Hepatitis Dalam Kehamilan

3/10/2018 Dengue: Practice Essentials, Background, Pathophysiology
This site is intended for healthcare professionals
Dengue
Updated: Sep 28, 2017
Author: Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM; Chief Editor: Michael
Stuart Bronze, MD more...
OVERVIEW
Practice Essentials
Dengue is the most common and important arthropodborne viral (arboviral) illness in humans.
It is transmitted by mosquitoes of the genus Aedes, which are widely distributed in subtropical
and tropical areas of the world (see the image below). The incidence of dengue has increased
dramatically in recent decades, with estimates of 40%50% of the world’s population at risk for
the disease in tropical, subtropical, and, most recently, more temperate areas. [1]
Drawing of Aedes aegypti mosquito. Picture from the Centers for Disease Control and Prevention (CDC)
Web site.
View Media Gallery
A small percentage of persons who have previously been infected by one dengue serotype
develop bleeding and endothelial leak upon infection with another dengue serotype. This
https://emedicine.medscape.com/article/215840‐overview?pa=Nt3NPRomlmTkLpvvR%2Fv7Zqyyrf6JUCDoNULsOkjrMob%2FoFCTWUkSi8KQz3%2F6C… 1/29
syndrome is termed severe dengue (also known as dengue hemorrhagic fever and dengue
shock syndrome).
Dengue fever is typically a selflimited disease with a mortality rate of less than 1% when
detected early and with access to proper medical care. When treated, severe dengue has a
mortality rate of 2%5%, but, when left untreated, the mortality rate is as high as 20%.
See 7 Bug Bites You Need to Know This Summer, a Critical Images slideshow, for helpful
images and information on various bug bites.
Signs and symptoms
On average, dengue becomes symptomatic after a 4 to 10day incubation period (range, 314
days). Dengue symptoms usually last 27 days.
Many individuals with dengue may be asymptomatic. Many patients with dengue experience a
prodrome of chills; rash, including erythematous mottling of the skin; and facial flushing, which
may last 23 days. Children younger than 15 years who have dengue usually have a
nonspecific febrile syndrome, which may be accompanied by a maculopapular rash. Dengue
should be suspected in individuals who present with high fever (104°F/40°C), retroorbital
headache, muscle and joint pain, nausea, lymphadenopathy, vomiting, and rash and who have
traveled within 2 weeks of symptom onset to an area where appropriate vectors are present
and dengue transmission may be occurring.
Accompanying symptoms in patients with dengue may include any of the following:
Headache
Retroorbital pain
Severe myalgias: Especially of the lower back, arms, and legs
Arthralgias: Usually of the knees and shoulders
Nausea and vomiting (diarrhea is rare)
Rash: A maculopapular or macular confluent rash over the face, thorax, and flexor
surfaces, with islands of skin sparing
Weakness, malaise, and lethargy
Altered taste sensation
Anorexia
Sore throat
Mild hemorrhagic manifestations (eg, petechiae, bleeding gums, epistaxis, menorrhagia,
hematuria)
Lymphadenopathy
Severe dengue (dengue hemorrhagic fever and dengue shock syndrome)
The initial phase of severe dengue is similar to that of dengue fever and other febrile viral
illnesses. Shortly after the fever breaks (37 days after symptom onset or sometimes within 24
hours before), signs of plasma leakage appear, along with the development of hemorrhagic
symptoms such as bleeding from sites of trauma, gastrointestinal bleeding, and hematuria.
Patients may also present with severe abdominal pain, persistent vomiting that may contain
blood, fatigue, and febrile seizures (in children).
The subsequent 24 hours frequently prove critical. If left untreated, hemorrhagic fever most
likely progresses to shock. Common symptoms in impending shock include abdominal pain,
vomiting, and restlessness. Patients also may have symptoms related to circulatory failure,
such as pallor, tachypnea, tachycardia, dizziness/lightheadedness, and a decreased level of
consciousness.
See Clinical Presentation for more detail.
Diagnosis
Laboratory criteria for the diagnosis of dengue include one or more of the following, which are
used to detect the virus, viral nucleic acid, antibodies or antigens, or a combination thereof:
Demonstration of a fourfold or greater change in reciprocal immunoglobulin G (IgG) or
IgM antibody titers to 1 or more dengue virus antigens in paired serum samples
Demonstration of dengue virus antigen in autopsy tissue via immunohistochemistry or
immunofluorescence or in serum samples via enzyme immunoassay (MACELISA, IgG
ELISA, nonstructural protein 1 [NS1] ELISA, EIA)
Detection of viral genomic sequences in autopsy tissue, serum, or cerebral spinal fluid
(CSF) samples via reversetranscriptase polymerase chain reaction (RTPCR) assay: RT
PCR provides earlier and more specific diagnosis.
