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Dengue fever
Tropical disease caused by the dengue virus, transmitted by mosquito

Dengue fever is a mosquito-borne disease caused by the dengue virus, mainly transmitted by Aedes aegypti mosquitoes. It is common in tropical and subtropical regions and often asymptomatic, but symptoms can include fever, headache, muscle and joint pain, and skin rash. Severe dengue may cause bleeding and dangerously low blood pressure. Approximately five serotypes exist, and infection with one provides lifelong immunity to it but short-term to others, increasing risks of complications on reinfection. Diagnosis involves detecting viral RNA or antibodies. There is no specific cure, so treatment is symptomatic with fluids given orally or intravenously. Prevention includes mosquito control and vaccines such as Dengvaxia and Qdenga. Dengue is a neglected tropical disease spreading beyond traditional zones due to climate change.

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Signs and symptoms

Typically, people infected with dengue virus are asymptomatic (80%) or have only mild symptoms such as an uncomplicated fever.1920 Others have more severe illness (5%), and in a small proportion it is life-threatening.2122 The incubation period (time between exposure and onset of symptoms) ranges from 3 to 14 days, but most often it is 4 to 7 days.23

The characteristic symptoms of mild dengue are sudden-onset fever, headache (typically located behind the eyes), muscle and joint pains, nausea, vomiting, swollen glands and a rash.2425 If this progresses to severe dengue the symptoms are severe abdominal pain, persistent vomiting, rapid breathing, bleeding gums or nose, fatigue, restlessness, blood in vomit or stool, extreme thirst, pale and cold skin, and feelings of weakness.26

Clinical course

The course of infection is divided into three phases: febrile, critical, and recovery.27

The febrile phase involves high fever (40 °C/104 °F), and is associated with generalized pain and a headache; this usually lasts two to seven days.2829 There may also be nausea, vomiting, a rash, and pains in the muscle and joints.30

Most people recover within a week or so. In about 5% of cases, symptoms worsen and can become life-threatening. This is called severe dengue (formerly called dengue hemorrhagic fever or dengue shock syndrome).3132 Severe dengue can lead to shock, internal bleeding, organ failure and even death.33 Warning signs include severe stomach pain, vomiting, difficulty breathing, and blood in the nose, gums, vomit or stools.34

During this period, there is leakage of plasma from the blood vessels, together with a reduction in platelets.35 This may result in fluid accumulation in the chest and abdominal cavity as well as depletion of fluid from the circulation and decreased blood supply to vital organs.36

The recovery phase usually lasts two to three days.37 The improvement is often striking, and can be accompanied with severe itching and a slow heart rate.38

The rash of dengue fever in the acute stage of the infection blanches when pressed.The rash that commonly forms during the recovery from dengue fever with its classic islands of white in a sea of red

Complications and sequelae

Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment.3940 A pregnant woman who develops dengue is at higher risk of miscarriage, low birth weight, and premature birth.41

Children and older individuals are at a risk of developing complications from dengue fever compared to other age groups; young children typically suffer from more intense symptoms. Concurrent infections with tropical diseases42 like Zika43 virus can worsen symptoms and make recovery more challenging.

Cause

Virology

Main article: Dengue virus

Dengue virus (DENV) is an RNA virus of the family Flaviviridae; genus Flavivirus. Other members of the same genus include yellow fever virus, West Nile virus, and Zika virus. Dengue virus genome (genetic material) contains about 11,000 nucleotide bases, which code for the three structural protein molecules (C, prM and E) that form the virus particle and seven other protein molecules that are required for replication of the virus.4445 There are four confirmed strains of the virus, called serotypes, referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes are based on their antigenicity.46

Transmission

Dengue virus is most frequently transmitted by the bite of mosquitos in the Aedes genus, particularly A. aegypti.47 They prefer to feed at dusk and dawn,48 but they may bite and thus spread infection at any time of day.49 Other Aedes species that may transmit the disease include A. albopictus, A. polynesiensis and A. scutellaris. Humans are the primary host of the virus,50 but it also circulates in nonhuman primates, and can infect other mammals.5152 An infection can be acquired via a single bite.53

