Dengue fever, also known as breakbone fever, is a mosquito-borne tropical disease caused

by the dengue virus. Symptoms include fever, headache, muscle and joint pains, and a
characteristic skin rash that is similar to measles. In a small proportion of cases, the disease
develops into the life-threatening dengue hemorrhagic fever, resulting in bleeding, low
levels of blood platelets and blood plasma leakage, or into dengue shock syndrome, where
dangerously low blood pressure occurs.
Dengue is transmitted by several species of mosquito within the genus Aedes, principally A.
aegypti. The virus has five different types;[1] infection with one type usually gives lifelong
immunity to that type, but only short-term immunity to the others. Subsequent infection with
a different type increases the risk of severe complications. As there is no commercially
available vaccine, prevention is sought by reducing the habitat and the number of mosquitoes
and limiting exposure to bites.
Treatment of acute dengue is supportive, using either oral or intravenous rehydration for mild
or moderate disease, and intravenous fluids and blood transfusion for more severe cases. The
number of cases of dengue fever has increased dramatically since the 1960s, with between 50
and 528 million people infected yearly.[2][3] Early descriptions of the condition date from
1779, and its viral cause and transmission were understood by the early 20th century. Dengue
has become a global problem since the Second World War and is endemic in more than
110 countries. Apart from eliminating the mosquitoes, work is ongoing on a dengue vaccine,
as well as medication targeted directly at the virus.

Signs and symptoms

Schematic depiction of the symptoms of dengue fever

Typically, people infected with dengue virus are asymptomatic (80%) or have only mild
symptoms such as an uncomplicated fever.[2][4][5] Others have more severe illness (5%), and in
a small proportion it is life-threatening.[2][5] 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.[6]
Therefore, travelers returning from endemic areas are unlikely to have dengue if fever or
other symptoms start more than 14 days after arriving home.[7] Children often experience

symptoms similar to those of the common cold and gastroenteritis (vomiting and diarrhea)[8]
and have a greater risk of severe complications,[7][9] though initial symptoms are generally
mild but include high fever.[9]

Clinical course

Clinical course of dengue fever[10]

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.[2][11] The course of
infection is divided into three phases: febrile, critical, and recovery.[10]
The febrile phase involves high fever, potentially over 40 C (104 F), and is associated with
generalized pain and a headache; this usually lasts two to seven days.[10][11] Nausea and
vomiting may also occur.[9] A rash occurs in 5080% of those with symptoms[11][12] in the first
or second day of symptoms as flushed skin, or later in the course of illness (days 47), as a
measles-like rash.[12][13] A rash described as "islands of white in a sea of red" has also been
observed.[14] Some petechiae (small red spots that do not disappear when the skin is pressed,
which are caused by broken capillaries) can appear at this point,[10] as may some mild
bleeding from the mucous membranes of the mouth and nose.[7][11] The fever itself is
classically biphasic or saddleback in nature, breaking and then returning for one or two days.
[13][14]

The rash of dengue fever in the acute stage of the infection blanches when pressed
In some people, the disease proceeds to a critical phase as fever resolves.[9] During this
period, there is leakage of plasma from the blood vessels, typically lasting one to two days.[10]
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.[10] There may also be
organ dysfunction and severe bleeding, typically from the gastrointestinal tract.[7][10] Shock
(dengue shock syndrome) and hemorrhage (dengue hemorrhagic fever) occur in less than 5%
of all cases of dengue,[7] however those who have previously been infected with other
serotypes of dengue virus ("secondary infection") are at an increased risk.[7][15] This critical
phase, while rare, occurs relatively more commonly in children and young adults.[9]

The rash that commonly forms during the recovery from dengue fever with its classic islands
of white in a sea of red.
The recovery phase occurs next, with resorption of the leaked fluid into the bloodstream.[10]
This usually lasts two to three days.[7] The improvement is often striking, and can be
accompanied with severe itching and a slow heart rate.[7][10] Another rash may occur with
either a maculopapular or a vasculitic appearance, which is followed by peeling of the skin.[9]
During this stage, a fluid overload state may occur; if it affects the brain, it may cause a

reduced level of consciousness or seizures.[7] A feeling of fatigue may last for weeks in adults.
[9]