Less frequently, isolation of the dengue virus from serum, plasma, leukocytes, or autopsy
samples
During the early phase of the disease (first 45 days), virus can be detected in serum, plasma,
circulating blood cells, and tissues. Virus isolation, nucleic acid detection, and antigen detection
are more useful to diagnose infection. At the end of the acute phase of illness, serology
becomes the method of choice.
The following laboratory tests should also be performed in the workup of patients with possible
dengue:
Complete blood cell (CBC) count
Metabolic panel
Serum protein and albumin levels
Liver panel
Coagulation panel with or without disseminated intravascular coagulation (DIC) panel
Characteristic laboratory findings in dengue are as follows:
Thrombocytopenia (platelet count <100 x 109/L)
Leukopenia
Mild to moderate elevation of aspartate aminotransferase and alanine aminotransferase
values
In patients with severe dengue, the following may be present:
Increased hematocrit level secondary to plasma extravasation and/or thirdspace fluid
loss
Hypoproteinemia
Prolonged prothrombin time
Prolonged activated partial thromboplastin time
Decreased fibrinogen
Increased amount of fibrin split products
Guaiac testing for occult blood in the stool should be performed on all patients in whom dengue
virus infection is suspected. Urinalysis identifies hematuria.
Imaging studies include the following:
Chest radiography
Head computed tomography (CT) scanning without contrast: To detect intracranial
bleeding or cerebral edema due to severe dengue
Ultrasonography: To detect fluid in the chest and abdominal cavities, pericardial effusion,
and a thickened gallbladder wall in patients with severe dengue
See Workup for more detail.
Management
Oral rehydration therapy is recommended for patients with moderate dehydration caused by
high fever and vomiting.
Patients who develop signs of severe dengue warrant closer observation. Admission for close
volume status monitoring and intravenous fluid administration is indicated for patients who
develop signs of dehydration, such as the following:
Tachycardia
Prolonged capillary refill time
Cool or mottled skin
Diminished pulse amplitude
Altered mental status
Decreased urine output
Rising hematocrit
Narrowed pulse pressure
Hypotension
Patients with internal or gastrointestinal bleeding may require transfusion, and patients with
coagulopathy may require fresh frozen plasma.
See Treatment and Medication for more detail.
Background
Dengue is the most common and important arthropodborne viral (arboviral) illness in humans.
Globally, 2.53 billion individuals live in approximately 112 countries that experience dengue
transmission. While the annual incidence is unclear owing to incomplete global reporting and
misclassification of illness, approximately 3.2 million individuals were infected globally in 2015.
It is caused by infection with 1 of the 4 serotypes of dengue virus, which is a Flavivirus (a genus
of singlestranded nonsegmented RNA viruses). Infection with one dengue serotype confers
lifelong homotypic immunity to that serotype and a brief period (approximately 2 years) of
partial heterotypic immunity to other serotypes, but an individual can eventually be infected by
all 4 serotypes. Several serotypes can be in circulation during an epidemic.
Dengue is transmitted by mosquitoes of the genus Aedes, which are widely distributed in
subtropical and tropical areas of the world (see the image below). An individual with dengue is
capable of transmitting the virus for 45 days (maximum, 12 days) to a capable vector. After an
incubation period of 510 days, the infected mosquito can transmit virus for the rest of its life
span (2 weeks to 1 month). Aedes albopictus is more cold tolerant than Aedes aegypti, so it
can survive and transmit virus in the more temperate regions of the United States and Europe.
The global incidence of dengue has increased dramatically in the last several decades, with an
estimated 40%50% of the world’s population in 128 countries at risk. [2, 3, 4] Today, severe
dengue largely affects Asian and Latin American countries, where it is a leading cause of
hospitalization and death.
Initial dengue infection may be asymptomatic (50%90%), [5] may result in a nonspecific febrile
illness, or may produce the symptom complex of classic dengue fever (DF). Classic dengue
fever is marked by rapid onset of high fever, headache, retroorbital pain, diffuse body pain
(both muscle and bone), weakness, vomiting, sore throat, altered taste sensation, and a
centrifugal maculopapular rash, among other manifestations. The severity of the pain led to the
term breakbone fever to describe dengue.
A small percentage of persons who have previously been infected by one dengue serotype
develop bleeding and endothelial leak upon infection with another dengue serotype. This
syndrome is termed severe dengue (reclassified in 2009 by the WHO, previously referred to as
dengue hemorrhagic fever and dengue shock syndrome).
Severe dengue has also been termed dengue vasculopathy. Vascular leakage in these patients
results in hemoconcentration and serous effusions and can lead to circulatory collapse. This, in
conjunction with severe hemorrhagic complications, can lead to a shock syndrome, which
poses a greater fatality risk than bleeding per se. [6]
Dengue virus transmission follows 2 general patterns: epidemic dengue and hyperendemic
dengue. Epidemic dengue transmission occurs when dengue virus is introduced into a region
as an isolated event that involves a single viral strain. If the number of vectors and susceptible
pediatric and adult hosts is sufficient, explosive transmission can occur, with an infection
incidence of 2550%. Mosquitocontrol efforts, changes in weather, and herd immunity
contribute to the control of these epidemics. Transmission appears to begin in urban centers
and then spreads to the rest of the country. [7] This is the current pattern of transmission in
parts of Africa and South America, areas of Asia where the virus has reemerged, and small
island nations. Travelers to these areas are at increased risk of acquiring dengue during these
periods of epidemic transmission.
