measures can be an effective means of reducing an individual's risk of exposure, they do little in terms of mitigating the frequency of outbreaks, which appear to be on the rise in some areas, probably due to urbanization increasing the habitat of A. aegypti. The range of the disease also appears to be expanding possibly due to climate change.

Vaccine
In 2016 a partially effective became commercially available in the Philippines and Indonesia. It has also been approved for use by Mexico, Brazil, El Salvador, Costa Rica, Singapore, Paraguay, much of Europe, and the United States. The vaccine is only to be used in people who have previously had a dengue infection as otherwise there was evidence it may worsen subsequent infections. In Indonesia it costs about US$207 for the recommended three doses.

The vaccine is produced by and goes by the brand name. It is based on a weakened combination of the and each of the four dengue serotypes. Two studies of a vaccine found it was 60% effective and prevented more than 80 to 90% of severe cases. This is less than wished for by some.

There are ongoing programs working on a dengue vaccine to cover all four serotypes. Now that there is a fifth serotype this will need to be factored in. One of the concerns is that a vaccine could increase the risk of severe disease through (ADE). 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.

Anti-dengue day
International Anti-Dengue Day is observed every year on 15 June. The idea was first agreed upon in 2010 with the first event held in, in 2011. Further events were held in 2012 in, and in 2013 in. Goals are to increase public awareness about dengue, mobilize resources for its prevention and control and, to demonstrate the Asian region's commitment in tackling the disease.

Management
There are no specific s for dengue; however, maintaining proper fluid balance is important. Treatment depends on the symptoms. Those who are able to drink, are passing urine, have no "warning signs" and are otherwise healthy can be managed at home with daily follow-up and. Those who have other health problems, have "warning signs", or cannot manage regular follow-up should be cared for in hospital. In those with severe dengue care should be provided in an area where there is access to an.

Intravenous hydration, if required, is typically only needed for one or two days. In children with due to dengue a rapid dose of 20 mL/kg is reasonable. The rate of fluid administration is then titrated to a of 0.5–1 mL/kg/h, stable  and normalization of hematocrit. The smallest amount of fluid required to achieve this is recommended.

Invasive medical procedures such as, s and arterial punctures are avoided, in view of the bleeding risk. (acetaminophen) is used for fever and discomfort while such as  and  are avoided as they might aggravate the risk of bleeding. is initiated early in people 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. or are recommended, while s and  are usually not. There is not enough evidence to determine if s have a positive or negative effect in dengue fever.

During the recovery phase intravenous fluids are discontinued to prevent a state of. If fluid overload occurs and vital signs are stable, stopping further fluid may be all that is needed. If a person is outside of the critical phase, a such as  may be used to eliminate excess fluid from the circulation.

Prognosis
Most people with dengue recover without any ongoing problems. The risk of death among those with severe dengue is 0.8% to 2.5%, and with adequate treatment this is less than 1%. However, those who develop significantly low blood pressure may have a fatality rate of up to 26%. The risk of death among children less than five years old is four times greater than among those over the age of 10. Elderly people are also at higher risk of a poor outcome.

Epidemiology
Dengue is in more than 110 countries. In 2013 it causes about 60 million symptomatic infections worldwide, with 18% admitted to hospital and about 13,600 deaths. The worldwide cost of dengue case is estimated US$9 billion. For the decade of the 2000s, 12 countries in Southeast Asia were estimated to have about 3 million infections and 6,000 deaths annually. In 2019 the Philippines declared a national dengue epidemic due to the deaths reaching 622 people that year. It is reported in at least 22 countries in Africa; but is likely present in all of them with 20% of the population at risk. This makes it one of the most common s worldwide.

Infections are most commonly acquired in the urban environment. In recent decades, the expansion of villages, towns and cities in the areas in which it is common, 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, and might pose a threat to Europe.