Associated problems
Dengue can occasionally affect several other body systems,[10] either in isolation or along with
the classic dengue symptoms.[8] A decreased level of consciousness occurs in 0.56% of
severe cases, which is attributable either to inflammation of the brain by the virus or
indirectly as a result of impairment of vital organs, for example, the liver.[8][14][16]
Other neurological disorders have been reported in the context of dengue, such as transverse
myelitis and Guillain-Barr syndrome.[8][16] Infection of the heart and acute liver failure are
among the rarer complications.[7][10]

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 genus include yellow fever virus, West Nile virus, St. Louis
encephalitis virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kyasanur forest
disease virus, and Omsk hemorrhagic fever virus.[14] Most are transmitted by arthropods
(mosquitoes or ticks), and are therefore also referred to as arboviruses (arthropod-borne
viruses).[14]
The dengue virus genome (genetic material) contains about 11,000 nucleotide bases, which
code for the three different types of protein molecules (C, prM and E) that form the virus
particle and seven other types of protein molecules (NS1, NS2a, NS2b, NS3, NS4a, NS4b,
NS5) that are found in infected host cells only and are required for replication of the virus.[15]
[17]
There are five[1] strains of the virus, called serotypes, of which the first four are referred to

as DENV-1, DENV-2, DENV-3 and DENV-4.[4] The fifth type was announced in 2013.[1] The
distinctions between the serotypes are based on their antigenicity.[18]

Transmission

The mosquito Aedes aegypti feeding on a human host

Dengue virus is primarily transmitted by Aedes mosquitoes, particularly A. aegypti.[4] These
mosquitoes usually live between the latitudes of 35 North and 35 South below an elevation
of 1,000 metres (3,300 ft).[4] They typically bite during the day, particularly in the early
morning and in the evening,[19][20] but they are able to bite and thus spread infection at any
time of day all during the year.[21] Other Aedes species that transmit the disease include A.
albopictus, A. polynesiensis and A. scutellaris.[4] Humans are the primary host of the virus,[4]
[14]
but it also circulates in nonhuman primates.[22] An infection can be acquired via a single
bite.[23] A female mosquito that takes a blood meal from a person infected with dengue fever,
during the initial 210 day febrile period, becomes itself infected with the virus in the cells
lining its gut.[24] About 810 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.[6] 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 vertebrates.[6]
Dengue can also be transmitted via infected blood products and through organ donation.[25][26]
In countries such as Singapore, where dengue is endemic, the risk is estimated to be between
1.6 and 6 per 10,000 transfusions.[27] Vertical transmission (from mother to child) during
pregnancy or at birth has been reported.[28] Other person-to-person modes of transmission
have also been reported, but are very unusual.[11] 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.[9]

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.[7] Other risk

factors for severe disease include female sex, high body mass index,[9] and viral load.[29]
While each serotype can cause the full spectrum of disease,[15] virus strain is a risk factor.[9]
Infection with one serotype is thought to produce lifelong immunity to that type, but only
short-term protection against the other three.[4][11] 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.[17]
Dengue can be life-threatening in people with chronic diseases such as diabetes and asthma.
[17]

Polymorphisms (normal variations) in particular genes have been linked with an increased
risk of severe dengue complications. Examples include the genes coding for the proteins
known as TNF, mannan-binding lectin,[2] CTLA4, TGF,[15] DC-SIGN, PLCE1, and
particular forms of human leukocyte antigen from gene variations of HLA-B.[9][17] A common
genetic abnormality, especially in Africans, known as glucose-6-phosphate dehydrogenase
deficiency, appears to increase the risk.[29] Polymorphisms in the genes for the vitamin D
receptor and FcR seem to offer protection against severe disease in secondary dengue
infection.[17]

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 white blood cells, 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 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 capillary permeability. As a
result, less blood circulates in the blood vessels, and the blood pressure becomes so low that
it cannot supply sufficient blood to vital organs. Furthermore, dysfunction of the bone
marrow due to infection of the stromal cells leads to reduced numbers of platelets, which are
necessary for effective blood clotting; this increases the risk of bleeding, the other major
complication of dengue fever.[29]