Hyperendemic dengue transmission is characterized by the continuous circulation of multiple
viral serotypes in an area where a large pool of susceptible hosts and a competent vector (with
or without seasonal variation) are constantly present. This is the predominant pattern of global
transmission. In areas of hyperendemic dengue, antibody prevalence increases with age, and
most adults are immune. Hyperendemic transmission appears to be a major risk for dengue
hemorrhagic fever. Travelers to these areas are more likely to be infected than are travelers to
areas that experience only epidemic transmission. [8]
Because the signs and symptoms of dengue fever are nonspecific, attempting laboratory
confirmation of dengue infection by serodiagnosis, reversetranscriptase polymerase chain
reaction (RTPCR), or culture is important. Serodiagnosis is made on the basis of a rise in
antibody titer in paired IgG or IgM specimens. Results vary depending on whether the infection
is primary or secondary (see Presentation and Workup). Dengue is a reportable disease in the
United States; known or suspected cases should be reported to public health authorities.
Dengue fever is usually a selflimited illness. Supportive care with analgesics, judicious fluid
replacement, and bed rest is usually sufficient. Successful management of severe dengue
requires intravascular volume replacement, with careful attention to fluid management and
proactive treatment of hemorrhage. Admission to an intensive care unit is indicated for patients
with severe dengue (see Treatment).
Historical background
The earliest known documentation of dengue fever–like illness was in the Chinese
Encyclopedia of Symptoms during the Chin Dynasty (CE 265420). The illness was called "the
water poison" and was associated with flying insects near water.
Earliest recorded outbreaks
Outbreaks of febrile illnesses compatible with dengue fever have been recorded throughout
history, with the first epidemic described in 1635 in the West Indies.
In 17791780, the first confirmed, reported outbreak of dengue fever occurred almost
simultaneously in Asia, North America, and Africa. In 1789, the American physician Benjamin
Rush published an account of a probable dengue fever epidemic that had occurred in
Philadelphia in 1780. Rush coined the term breakbone fever to describe the intense symptoms
reported by one of his patients.
A denguelike epidemic in East Africa in the early 1820s was called, in Swahili, ki denga pepo
("it is a sudden overtaking by a spirit"). The English version of this term, “Dandy fever,” was
applied to an 182728 Caribbean outbreak, and in the Spanish Caribbean colonies, that term
was altered to “dengue.”
Increased distribution after World War II
Probable outbreaks of dengue fever occurred sporadically every 1030 years until after World
War II. The socioeconomic disruptions caused by World War II resulted in increased worldwide
spread of dengue viruses and capable vectors. The first epidemic of dengue hemorrhagic fever
in the modern era was described in Manila in 1953. After that, outbreaks of dengue fever
became more common.
A pattern developed in which dengue fever epidemics occurred with increasing frequency and
were associated with occasional dengue hemorrhagic fever cases. Subsequently, dengue
hemorrhagic fever epidemics occurred every few years. Eventually, dengue hemorrhagic fever
epidemics occurred yearly, with major outbreaks occurring approximately every 3 years. This
pattern has repeated itself as dengue fever has spread to new regions.
Although initial epidemics were located in urban areas, increased dengue spread has involved
suburban and rural locales in Asia and Latin America. The only continents that do not
experience dengue transmission are Europe and Antarctica. In the 1950s, 9 countries reported
dengue outbreaks; currently, the geographic distribution includes more than 100 countries
worldwide. Several of these countries had not previously reported dengue, and many had not
reported dengue in 20 years.
Dengue transmission spread from Southeast Asia into surrounding subtropical and tropical
Asian countries, southern China and southern Taiwan, the Indian subcontinent and Sri Lanka,
and down the island nations of Malaysia, the Philippines, New Guinea, northeastern Australia,
and several Pacific islands, including Tahiti, Palau, Tonga, and the Cook Islands.
Hyperendemic transmission is reported in Vietnam, Thailand, Indonesia, Pakistan, India,
Malaysia, and the Philippines. Dengue continues to extend its range.
In the Americas, dengue epidemics were rare post war because Aedes mosquitoes had been
eradicated from most of the region through coordinated vectorcontrol efforts. Systematic
spraying was halted in the early 1970s because of environmental concerns. By the 1990s, A
aegypti mosquitoes repopulated most of the countries in which they had been eliminated.