For 2 to 10 days after becoming newly infected, a person's bloodstream will contain a high level of virus particles (the viremic period). A female mosquito that takes a blood meal from the infected host then propagates the virus in the cells lining its gut.54 Over the next few days, the virus spreads to other tissues including the mosquito's salivary glands and is released into its saliva. Next time the mosquito feeds, the infectious saliva will be injected into the bloodstream of its victim, thus spreading the disease.55 The virus seems to have no detrimental effect on the mosquito, which remains infected for life.56

Dengue can also be transmitted via infected blood products and through organ donation.57 Vertical transmission (from mother to child) during pregnancy or at birth has been reported.58

Risk factors

The principal risk for infection with dengue is the bite of an infected mosquito.59 This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed.60 It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective).61

Chronic diseases – such as asthma, sickle cell anemia, and diabetes mellitus – increase the risk of developing a severe form of the disease.62 Other risk factors for severe disease include female sex and high body mass index.6364 Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three.65 Subsequent re-infection with a different serotype increases the risk of severe complications due to a phenomenon known as antibody-dependent enhancement (ADE).6667

The exact mechanism of ADE is not fully understood.68 It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fcγ receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself.6970

Mechanism of infection

When a dengue virus carrying mosquito bites a person, the virus enters the skin together with the mosquito's saliva. The virus infects nearby skin cells called keratinocytes, as well as specialized immune cells located in the skin, called Langerhans cells.71 The Langerhans cells migrate to the lymph nodes, where the infection spreads to white blood cells, and reproduces inside the cells while they move throughout the body.72

The white blood cells respond by producing several signaling proteins, such as cytokines and interferons, which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability. As a result, blood volume decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to 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 fever.73

Prevention

Vector control

Main article: Mosquito control

The principal risk for infection with dengue is the bite of an infected mosquito.74 This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed.75 It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective);76 it is also advisable to treat clothing, nets and tents with 0.5% permethrin.77

Protection of the home can be achieved with door and window screens, by using air conditioning, and by regularly emptying and cleaning all receptacles both indoors and outdoors which may accumulate water (such as buckets, planters, pools or trashcans).78

The primary method of controlling A. aegypti is by eliminating its habitats. This is done by eliminating open sources of water, or if this is not possible, by adding insecticides or biological control agents to these areas. Generalized spraying with organophosphate or pyrethroid insecticides, while sometimes done, is not thought to be effective.79 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. Ideally, mosquito control would be a community activity, e.g. when all members of a community clear blocked gutters and street drains and keep their yards free of containers with standing water.80 If residences have direct water connections this eliminates the need for wells or street pumps and water-carrying containers.81

Vaccine

Main article: Dengue vaccine

As of March 2024, there are two vaccines to protect against dengue infection; Dengvaxia and Qdenga.82

Dengvaxia (formerly CYD-TDV) became available in 2015, and is approved for use in the US, EU and in some Asian and Latin American countries.83 It is an attenuated virus, is suitable for individuals aged 6–45 years and protects against all four serotypes of dengue.84 Due to safety concerns about antibody-dependent enhancement (ADE), it should only be given to individuals who have previously been infected with dengue, in order to protect them from reinfection.85 It is given subcutaneously as three doses at six month intervals.86

Qdenga (formerly TAK-003) completed clinical trials in 2022 and was approved for use in the European Union in December 2022;87 it has been approved by a number of other countries including Indonesia and Brazil, and has been recommended by the SAGE committee of the World Health Organization.88 It is indicated for the prevention of dengue disease in individuals four years of age and older, and can be administered to people who have not been previously infected with dengue. It is a live attenuated vaccine containing the four serotypes of dengue virus, administered subcutaneously as two doses three months apart.89

Severe disease

The World Health Organization's International Classification of Diseases divides dengue fever into two classes: uncomplicated and severe.90 Severe dengue is defined as that associated with severe bleeding, severe organ dysfunction, or severe plasma leakage.91

Severe dengue can develop suddenly, sometimes after a few days as the fever subsides.92 Leakage of plasma from the capillaries results in extreme low blood pressure and hypovolemic shock; Patients with severe plasma leakage may have fluid accumulation in the lungs or abdomen, insufficient protein in the blood, or thickening of the blood. Severe dengue is a medical emergency which can cause damage to organs, leading to multiple organ failure and death.93