Rates 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. The geographical distribution is around the equator. Of the 2.5 billion people living in areas where it is common 70% are from Asia and the Pacific. An infection with dengue is second only to malaria as a diagnosed cause of fever among travelers returning from the developing world. It is the most common viral disease transmitted by arthropods, and has a estimated at 1,600 s per million population. The World Health Organization counts dengue as one of seventeen.

Like most arboviruses, dengue virus is maintained in nature in cycles that involve preferred blood-sucking vectors and vertebrate hosts. The viruses are maintained in the forests of Southeast Asia and Africa by transmission from female Aedes mosquitos—of species other than A. aegypti—to their offspring and to lower primates. In towns and cities, the virus is primarily transmitted by the highly domesticated A. aegypti. In rural settings the virus is transmitted to humans by A. aegypti and other species of Aedes such as . Both these species had expanding ranges in the second half of the 20th century. In all settings the infected lower primates or humans greatly increase the number of circulating dengue viruses, in a process called amplification. One projection estimates that, , and other factors could result in more than 6 billion people at risk of dengue infection by 2080.

History
The first record of a case of probable dengue fever is in a Chinese medical encyclopedia from the (265–420 AD) which referred to a "water poison" associated with flying insects. The primary vector, A. aegypti, spread out of Africa in the 15th to 19th centuries due in part to increased globalization secondary to the. 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. From that time until 1940, epidemics were infrequent.

In 1906, transmission by the Aedes mosquitos was confirmed, and in 1907 dengue was the second disease (after yellow fever) that was shown to be caused by a virus. Further investigations by and  completed the basic understanding of dengue transmission.

The marked spread of dengue during and after the has 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 in 1953; by the 1970s, it had become a major cause of  and had emerged in the Pacific and the Americas. Dengue hemorrhagic fever and dengue shock syndrome were first noted in Central and South America in 1981, as DENV-2 was contracted by people who had previously been infected with DENV-1 several years earlier.

Etymology
The origins of the Spanish word dengue are not certain, but it is possibly derived from dinga in the phrase Ka-dinga pepo, which describes the disease as being caused by an. Slaves in the West Indies having contracted dengue were said to have the posture and gait of a, and the disease was known as "dandy fever".

The term "break-bone fever" was applied by physician and, in a 1789 report of the 1780 epidemic in. In the report title he uses the more formal term "bilious remitting fever". The term dengue fever came into general use only 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".

Blood donation
Outbreaks of dengue fever increases the need for blood products while decreasing the number of potential s due to potential infection with the virus. Someone who has a dengue infection typically is not allowed to donate blood for the next at least six months.

Awareness efforts
A National Dengue Day is held in India on May 16 in an effort to raise awareness in affected countries. Efforts are ongoing as of 2019 to make it a global event. The Philippines has an awareness month in June since 1998.

Research
Research efforts to prevent and treat dengue include various means of vector control, vaccine development, and antiviral drugs.

Vector
With regards to control, a number of novel methods have been used to reduce mosquito numbers with some success including the placement of the guppy () or  in standing water to eat the mosquito larvae. There are also trials with genetically modified male A. aegypti that after release into the wild mate with females, and render their offspring unable to fly.

Wolbachia
Attempts are ongoing to infect the mosquito population with bacteria of the genus , which makes the mosquitos partially resistant to dengue virus. While artificially induced infection with Wolbachia is effective, it is unclear if naturally acquired infections are protective. Work is still ongoing to determine the best type of Wolbachia to use.

Treatment
Apart from attempts to control the spread of the Aedes mosquito there are ongoing efforts to develop s that would be used to treat attacks of dengue fever and prevent severe complications. Discovery of the structure of the viral proteins may aid the development of effective drugs. There are several plausible targets. The first approach is inhibition of the viral (coded by NS5), which copies the viral genetic material, with s. Secondly, it may be possible to develop specific  of the viral  (coded by NS3), which  viral proteins. Finally, it may be possible to develop s, which stop the virus entering cells, or inhibitors of the ping process, which is required for viral replication.