In 2014, increased cases of dengue were reported to the WHO in the Peoples Republic of
China, Cook Island, Fiji, Malaysia, and Vanuatu, which experienced an outbreak of dengue
serotype 3 (DENV3) after a 10year hiatus. In 2015, large outbreaks of dengue were reported
in the Philippines (>169,000 cases), Malaysia (>111,000 suspected cases), and Brazil (>1.5
million cases). Delhi, India, experienced its worse outbreak since 2006.
DENV1 and DENV2
Serotype 1 dengue (DENV1) was introduced into a largely susceptible population in Cuba in
1977. Serosurveys indicated that more than 44% of the population was infected, with only mild
disease reported. The first dengue hemorrhagic fever epidemic in the Americas occurred in
Cuba in 1981 and involved serotype 2 dengue (DENV2), with hundreds of thousands of cases
of dengue in both children and adults, 24,000 cases of dengue hemorrhagic fever, 10,000
cases of dengue shock syndrome, and 158 reported deaths.
In 1997, Asian genotype DENV2 was reintroduced, and dengue shock syndrome and dengue
hemorrhagic fever were seen only in adults who had previously been infected with DENV1 in
1977. Disease and casefatality rates were higher in those who had been infected with DENV2
20 years after their initial DENV1 infection than those who were infected 4 years apart.
Data from other countries supports the finding that the severity of secondary dengue infections
appears to intensify with longer intervals between infections. [9, 10] Since then, dengue fever
and dengue hemorrhagic fever cases have progressively increased.
United States
In 1986, the first clearly identified local transmission of dengue in the United States occurred in
Texas. Carriers of the virus were believed to have crossed the border from Mexico; the local
vector population was then infected. Since then, seasonal autochthonous infection has been
reported in both Texas and Hawaii.
In 20012002, Hawaii experienced its first outbreak of dengue since World War II ended. The
outbreak involved 2 variants of DENV1 that were transmitted by A albopictus. Predominantly
affecting young adults and adults, 122 cases of dengue fever spread slowly on Maui, Oahu,
and Kauai. The epidemic was traced to viremic visitors from Tahiti, which was then
experiencing a severe outbreak of the infection. In 2015, Hawaii reported more than 65,000
cases, with ongoing transmission reported in 2016.
Two competent vectors, A aegypti and A albopictus, are currently seasonally abundant in some
areas of the southwestern and southeastern United States, including Texas, Arizona, New
Mexico, Louisiana, Mississippi, Alabama, Georgia, and mid to south Florida. A aegypti has also
been reported sporadically in portions of North Carolina, South Carolina, Tennessee, Arkansas,
Maryland, and New Jersey. The range of A albopictus extends almost as far north as the Great
Lakes.
As suggested by a reported case of a woman aged 63 years who died from complications of
dengue acquired in New Mexico or Texas in 2012, the disease may not be adequately
recognized in the United States as a source of potentially fatal acute febrile illness. The patient
had initially been diagnosed with West Nile virus, but a postmortem bone marrow biopsy
revealed the presence of dengue virus. [11, 12]
In addition, the patient’s records revealed that she met the clinical case definition for
hemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome that is sometimes
associated with dengue and that, in this instance, was the cause of death.
Europe
Dengue fever did not naturally occur in the European Union and in continental Europe because
these areas did not have an appropriate vector population to allow further spread of dengue
from viremic individuals returning from other countries. However, dengue does occur in several
overseas territories of European Union members. In recent decades, reports of dengue
infections in longterm expatriates, aid workers, military personnel, immigrants, and travelers
returning from the tropics and subtropics have been increasing. In 2010, local transmission was
reported in France and Croatia. Another outbreak with more than 2000 cases occurred in
Madeira in 2012.
Factors believed to be responsible for the spread of dengue include the following:
Explosive population growth
Unplanned urban overpopulation with inadequate public health systems
Poor control of standing water and vectors
Viral evolution
Increased international recreational, business, and military travel to endemic areas
All of these factors must be addressed to control the spread of dengue and other mosquito
borne infections. Unplanned urbanization is believed to have had the largest impact on disease
amplification in individual countries, whereas travel is believed to have had the largest impact
on global spread. [5, 7, 8, 10, 13]
Travel surveillance
Over the past decades, the GeoSentinel Network of Travel Medicine providers has
demonstrated that dengue has become more frequently diagnosed than malaria in travelers
returning from tropical areas other than Africa. Such sentinel travel surveillance can augment
global and national public health surveillance. More recent studies have not supported an
earlier suggestion that climate change is also directly responsible for increased transmission. [9,
8, 10]
Pathophysiology
Dengue fever is a mosquitoborne viral disease caused by 1 of 4 closely related but
antigenically distinct serotypes of dengue virus, serotypes DENV1 through DEN4. [14]
Infection with one dengue serotype confers lifelong homotypic immunity and a brief period of
partial heterotypic immunity (2 years), but each individual can eventually be infected by all 4
serotypes. Several serotypes can be in circulation during an epidemic.