Diagnosis

Mild cases of dengue fever can easily be confused with several common diseases including Influenza, measles, chikungunya, and zika.9495 Dengue, chikungunya and zika share the same mode of transmission (Aedes mosquitoes) and are often endemic in the same regions, so that it is possible to be infected simultaneously by more than one disease.96 For travellers, dengue fever diagnosis should be considered in anyone who develops a fever within two weeks of being in the tropics or subtropics.97

Warning symptoms of severe dengue include abdominal pain, persistent vomiting, odema, bleeding, lethargy, and liver enlargement. Once again, these symptoms can be confused with other diseases such as malaria, gastroenteritis, leptospirosis, and typhus.98

Blood tests can be used to confirm a diagnosis of dengue. During the first few days of infection, enzyme-linked immunosorbent assay (ELISA) can be used to detect the NS1 antigen; however this antigen is produced by all flaviviruses.99100 Four or five days into the infection, it is possible to reliably detect anti-dengue IgM antibodies, but this does not determine the serotype.101 Nucleic acid amplification tests provide the most reliable method of diagnosis.102

Treatment

As of July 2024, there is no specific antiviral treatment available for dengue fever.103

Most cases of dengue fever have mild symptoms, and recovery takes place in a few days.104 No treatment is required for these cases. Acetaminophen (Paracetamol, Tylenol) may be used to relieve mild fever or pain. Other common pain relievers, including aspirin, ibuprofen (Advil, Motrin IB, others) and naproxen sodium (Aleve) should be avoided as they can increase the risk of bleeding complications.105

For moderate illness, those who can drink, are passing urine, have no warning signs and are otherwise reasonably healthy can be monitored carefully at home. Supportive care with analgesics, fluid replacement, and bed rest are recommended.106107

Severe dengue is a life-threatening emergency, requiring hospitalization and potentially intensive care.108 Warning signs include dehydration, decreasing platelets and increasing hematocrit.109 Treatment modes include intravenous fluids, and transfusion with platelets or plasma.110

Prognosis

Most people with dengue recover without any ongoing problems. The risk of death among those with severe dengue is 0.8–2.5%,111 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%.112 The risk of death among children less than five years old is four times greater than among those over the age of 10.113 Elderly people are also at higher risk of a poor outcome.114

Epidemiology

See also: Dengue fever outbreaks

As of March 2023, dengue is endemic in more than 100 countries with cases reported in every continent with the exception of Antarctica.115116 The Americas, Southeast Asia and the Western Pacific regions are the most seriously affected.117118 It is difficult to estimate the full extent of the disease, as many cases are mild and not correctly diagnosed. WHO currently estimates that 3.9 billion people are at risk of dengue infection.119120 In 2013, it was estimated that 390 million dengue infections occur every year, with 500,000 of these developing severe symptoms and 25,000 deaths.121122

Generally, areas where dengue is endemic have only one serotype of the virus in circulation. The disease is said to be hyperendemic in areas where more than one serotype is circulating; this increases the risk of severe disease on a second or subsequent infection.123

Infections are most commonly acquired in urban environments where the virus is primarily transmitted by the mosquito species Aedes aegypti.124 This species has adapted to the urban environment, is generally found close to human habitation, prefers humans as its host, and takes advantage of small bodies of standing water (such as tanks and buckets) in which to breed. In rural settings the virus is transmitted to humans by A. aegypti and other related mosquitoes such as Aedes albopictus.125 Both these species have expanding ranges.126 There are two subspecies of Aedes aegypti, where Aedes aegypti formosus can be found in natural habitats such as forests and Aedes aegypti aegypti has adapted to urban domestic habitats.127

Dengue has increased in incidence in recent decades, with WHO recording a ten fold increase between 2010 and 2019 (from 500,000 to 5 million recorded cases).128 This increase is tied closely to the increasing range of Aedes mosquitoes, which is attributed to a combination of urbanization, population growth, and an increasingly warm climate.129130 In endemic areas, dengue infections peak when rainfall is optimal for mosquito breeding.131 In October 2023, the first confirmed symptomatic case of locally acquired dengue (i.e. not while travelling) in the US was identified in California.132

