Dengue fever

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"Dengue Fever" redirects here. For the band of the same name, see Dengue Fever (band).
Dengue fever
Classification and external resources
ICD-10 A90.
ICD-9 061
DiseasesDB 3564
MedlinePlus 001374
eMedicine med/528
MeSH C02.782.417.214
Dengue virus

A TEM micrograph showing Dengue virus virions

(the cluster of dark dots near the center).
Virus classification
Group: Group IV ((+)ssRNA)
Family: Flaviviridae
Genus: Flavivirus
Species: Dengue virus

Dengue fever (pronounced UK: /ˈdɛŋɡeɪ/, US: /ˈdɛŋɡiː/) and dengue hemorrhagic fever
(DHF) are acute febrile diseases which occur in the tropics, can be life-threatening, and
are caused by four closely related virus serotypes of the genus Flavivirus, family
Flaviviridae.[1] It is also known as breakbone fever, since it can be extremely painful. It
occurs widely in the tropics, including northern Argentina, northern Australia,
Bangladesh, Barbados, Bolivia[2], Belize, Brazil, Cambodia, Colombia, Costa Rica, Cuba,
Dominican Republic,French Polynesia, Guadeloupe, El Salvador, Guatemala, Guyana,
Haiti, Honduras, India, Indonesia, Jamaica, Laos, Malaysia, Melanesia, Mexico,
Micronesia, Nicaragua, Pakistan, Panama, Paraguay[3], Philippines, Puerto Rico, Samoa[4],
Western Saudi Arabia, Singapore, Sri Lanka, Suriname, Taiwan, Thailand, Trinidad,
Venezuela and Vietnam, and increasingly in southern China[5]. Unlike malaria, dengue is
just as prevalent in the urban districts of its range as in rural areas. Each serotype is
sufficiently different that there is no cross-protection and epidemics caused by multiple
serotypes (hyperendemicity) can occur. Dengue is transmitted to humans by the Aedes
(Stegomyia) aegypti or more rarely the Aedes albopictus mosquito, both of which feed
exclusively during daylight hours. [6]

The WHO says some 2.5 billion people, two fifths of the world's population, are now at
risk from dengue and estimates that there may be 50 million cases of dengue infection
worldwide every year. The disease is now endemic in more than 100 countries.[7]

Contents
[hide]

• 1 Signs and symptoms

• 2 Cause
o 2.1 DENV
o 2.2 DENV E and M Proteins and the Assembly and Maturation of the Viral
Glycoprotein Shell
 2.2.1 E protein
 2.2.2 prM/M protein
o 2.3 Non-Structural proteins
 2.3.1 NS3 protein
 2.3.2 NS5 protein
• 3 Diagnosis
• 4 Prevention
o 4.1 Vaccine development
• 5 Treatment
• 6 Epidemiology
o 6.1 Recent outbreaks
o 6.2 Blood transfusion
• 7 History
 o 7.1 Etymology
o 7.2 History of the literature
• 8 Society and culture
o 8.1 Use as a biological weapon
• 9 Research
o 9.1 Wolbachia
o 9.2 Antiviral approaches
o 9.3 Sterile insect technique
• 10 See also
• 11 References

• 12 External links

[edit] Signs and symptoms

The disease manifests as fever of sudden onset associated with headache, muscle and
joint pains (myalgias and arthralgias—severe pain that gives it the nickname break-bone
fever or bonecrusher disease), distinctive retro-orbital pain, and rash.[8] The classic
dengue rash is a generalised maculopapular rash with islands of sparing. A hemorrhagic
rash of characteristically bright red pinpoint spots, known as petechiae can occur later
during the illness and is associated with thrombocytopenia. It usually appears first on the
lower limbs and the chest; in some patients, it spreads to cover most of the body. There
may also be severe retro-orbital pain, (a pain from behind the eyes that is distinctive to
Dengue infections), and gastritis with some combination of associated abdominal pain,
nausea, vomiting coffee-grounds-like congealed blood, or diarrhea. Some cases develop
much milder symptoms which can be misdiagnosed as influenza or other viral infection
when no rash or retro-orbital pain is present. Febrile travelers from tropical areas may
transmit dengue inadvertently to previously Dengue free populations of Aedes
(Stegomyia) Aegypti mosquitoes, having not been properly diagnosed for Dengue.
Patients only transmit Dengue when they are febrile and bitten by Aedes (Stegomyia)
Aegypti mosquitoes, or (much more unusually) via blood products. The classic dengue
fever lasts about two to seven days, with a smaller peak of fever at the trailing end of the
disease (the so-called "biphasic pattern"). Clinically, the platelet count will drop until
after the patient's temperature is normal. Cases of DHF also show higher fever, variable
hemorrhagic phenomena including bleeding from the eyes,nose,mouth and ear into the
gut, and oozing blood from skin pores, thrombocytopenia, and hemoconcentration. When
Dengue infections proceed to DHF symptoms, DHF causes vascular leak syndrome
which includes fluid in the blood vessels leaking through the skin and into spaces around
the lungs and belly. This fluid loss and severe bleeding can cause blood pressure to fall,
then Dengue Shock Syndrome (DSS) sets in, which has a high mortality rate.