The Aedes mosquito
Dengue viruses are transmitted by the bite of an infected female Aedes (subgenus Stegomyia)
mosquito. [15] Both males and females require nectar for energy. Females require a blood meal
as a source of appropriate protein for egg development. Globally, Aedes aegypti is the
predominant highly efficient mosquito vector for dengue infection, but the Asian tiger mosquito,
Aedes albopictus, and other Aedes species can also transmit dengue with varying degrees of
efficiency (see the images below).
Drawing of Aedes aegypti mosquito. Picture from the Centers for Disease Control and Prevention (CDC)
Web site.
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Aedes aegypti mosquito. Picture from the Centers for Disease Control and Prevention (CDC) Web site.
View Media Gallery
Aedes albopictus. From CDC Public Domain.
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Aedes mosquito species have adapted well to human habitation, often breeding around
dwellings in small amounts of stagnant water found in old tires or other small containers
discarded by humans. Even a bottle cap filled with water can serve as to incubate and hatch
Aedes eggs. Eggs can survive periods of drying and will hatch when exposed to water. Humans
are the preferred hosts.
Female Aedes mosquitoes are daytime feeders. They inflict an innocuous bite, usually on the
back of the neck and the ankles, and are easily disturbed during a blood meal, causing them to
move on to finish a meal on another individual, making them efficient vectors. Not uncommonly,
entire families develop infection within a 24 to 36hour period, presumably from the bites of a
single infected mosquito.
Hosts for transmission
Humans serve as the primary reservoir for dengue. Certain nonhuman primates in Africa and
Asia also serve as hosts but do not develop dengue hemorrhagic fever. Mosquitoes acquire the
virus when they feed on a carrier of the virus. Persons with dengue viruses in their blood can
transmit the viruses to the mosquito 1 day before the onset of the febrile period. The patient
usually remains infectious for the subsequent 45 days (up to 12 days).
The mosquito can transmit dengue if it immediately bites another host. In addition, transmission
occurs after 812 days of viral replication in the mosquito's salivary glands (extrinsic incubation
period). The virus does not adversely affect the mosquito. The mosquito remains infected for
the remainder of its life. The life span of A aegypti is usually 21 days but ranges from 15 to 65
days. Vertical transmission of dengue virus in mosquitoes has been documented. [16] The eggs
of Aedes mosquitoes withstand long periods of desiccation, reportedly as long as 1 year, but
are killed by temperatures of less than 10°C. Rare cases of vertical dengue transmission have
been reported. In addition, rare reports of humantohuman transmission via needlestick
injuries have been published. [17]
Once inoculated into a human host, dengue has an incubation period of 314 days (average 47
days) while viral replication takes place in target dendritic cells. Infection of target cells,
primarily those of the reticuloendothelial system, such as dendritic cells, macrophages,
hepatocytes, and endothelial cells, [18, 19, 20, 21] result in the production of immune mediators
that serve to shape the quantity, type, and duration of cellular and humoral immune response to
both the initial and subsequent virus infections. [18, 22, 23, 24, 25, 26, 27]
Dengue viral infections frequently are not apparent. In most cases, especially in children
younger than 15 years, the patient is asymptomatic or has a mild undifferentiated febrile illness
lasting 57 days. Classic dengue fever primarily occurs in nonimmune, nonindigenous adults
and children and is typically selflimiting. Recovery is usually complete by 710 days. Severe
dengue (dengue hemorrhagic fever/dengue shock syndrome) usually occur around the third to
seventh day of illness during a second dengue infection in persons with preexisting actively or
passively (maternally) acquired immunity to a heterologous dengue virus serotype.
Dengue fever
Dengue presents in a nonspecific manner similarly to that of many other viral and bacterial
illnesses. Fever typically begins on the third day of illness and persists 57 days, abating with
the cessation of viremia. Fever may reach 41C°. Occasionally, and more frequently in children,
the fever abates for a day and recurs, a pattern that is termed a saddleback fever; however, this
pattern is more commonly seen in dengue hemorrhagic fever.
Leukopenia, lymphopenia near the end of the febrile phase, and thrombocytopenia are
common findings in dengue fever and are believed to be caused by direct destructive actions of
the virus on bone marrow precursor cells. The resulting active viral replication and cellular
destruction in the bone marrow are believed to cause the bone pain. Approximately one third of
patients with dengue fever may have mild hemorrhagic symptoms, including petechiae, gingival
bleeding, and a positive tourniquet test (>20 petechiae in an area of 2.5 X 2.5 cm). Dengue
fever is rarely fatal.
Severe dengue (dengue hemorrhagic fever)
Severe dengue occurs less frequently than dengue fever but has a more dramatic clinical
presentation. In most of Asia, where it first was described, severe dengue is primarily a disease
of children. However, in the Americas, and more recently reported in Taiwan, severe dengue
has an equal distribution in all ages.
