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= Dengue fever =
======================================================================
Introduction
======================================================================
Dengue fever is a mosquito-borne tropical disease caused by the dengue
virus. Symptoms typically begin three to fourteen days after
infection. This may include a high fever, headache, vomiting, muscle
and joint pains, and a characteristic skin rash. 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 bleeding, low levels of blood platelets and blood plasma
leakage, or into dengue shock syndrome, where dangerously low blood
pressure occurs.
Dengue is spread by several species of female mosquitoes of the
'Aedes' type, principally 'A. aegypti'. The virus has five types;
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. A number
of tests are available to confirm the diagnosis including detecting
antibodies to the virus or its RNA.
A vaccine for dengue fever 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 intravenously for mild or moderate disease. For more severe cases,
blood transfusion may be required. About half a million people require
hospital admission every year. Paracetamol (acetaminophen) is
recommended instead of nonsteroidal anti-inflammatory drugs (NSAIDs)
for fever reduction and pain relief in dengue due to an increased risk
of bleeding from NSAID use.
Dengue has become a global problem since the Second World War and is
common in more than 110 countries, mainly in Asia and South America.
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 neglected tropical disease.
Signs and symptoms
======================================================================
Typically, people infected with dengue virus are asymptomatic (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 incubation period (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 common cold and gastroenteritis (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 flushed skin, or later in the course of illness (days
4-7), as a measles-like rash. A rash described as "islands of white in
a sea of red" has also been observed. 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, as may some mild
bleeding from the mucous membranes of the mouth and nose. The fever
itself is classically biphasic 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 chest and abdominal cavity as well as
depletion of fluid from the circulation and decreased blood supply to
vital organs. There may also be organ dysfunction and severe bleeding,
typically from the gastrointestinal tract. Shock (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 serotypes 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
itching and a slow heart rate. Another rash may occur with either a
maculopapular or a vasculitic appearance, which is followed by peeling
of the skin. During this stage, a fluid overload state may occur; if
it affects the brain, it may cause a reduced level of consciousness or
seizures. A feeling of fatigue may last for weeks in adults.
Associated problems
=====================
Dengue can occasionally affect several other body systems, 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 inflammation of the brain by the virus or
indirectly as a result of impairment of vital organs, for example, the
liver.
Other neurological disorders have been reported in the context of
dengue, such as transverse myelitis and Guillain-Barré syndrome.
Infection of the heart and acute liver failure are among the rarer
complications.
A pregnant woman who develops dengue may be at a higher risk of
miscarriage as well as low birth weight and premature birth.
Virology
==========
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, Zika virus, St. Louis
encephalitis virus, Japanese encephalitis virus, tick-borne
encephalitis virus, Kyasanur forest disease virus, and Omsk
hemorrhagic fever virus. Most are transmitted by arthropods (mosquitos
or ticks), and are therefore also referred to as arboviruses
('ar'thropod-'bo'rne viruses).
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
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
serotypes, 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 antigenicity.
Transmission
==============
Dengue virus is primarily transmitted by 'Aedes' mosquitos,
particularly 'A. aegypti'. These mosquitos usually live between the
latitudes of 35° North and 35° South below an elevation 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 'A. albopictus', 'A.
polynesiensis' and 'A. scutellaris'. Humans are the primary host of
the virus, but it also circulates in nonhuman primates. 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 salivary glands and
is subsequently released into its saliva. The virus seems to have no
detrimental effect on the mosquito, which remains infected for life.
'Aedes aegypti' 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.
Dengue can also be transmitted via infected blood products and through
organ donation. In countries such as Singapore, where dengue is
endemic, the risk is estimated to be between 1.6 and 6 per 10,000
transfusions. Vertical transmission (from mother to child) during
pregnancy or at birth has been 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 risk factors for severe disease
include female sex, high body mass index, and viral load. 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 chronic
diseases such as diabetes and asthma.
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 TNFα, mannan-binding lectin,
CTLA4, TGFβ, DC-SIGN, PLCE1, and particular forms of human leukocyte
antigen from gene variations of HLA-B. A common genetic abnormality,
especially in Africans, known as glucose-6-phosphate dehydrogenase
deficiency, appears to increase the risk. Polymorphisms in the genes
for the vitamin D receptor and FcγR 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
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.
Viral replication
===================
Once inside the skin, dengue virus binds to Langerhans cells (a
population of dendritic cells in the skin that identifies pathogens).
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. 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
lymph node. Meanwhile, the virus genome is translated in
membrane-bound 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 are released by
exocytosis. They are then able to enter other white blood cells, such
as monocytes and macrophages.
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. 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.
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. 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 complement system.
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. These changes appear associated
with a disordered state of the endothelial glycocalyx, which acts as a
molecular filter 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
necrotic—which 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.
Diagnosis
======================================================================
|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. However, early disease can be difficult to
differentiate from other viral infections. A probable diagnosis is
based on the findings of fever plus two of the following: nausea and
vomiting, rash, generalized pains, low white blood cell count,
positive tourniquet test, or any warning sign (see table) in someone
who lives in an endemic area. Warning signs typically occur before the
onset of severe dengue. The tourniquet test, which is particularly
useful in settings where no laboratory investigations are readily
available, involves the application of a blood pressure cuff 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).