The disease infects all races, sexes, and ages equally. In endemic areas, the infection is most commonly seen in children who then acquire a lifelong partial immunity.133

History

The first historical record of a case of probable dengue fever is in a Chinese medical encyclopedia from the Jin dynasty (266–420) which referred to a "water poison" associated with flying insects.134135

The principal mosquito vector of dengue, Aedes aegypti, spread out of Africa in the 15th to 19th centuries due to the slave trade and consequent expansion of international trading.136 There have been descriptions of epidemics of dengue-like illness in the 17th century, and it is likely that epidemics in Jakarta, Cairo, and Philadelphia during the 18th century were caused by dengue.137138

It is assumed that dengue was constantly present in many tropical urban centres throughout the 19th and early 20th centuries, even though significant outbreaks were infrequent.139 The marked spread of dengue during and after the Second World War has been attributed partly to disruption caused by the war, and partly to subsequent urbanisation in south-east Asia.140 As novel serotypes were introduced to regions already endemic with dengue, outbreaks of severe disease followed. The severe hemorrhagic form of the disease was first reported in the Philippines in 1953; by the 1970s, it had become recognised as a major cause of child mortality in Southeast Asia.141

In Central and South America, the Aedes mosquito had been eradicated in the 1950s; however the eradication program was discontinued in the 1970s and the disease re-established itself in the region during the 1980s, becoming hyperendemic and causing significant epidemics.142

Dengue has continued to increase in prevalence during the 21st century, as the mosquito vector continues to expand its range. This is attributed partly to continuing urbanisation, and partly to the impact of a warmer climate.143

Etymology

The name came into English in the early 19th century from West Indian Spanish, which borrowed it from the Kiswahili term dinga / denga, meaning "cramp-like seizure" – the full term of the condition being ki-dinga pepo: "a sort of cramp-like seizure (caused by) an evil spirit".144 The borrowed term changed to dengue in Spanish due to this word existing in Spanish with the meaning "fastidiousness" and this folk etymology referring to the dislike of movement by affected patients.145146 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".147148

The term break-bone fever was applied by physician and United States Founding Father Benjamin Rush, in a 1789 report of the 1780 epidemic in Philadelphia, due to the associated muscle and joint pains. In the report title he uses the more formal term "bilious remitting fever".149 The term dengue fever came into general use only after 1828.150 Other historical terms include "breakheart fever" and "la dengue".151 Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine", "Thai", or "Singapore hemorrhagic fever".152

Research

Research directions include dengue pathogenesis (the process by which the disease develops in humans), as well as the biology, ecology and behaviour of the mosquito vector. Improved diagnostics would enable faster and more appropriate treatment.153 Attempts are ongoing to develop an antiviral medicine targeting the NS3 or NS5 proteins.154

In addition to the two vaccines which are already available, several vaccine candidates are in development.155

Effects of climate change

Rising temperatures and altered rainfall patterns are expanding the season and habitats of Aedes mosquitoes, the primary vectors of the disease.156 In India, a study has developed an early warning system that analyzes regional climate factors—such as temperature, rainfall, and humidity—to predict potential dengue outbreaks two months in advance, enhancing preparedness and response strategies.157158 Future projections indicate that dengue transmission risk will continue to rise with the rise in temperatures.159

Society and culture

Blood donation

Outbreaks of dengue fever increase the need for blood products while decreasing the number of potential blood donors due to potential infection with the virus.160 Someone who has a dengue infection is typically not allowed to donate blood for at least the next six months.161

Public awareness

International Anti-Dengue Day is observed every year on 15 June in a number of countries.162 The idea was first agreed upon in 2010 with the first event held in Jakarta, Indonesia, in 2011.163 Further events were held in 2012 in Yangon, Myanmar, and in 2013 in Vietnam.164 Goals are to increase public awareness about dengue, mobilize resources for its prevention and control and, to demonstrate the Southeast Asian region's commitment in tackling the disease.165 Efforts are ongoing as of 2019 to make it a global event.166

The Philippines has an awareness month in June since 1998.167168

A National Dengue Day is held in India annually on 16 May.169

Economic burden

A study estimated that the global burden of dengue in 2013 amounted to US$8.9 billion.170

See also

References

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