Severe dengue typically begins with the initial manifestations of dengue fever. The acute febrile
illness (temperatures ≤40°C), like that of dengue fever, lasts approximately 27 days. However,
in persons with severe dengue, the fever reappears, giving a biphasic or saddleback fever
curve.
Along with biphasic fever, patients with severe dengue have progressive thrombocytopenia,
increasing hematocrit (20% absolute rise from baseline) and low albumin (signs of
hemoconcentration preceding shock), more obvious hemorrhagic manifestations (>50% of
patients have a positive tourniquet test), and progressive effusions (pleural or peritoneal).
Lymphocytosis, often with atypical lymphocytes, commonly develops before defervescence or
the onset of shock. Transaminase levels may be mildly elevated or present in the several
thousands associated with hepatomegaly in those patients with acute hepatitis. Low fibrinogen
and elevated fibrin split products are signs of disseminated intravascular coagulation. Severe
metabolic acidosis and circulatory failure can occur.
The critical feature of severe dengue is plasma leakage. Plasma leakage is caused by
increased capillary permeability and may manifest as hemoconcentration, as well as pleural
effusion and ascites. Bleeding is caused by capillary fragility and thrombocytopenia and may
manifest in various forms, ranging from petechial skin hemorrhages to lifethreatening
gastrointestinal bleeding.
Liver damage manifests as increases in levels of alanine aminotransferase and aspartate
aminotransferase, low albumin levels, and deranged coagulation parameters (prothrombin time,
partial thromboplastin time). [28, 29] In persons with fatal dengue hepatitis, infection was
demonstrated in more than 90% of hepatocytes and Kupffer cells with minimal cytokine
response (tumor necrosis factor [TNF]–alpha, interleukin [IL]–2). This is similar to that seen with
fatal yellow fever and Ebola infections. [28]
As the term implies, severe dengue shock is essentially dengue hemorrhagic fever with
progression into circulatory failure, with ensuing hypotension, narrow pulse pressure (< 20 mm
Hg), and, ultimately, shock and death if left untreated. Death may occur 824 hours after onset
of signs of circulatory failure. The most common clinical findings in impending shock include
hypothermia, abdominal pain, vomiting, and restlessness.
Secondary infection
The immunopathology of severe dengue remains incompletely understood. Most patients who
develop severe dengue have had prior infection with one or more dengue serotypes. When an
individual is infected with another serotype (ie, secondary infection) and produces low levels of
nonneutralizing antibodies, these antibodies, directed against 1 of 2 surface proteins (precursor
membrane protein and envelope protein), when bound by macrophage and monocyte Fc
receptors, have been proposed to fail to neutralize virus and instead form an antigenantibody
complex.
This results in increased viral entry into macrophages bearing IgG receptors, allowing
unchecked viral replication with higher viral titers and increased cytokine production and
complement activation, a phenomenon called antibodydependent enhancement. [30, 31]
The affected macrophages release vasoactive mediators that increase vascular permeability,
leading to vascular leakage, hypovolemia, and shock. This mechanism, along with individual
host and viral genome variations, plays an active role in pathogenesis. Infants born to mothers
who have had dengue, as maternally derived dengue neutralizing IgGs wane, are also thought
to be at risk for enhanced disease. [30, 31]
Some researchers suggest that Tcell immunopathology may play a role, with increased Tcell
activation and apoptosis. Increased concentrations of interferon have been recorded 12 days
following fever onset during symptomatic secondary dengue infections. [32] The activation of
cytokines, including TNFalpha, TNF receptors, soluble CD8, and soluble IL2 receptors, has
been correlated with disease severity. [18]
Cuban studies have shown that stored serum sample analysis demonstrated progressive loss
of crossreactive neutralizing antibodies to DENV2 as the interval since DENV1 infection
increased. [25] In addition, certain dengue strains, particularly those of DENV2, have been
proposed to be more virulent, in part because more epidemics of dengue hemorrhagic fever
have been associated with DENV2 than with the other serotypes.
DENV2–activated platelets were phagocytized in large numbers when the platelet activation
inhibitor prostacyclin was added. [33]
Several recent studies have investigated the causes of thrombocytopenia in dengue.
Laboratory and human studies have suggested a direct correlation between activation and
depletion of platelets, with a sharp drop occurring on day 4 of fever. A high number of dengue
virus genome copies have been found in these activated platelets. Increased binding of
complement C3 and IgG have also been found on the surface of these platelets. In addition to
platelet activation, dengue infection has been found to activate the intrinsic pathway of
apoptosis, with increased surface phosphatidylserine exposure, mitochondrial depletion, and
activation of caspase 3 and 9. [34]
Etiology
Dengue infection is caused by dengue virus (DENV), which is a singlestranded RNA virus
(approximately 11 kilobases long) with an icosahedral nucleocapsid and covered by a lipid
envelope. The virus is in the family Flaviviridae, genus Flavivirus, and the typespecific virus is
yellow fever.