[edit] Cause
[edit] DENV
Dengue fever is caused by Dengue virus (DENV), a mosquito-borne flavivirus. DENV is
an ssRNA positive-strand virus of the family Flaviviridae; genus Flavivirus. There are
four serotypes of DENV. The virus has a genome of about 11000 bases that codes for
three structural proteins, C, prM, E; seven nonstructural proteins, NS1, NS2a, NS2b,
NS3, NS4a, NS4b, NS5; and short non-coding regions on both the 5' and 3' ends.[9]

[edit] DENV E and M Proteins and the Assembly and Maturation of the
Viral Glycoprotein Shell

[edit] 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.[10] ,CD209 [11], Rab 5 [12], GRP 78 [13], and
The Mannose Receptor [14])have been shown to be important factors mediating attachment
and viral entry.[15]

[edit] 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.[15]

The glycoprotein shell of the mature DENV virion is comprised of 180 copies each of the
E protein and M protein. The immature virion starts out with the E and prM proteins
forming 90 heretodimers 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 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.[15]

[edit] Non-Structural proteins

[edit] 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 dependant 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.[15]

[edit] 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 at its C-
terminal end (residues 320–900). The methyltransferase domain is comprised of an α/β/β
sandwich flanked by N-and C-terminal subdomains. The DENV RNA-dependent RNA
polymerase is similar to other to other RdRps containing palm, finger, and thumb
subdomains and a GDD motif for incorporating nucleotides.[15]

The potential factors causing hemorrhagic fever are varied. The most suspected factors
are human's cross-serotypic immune response and membrane fusion process.

Human antibodies produced in response to the virus actually increase the infection.[16]

[edit] Diagnosis
The diagnosis of dengue is usually made clinically. The classic picture is high fever with
no localising source of infection, a rash with thrombocytopenia and relative leukopenia -
low platelet and white blood cell count. Dengue infection can affect many organs and
thus may present unusually as liver dysfunction, renal impairment, meningo-encephalitis
or gastroenteritis.

1. Fever, headaches, eye pain, severe dizziness and loss of appetite.

2. Hemorrhagic tendency (positive tourniquet test, spontaneous bruising, bleeding
from mucosa, gingiva, injection sites, etc.; vomiting blood, or bloody diarrhea)
3. Thrombocytopenia (<100,000 platelets per mm³ or estimated as less than 3
platelets per high power field)
4. Evidence of plasma leakage (hematocrit more than 20% higher than expected, or
drop in hematocrit of 20% or more from baseline following IV fluid, pleural
effusion, ascites, hypoproteinemia)
5. Encephalitic occurrences.

Dengue shock syndrome is defined as dengue hemorrhagic fever plus:

• Weak rapid pulse,

• Narrow pulse pressure (less than 20 mm Hg)
• Cold, clammy skin and restlessness.

Dependable, immediate diagnosis of dengue can be performed in rural areas by the use of
Rapid Diagnostic Test kits, which also differentiate between primary and secondary
dengue infections.[17] Serology and polymerase chain reaction (PCR) studies are available
to confirm the diagnosis of dengue if clinically indicated. Dengue can be a life
threatening fever.