Viral replication
Once inside the skin, dengue virus binds to Langerhans cells (a population of dendritic cells
in the skin that identifies pathogens).[29] 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.[15] DC-SIGN, a non-specific receptor for
foreign material on dendritic cells, seems to be the main point of entry.[17] The dendritic cell
moves to the nearest lymph node. Meanwhile, the virus genome is translated in membranebound vesicles on the cell's endoplasmic reticulum, where the cell's protein synthesis
apparatus produces new viral proteins that replicate the viral RNA and begin to form viral
particles. Immature virus particles are transported to the Golgi apparatus, the part of the cell
where some of the proteins receive necessary sugar chains (glycoproteins). The now mature
new viruses bud on the surface of the infected cell and are released by exocytosis. They are
then able to enter other white blood cells, such as monocytes and macrophages.[15]

The initial reaction of infected cells is to produce 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 dengue virus appear to have mechanisms to slow down this process. Interferon also
activates the adaptive immune system, which leads to the generation of antibodies against the
virus as well as T cells that directly attack any cell infected with the virus.[15] 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.[15]

Severe disease
It is not entirely clear why secondary infection with a different strain of dengue virus places
people at risk of dengue hemorrhagic fever and dengue shock syndrome. The most widely
accepted hypothesis is that of antibody-dependent enhancement (ADE). The exact
mechanism behind ADE is unclear. It may be caused by poor binding of non-neutralizing
antibodies and delivery into the wrong compartment of white blood cells that have ingested
the virus for destruction.[15][17] There is a suspicion that ADE is not the only mechanism
underlying severe dengue-related complications,[2][16] and various lines of research have
implied a role for T cells and soluble factors such as cytokines and the complement system.[29]
Severe disease is marked by the problems of capillary permeability (an allowance of fluid and
protein normally contained within blood to pass) and disordered blood clotting.[8][9] These
changes appear associated with a disordered state of the endothelial glycocalyx, which acts as
a molecular filter of blood components.[9] Leaky capillaries (and the critical phase) are
thought to be caused by an immune system response.[9] Other processes of interest include
infected cells that become necroticwhich affect both coagulation and fibrinolysis (the
opposing systems of blood clotting and clot degradation)and low platelets in the blood,
also a factor in normal clotting.[29]

Diagnosis
Warning signs[9][30]
Worsening abdominal pain
Ongoing vomiting
Liver enlargement
Mucosal bleeding
High hematocrit with low platelets
Lethargy or restlessness
Serosal effusions
The diagnosis of dengue is typically made clinically, on the basis of reported symptoms and
physical examination; this applies especially in endemic areas.[2] However, early disease can
be difficult to differentiate from other viral infections.[7] 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.[30] Warning signs typically occur before the onset of severe

dengue.[10] The tourniquet test, which is particularly useful in settings where no laboratory
investigations are readily available, involves the application of a blood pressure cuff at
between the diastolic and systolic pressure for five minutes, followed by the counting of any
petechial 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).[10][31]
The diagnosis should be considered in anyone who develops a fever within two weeks of
being in the tropics or subtropics.[9] It can be difficult to distinguish dengue fever and
chikungunya, a similar viral infection that shares many symptoms and occurs in similar parts
of the world to dengue.[11] Often, investigations are performed to exclude other conditions that
cause similar symptoms, such as malaria, leptospirosis, viral hemorrhagic fever, typhoid
fever, meningococcal disease, measles, and influenza.[7][32]
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.[7] A moderately elevated
level of aminotransferase (AST and ALT) from the liver is commonly associated with low
platelets and white blood cells.[9] In severe disease, plasma leakage results in
hemoconcentration (as indicated by a rising hematocrit) and hypoalbuminemia.[7] Pleural
effusions or ascites can be detected by physical examination when large,[7] but the
demonstration of fluid on ultrasound may assist in the early identification of dengue shock
syndrome.[2][7] The use of ultrasound is limited by lack of availability in many settings.[2]
Dengue shock syndrome is present if pulse pressure drops to 20 mm Hg along with
peripheral vascular collapse.[9] Peripheral vascular collapse is determined in children via
delayed capillary refill, rapid heart rate, or cold extremities.[10] 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