The dengue virus has 4 related but antigenically distinct serotypes: DENV1, DENV2, DENV3,
and DENV4. Genetic studies of sylvatic strains suggest that the 4 serotypes evolved from a
common ancestor in primate populations approximately 1000 years ago and that all 4
separately emerged into a human urban transmission cycle 500 years ago in either Asia or
Africa. [5, 35] Albert Sabin speciated these viruses in 1944. Each serotype is known to have
several different genotypes. Viral genotype and serotype, and the sequence of infection with
different serotypes, appear to affect disease severity.
Living in endemic areas of the tropics (or warm, moist climates such as the southern United
States) where the vector mosquito thrives is an important risk factor for infection. [14, 36, 37, 38,
39] Poorly planned urbanization combined with explosive global population growth brings the
mosquito and the human host into close proximity. Increased air travel easily transports
infectious diseases between populations.
Epidemiology
United States statistics
In the United States, of the 100200 reported cases per year, dengue occurs principally in
travelers returning from endemic transmission areas. During 2006–2008, an average of 244
confirmed and probable travelassociated dengue cases were reported in the United States,
according to the US Centers for Disease Control and Prevention (CDC). [40] The CDC reports
that cases of dengue in returning US travelers have increased steadily during the past 20
years, and dengue has become the leading cause of acute febrile illness in US travelers
returning from the Caribbean, South America, and Asia. [41]
Dengue was once epidemic in the southeastern United States, and the potential exists for its
reemergence. The principal mosquito vector for dengue, A aegypti, is found in the southern and
southeastern United States, along with A albopictus, a less efficient vector species introduced
in 1985. A aegypti breeds yearround in southern Florida.
Most dengue cases in US citizens occur in Puerto Rico, the US Virgin Islands, Guam, and
Samoa. Puerto Rico has experienced several seasonal outbreaks since 2015, with more
significant transmission occurring from August to November. The last dengue epidemic in
Florida (in the Tampa and Miami areas) occurred in 19341935 and affected an estimated
15,000 people of the population of 135,000 in Miami. The last recorded epidemic in the
southeastern United States occurred in Louisiana in 1945. Outbreaks of dengue also occurred
in Laredo, Texas, in 1998. Dengue reemerged in Florida in 20092010, however, with 27 locally
acquired cases in Key West. [41] The index case in this outbreak was diagnosed after returning
home to New York from a visit to Key West. This illustrates the importance of awareness of
dengue among physicians outside endemic areas. Since January 2010, dengue has been a
reportable disease in the United States. [41]
International statistics
The overall incidence of dengue, as well as the explosive outbreaks of dengue, has been
increasing dramatically over the last several years. Older data suggested an estimated 50100
million cases of dengue fever and 500,000 cases of dengue hemorrhagic fever occur
worldwide, with 22,000 deaths (mainly in children). [42, 43, 44] In 2015, official data from WHO
member states reported more than 3.2 million cases, with 2.35 million cases in the Americas
alone, including 10,200 cases of severe dengue and 1181 deaths. An estimated 2.53 billion
people (approximately 40%50% of the world’s population) in approximately 112 tropical and
subtropical countries worldwide are at risk for dengue infection. The only continent that has not
experienced dengue transmission is Antarctica.
Worldwide distribution of dengue in 2000. Picture from the Centers for Disease Control and Prevention
(CDC) Web site.
View Media Gallery
(CDC) Web site.
View Media Gallery
(CDC) Web site.
View Media Gallery
According to the World Health Organization, dengue ranks as the most important mosquito
borne viral disease in the world. In the last 50 years, the incidence of dengue has increased 30
fold worldwide. [44] In the Americas alone, the incidence rose from 250,000 cases of dengue
fever and 7,000 cases of dengue hemorrhagic fever in 1995 to more than 890,000 cases of
dengue fever and 26,000 cases of dengue hemorrhagic fever in 2007 (see the image below).
Increasing rates of dengue infection by regions of the world. Graphs from the World Health Organization
(WHO) Web site.
View Media Gallery
The world's largest known epidemic of dengue occurred in Cuba in 1981, with more than
116,000 persons hospitalized and as many as 11,000 cases reported in a single day. Current
outbreaks can be monitored via the ProMed listserve by contacting owner
promed@promedmail.org.
Since 2000, at least 8 areas previously without dengue have reported outbreaks, including
Nepal, Bhutan, Macau, Hong Kong, Taiwan, [45] Madagascar, the Galapagos, and Easter
Island. The Pan American Health Organization (PAHO) reported that 2007 saw the highest
number of dengue fever and dengue hemorrhagic fever cases (918,495) in the Americas since
1985.
Southeast Asia
Currently, dengue hemorrhagic fever is one of the leading causes of hospitalization and death
in children in many Southeast Asian countries, with Indonesia reporting the majority of dengue
hemorrhagic fever cases. Of interest and significance in prevention and control, 3 surveillance
studies in Asia report an increasing age among infected patients and increasing mortality rate.