[edit] Prevention
[edit] Vaccine development

There is no tested and approved vaccine for the dengue flavivirus. There are many
ongoing vaccine development programs. Among them is the Pediatric Dengue Vaccine
Initiative set up in 2003 with the aim of accelerating the development and introduction of
dengue vaccine(s) that are affordable and accessible to poor children in endemic
countries.[18] Thai researchers are testing a dengue fever vaccine on 3,000–5,000 human
volunteers after having successfully conducted tests on animals and a small group of
human volunteers.[19] A number of other vaccine candidates are entering phase I or II
testing.[20] As of July 2010, the National Institutes of Health reported on their
ClinicalTrials.Gov Web site that there were 19 vaccines undergoing testing or recruiting
for participants. [21] Because exposure to one of dengue's 4 serotypes provides no
immunity against infection by the other types, and may make the patient susceptible to
more severe disease symptoms, testing vaccines must be performed carefully, and usually
not in areas where the disease is endemic for fear that even attenuated virus vaccines may
cause severe reactions.[22]

In 1998, scientists from the Queensland Institute of Medical Research (QIMR) in

Australia and Vietnam's Ministry of Health introduced a scheme that encouraged children
to place a water bug, the crustacean Mesocyclops, in water tanks and discarded containers
where the Aedes aegypti mosquito was known to thrive.[23] This method is viewed as
being more cost-effective and more environmentally friendly than pesticides, though not
as effective, and requires the continuing participation of the community.[24]

Even though this method of mosquito control was successful in rural provinces, not much
is known about how effective it could be if applied to cities and urban areas. The
Mesocyclops can survive and breed in large water containers but would not be able to do
so in small containers that most urban dwellers have in their homes. Also, Mesocyclops
are hosts for the guinea worm, a pathogen that causes a parasite infection, and so this
method of mosquito control cannot be used in countries that are still susceptible to the
guinea worm. The biggest dilemma with Mesocyclops is that its success depends on the
participation of the community. This idea of a possible parasite-bearing creature in
household water containers dissuades people from continuing the process of inoculation
and, without the support and work of everyone living in the city, this method will not be
successful.[25]

[edit] Treatment
The mainstay of treatment is timely supportive therapy to tackle circulatory shock due to
hemoconcentration and bleeding. Close monitoring of vital signs in the critical period (up
to 2 days after defervescence - the departure or subsiding of a fever) is critical. Increased
oral fluid intake is recommended to prevent dehydration. Supplementation with
intravenous fluids may be necessary to prevent dehydration and significant concentration
of the blood if the patient is unable to maintain oral intake. A platelet transfusion may be
indicated if the platelet level drops significantly (below 20,000) or if there is significant
bleeding. The presence of melena may indicate internal gastrointestinal bleeding
requiring platelet and/or red blood cell transfusion.

Aspirin and non-steroidal anti-inflammatory drugs should be avoided as these drugs may
worsen the bleeding tendency associated with some of these infections. Patients may
receive paracetamol preparations to deal with these symptoms if dengue is suspected.[26]

[edit] Epidemiology

Disability-adjusted life year for dengue fever per 100,000 inhabitants in 2002.
no data < 15 15-30 30-45 45-60 90-105 105-120 120-135 135-150
60-75 75-90 150-250 > 250

Worldwide dengue distribution, 2006. Red: Epidemic dengue. Blue: Aedes aegypti.

Worldwide dengue distribution, 2000.

Dengue is transmitted by Aedes mosquitoes, particularly A. aegypti and A. albopictus.

The first recognized Dengue epidemics occurred almost simultaneously in Asia, Africa,
and North America in the 1780s, shortly after the identification and naming of the disease
in 1779. A pandemic began in Southeast Asia in the 1950s, and by 1975 DHF had
become a leading cause of death among children in the region. Epidemic dengue has
become more common since the 1980s. By the late 1990s, dengue was the most
important mosquito-borne disease affecting humans after malaria, with around 40 million
cases of dengue fever and several hundred thousand cases of dengue hemorrhagic fever
each year. Significant outbreaks of dengue fever tend to occur every five or six months.
The cyclical rise and fall in numbers of dengue cases is thought to be the result of
seasonal cycles interacting with a short-lived cross-immunity[clarification needed] for all four
strains in people who have had dengue. When the cross-immunity wears off the
population is more susceptible to transmission whenever the next seasonal peak occurs.
Thus over time there remain large numbers of susceptible people in affected populations
despite previous outbreaks due to the four different serotypes of dengue virus and the
presence of unexposed individuals from childbirth or immigration.