The diagnosis should be considered in anyone who develops a fever
within two weeks of being in the tropics or subtropics. 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. 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. Zika fever 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 low platelets
and metabolic acidosis. A moderately elevated level of
aminotransferase (AST and ALT) from the liver is commonly associated
with low platelets and white blood cells. In severe disease, plasma
leakage results in hemoconcentration (as indicated by a rising
hematocrit) and hypoalbuminemia. Pleural effusions or ascites can be
detected by physical examination when large, but the demonstration of
fluid on ultrasound may assist in the early identification of dengue
shock syndrome. The use of ultrasound is limited by lack of
availability in many settings. Dengue shock syndrome is present if
pulse pressure drops to ≤ 20 mm Hg along with peripheral vascular
collapse. Peripheral vascular collapse is determined in children via
delayed capillary refill, 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 World Health Organization'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 pulse 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 cell
cultures, nucleic acid detection by PCR, viral antigen detection (such
as for NS1) or specific antibodies (serology). Virus isolation and
nucleic acid detection are more accurate than antigen detection, but
these tests are not widely available due to their greater cost.
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 IgG and IgM, can be useful in
confirming a diagnosis in the later stages of the infection. Both IgG
and IgM are produced after 5-7 days. The highest levels (titres) of
IgM are detected following a primary infection, but IgM is also
produced in 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:
# Advocacy, social mobilization and legislation to ensure that public
health bodies and communities are strengthened;
# Collaboration between the health and other sectors (public and
private);
# An integrated approach to disease control to maximize use of
resources;
# Evidence-based decision making to ensure any interventions are
targeted appropriately; and
# Capacity-building to ensure an adequate response to the local
situation.
The primary method of controlling 'A. aegypti' is by eliminating its
habitats. This is done by getting rid of 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. 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 mosquito netting
while resting, and/or the application of insect repellent (DEET 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 vaccine for dengue fever 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 Sanofi and goes by the brand name
Dengvaxia. It is based on a weakened combination of the yellow fever
virus 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 antibody-dependent enhancement
(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
Jakarta, Indonesia in 2011. Further events were held in 2012 in
Yangon, Myanmar and in 2013 in Vietnam. 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 antiviral drugs 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 oral rehydration therapy. 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 intensive
care unit.
Intravenous hydration, if required, is typically only needed for one
or two days. In children with shock due to dengue a rapid dose of 20
mL/kg is reasonable. The rate of fluid administration is then titrated
to a urinary output of 0.5-1 mL/kg/h, stable vital signs and
normalization of hematocrit. The smallest amount of fluid required to
achieve this is recommended.
Invasive medical procedures such as nasogastric intubation,
intramuscular injections and arterial punctures are avoided, in view
of the bleeding risk. Paracetamol (acetaminophen) is used for fever
and discomfort while NSAIDs such as ibuprofen and aspirin are avoided
as they might aggravate the risk of bleeding. Blood transfusion 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. Packed red blood cells or whole blood are
recommended, while platelets and fresh frozen plasma are usually not.
There is not enough evidence to determine if corticosteroids have a
positive or negative effect in dengue fever.
During the recovery phase intravenous fluids are discontinued to
prevent a state of fluid overload. 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 loop diuretic such as
furosemide 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 common 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 vector-borne diseases 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 global warming. 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 disease burden estimated at 1,600 disability-adjusted life
years per million population. The World Health Organization counts
dengue as one of seventeen neglected tropical diseases.
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 'A. albopictus'.
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 climate change,
urbanization, 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 Jin Dynasty (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
slave trade. 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 John Burton Cleland
and Joseph Franklin Siler completed the basic understanding of dengue
transmission.
The marked spread of dengue during and after the Second World War has
been attributed to ecologic disruption. The same trends also led to
the spread of different serotypes of the disease to new areas, and to
the emergence of dengue hemorrhagic fever. This severe form of the
disease was first reported in the Philippines in 1953; by the 1970s,
it had become a major cause of child mortality 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 Swahili phrase 'Ka-dinga pepo',
which describes the disease as being caused by an evil spirit. 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".
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. 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 blood donors 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 vector control, a number of novel methods have been
used to reduce mosquito numbers with some success including the
placement of the guppy ('Poecilia reticulata') or copepods 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 'Wolbachia', 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
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Apart from attempts to control the spread of the 'Aedes' mosquito
there are ongoing efforts to develop antiviral drugs 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 RNA-dependent
RNA polymerase (coded by NS5), which copies the viral genetic
material, with nucleoside analogs. Secondly, it may be possible to
develop specific inhibitors of the viral protease (coded by NS3),
which splices viral proteins. Finally, it may be possible to develop
entry inhibitors, which stop the virus entering cells, or inhibitors
of the 5′ capping process, which is required for viral replication.
License
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License URL: http://creativecommons.org/licenses/by-sa/3.0/
Original Article: http://en.wikipedia.org/wiki/Dengue_fever