There is significant evidence, originally suggested by S.B. Halstead in the 1970s, that
dengue hemorrhagic fever is more likely to occur in patients who have secondary
infections by another one of dengue fever's four serotypes. One model to explain this
process is known as antibody-dependent enhancement (ADE), which allows for increased
uptake and virion replication during a secondary infection with a different strain.
Through an immunological phenomenon, known as original antigenic sin, the immune
system is not able to adequately respond to the stronger infection, and the secondary
infection becomes far more serious.[27]

Reported cases of dengue are an under-representation of all cases when accounting for
subclinical cases and cases where the patient did receive medical treatment.

There was a serious outbreak in Rio de Janeiro in February 2002 affecting around one
million people and killing sixteen. On March 20, 2008, the secretary of health of the state
of Rio de Janeiro, Sérgio Côrtes, announced that 23,555 cases of dengue, including 30
deaths, had been recorded in the state in less than three months. Côrtes said, "I am
treating this as an epidemic because the number of cases is extremely high." Federal
Minister of Health, José Gomes Temporão also announced that he was forming a panel to
respond to the situation. Cesar Maia, mayor of the city of Rio de Janeiro, denied that
there was serious cause for concern, saying that the incidence of cases was in fact
declining from a peak at the beginning of February.[28] By April 3, 2008, the number of
cases reported rose to 55,000 [29]

In Singapore, there are 4,000–5,000 reported cases of dengue fever or dengue

haemorrhagic fever every year. In the year 2004, there were seven deaths from dengue
shock syndrome.[30]

[edit] Recent outbreaks

Main articles: 2005 dengue outbreak in Singapore, 2006 dengue outbreak in India, 2006
dengue outbreak in Pakistan, and 2009 Bolivian dengue fever epidemic

An outbreak of dengue fever was declared in Cairns, located in the tropical north of
Queensland, Australia on 1 December 2008. As at 3 March 2009 there were 503
confirmed cases of dengue fever, in a residential population of 152,137. Outbreaks were
subsequently declared the neighbouring cities and towns of Townsville (outbreak
declared 5 January 2009), Port Douglas (6 February 2009), Yarrabah (19 February 2009),
Injinoo (24 February 2009), Innisfail (27 February 2009) and Rockhampton (10 March
2009). There have been occurrences of dengue types one, two, three, and four in the
region. On March 4, 2009, Queensland Health had confirmed an elderly woman had died
from dengue fever in Cairns, in the first fatality since the epidemic began last year. The
statement said that although the woman had other health problems, she tested positive for
dengue and the disease probably contributed to her death.

An epidemic broke out in Bolivia in early 2009, in which 18 people have died and 31,000
infected.

In 2009, in Argentina, a dengue outbreak was declared the northern provinces of Chaco,
Catamarca, Salta, Jujuy, and Corrientes, with over 9673 cases reported as of April 11,
2009 by the Health Ministry [3]. Some travelers from the affected zones have spread the
fever as far south as Buenos Aires [4]. Major efforts to control the epidemic in Argentina
are focused on preventing its vector (the Aedes mosquitoes) from reproducing. This is
addressed by asking people to dry out all possible water reservoirs from where
mosquitoes could proliferate (which is, in other countries, known as "descacharrado").
There have also been information campaigns concerning prevention of the dengue fever;
and the government is fumigating with insecticide in order to control the mosquito
population.[31]

The first cases of dengue fever have recently been reported on the island nation of
Mauritius in the Indian Ocean. One of the South Asian countries still suffering highly
from this problem is Sri Lanka.[32]

[edit] Blood transfusion

Dengue may also be transmitted via infected blood products (blood transfusions, plasma,
and platelets),[33][34] and in countries such as Singapore, where dengue is endemic, the risk
was estimated to be between 1.6 and 6 per 10,000 blood transfusions.[35]

[edit] History
[edit] 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.[36] 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.[37] Alternatively, the use of the Spanish word
may derive from the similar-sounding Swahili.[38]

[edit] History of the literature

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".[39] 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.[38] The first
confirmed case report dates from 1789 and is by Benjamin Rush, who coined the term
"breakbone fever" because of the symptoms of myalgia and arthralgia.[40] The viral
etiology and the transmission by mosquitoes were discovered in the 20th century by Sir
John Burton Cleland.

Population movements during World War II spread the disease globally. A pandemic of
dengue began in Southeast Asia after World War II and has spread around the globe since
then.[41]

[edit] Society and culture