A 5year prospective study in Thai children examined the relative economic burden of dengue
infection in children on the local population. Most disabilityadjusted life years (DALYs) lost to
dengue resulted from longduration illness in children who had not been hospitalized. The
infecting serotype appeared to be a determining factor of DALYs lost, with DENV2 and DENV
3 responsible for 30% and 29%, respectively. The mean cost of illness from dengue was
significantly higher than that from other febrile illnesses. [46]
Since 1982 in Singapore, more than 50% of deaths have occurred in individuals older than 15
years. In Indonesia, young adults in Jakarta and provincial areas make up a larger percentage
of infected patients. During the 2000 epidemic in Bangladesh, up to 82% of hospitalized
patients were adults, and all deaths occurred in patients older than 5 years.
Africa
The epidemiology of dengue fever in Africa is more poorly characterized. Aedes aegypti is
present in a large portion of the Middle East and subSaharan Africa. Dengue fever is present
in 19 countries on the African continent. In a 1993 epidemic in the Comoros, an estimated
60,000 persons were infected with dengue. Of note, no major dengue hemorrhagic fever
epidemics have occurred in Africa, despite the fact that all 4 dengue serotypes circulate in the
continent. This may be explained by a genetic factor in these populations.
South America
Hyperendemic circulation of all 4 dengue serotypes is present in the northern countries of
South America. Brazil (700,000 cases in 2002), Colombia, and Venezuela report the most
cases of dengue and dengue hemorrhagic fever, with lowlevel transmission occurring year
round but with most occurring during periods of epidemic transmission. Since the 1970s,
outbreaks of dengue fever have increased in frequency and severity in the Caribbean.
Significant outbreaks of dengue have been reported in 2005 and 2006 in Puerto Rico, the US
Virgin Islands, the Dominican Republic, Barbados, Curacao, Cuba, Guadeloupe, and
Martinique.
Race, sex, and agerelated demographics
The distribution of dengue is geographically determined. Dengue affects all races. Some
African and Haitian data demonstrate a relative dearth of dengue hemorrhagic fever and
dengue shock syndrome during dengue fever epidemics, suggesting that these populations
may share a genetic advantage to the virus. This merits further study.
The incidence of dengue is equal in males and females. However, fewer cases of dengue
hemorrhagic fever and dengue shock syndrome have been reported in men than in women.
Dengue affects people of all ages. However, children younger than 15 years typically present
with only a nonspecific, selflimited, febrile illness. In endemic areas, a high prevalence of
immunity in adults may limit outbreaks to children.
In Southeast Asia, where dengue is hyperendemic, dengue hemorrhagic fever usually affects
children younger than 15 years. However, in the Americas, where dengue is becoming
progressively hyperendemic, dengue hemorrhagic fever shows no age predilection.
Prognosis
Dengue fever is typically a selflimiting disease with a mortality rate of less than 1%. When
treated, dengue hemorrhagic fever has a mortality rate of 25%. When left untreated, dengue
hemorrhagic fever has a mortality rate as high as 50%. Survivors usually recover without
sequelae and develop immunity to the infecting serotype.
The fatality rate associated with severe dengue varies by country, from 1244%. In a 1997
Cuban epidemic, the fatality rate in patients who met criteria for severe dengue was
approximately 6%. The mortality rate associated with dengue fever is less than 1%. Data from
the 1997 Cuban epidemic suggest that, for every clinically apparent case of dengue fever, 13.9
cases of dengue infection went unrecognized because of absent or minimal symptoms.
A 2005 review from Singapore of 14,209 patients found that useful predictors of death included
the following [47] :
Atypical presentations
Significant comorbid illness
Abnormal serum markers (including albumin and coagulation studies)
Secondary bacterial infections
Factors that affect disease severity include the following:
Patient age
Pregnancy
Nutritional status
Ethnicity
Sequence of infection with different dengue serotypes
Virus genotype
Quality and extent of available medical care
Complications and sequelae of dengue virus infections are rare but may include the following:
Cardiomyopathy
Seizures, encephalopathy, and viral encephalitis
Hepatic injury
Depression
Pneumonia
Iritis
Orchitis
Oophoritis
In 2030% of dengue hemorrhagic fever cases, the patient develops shock, known as the
dengue shock syndrome. Worldwide, children younger than 15 years constitute 90% of dengue
hemorrhagic fever patients [42] ; however, in the Americas, dengue hemorrhagic fever occurs in
both adults and children.
Although dengue is an extremely important arboviral illness globally, literature evaluating the
economic impact is fairly sparse, with some conflicting findings. A recent expert panel
assessment and 2 studies in the Americas recommended additional research to fill important
information gaps, including disease outcomes and accurate statistics regarding disease burden,
that could better inform future decision making regarding control and prevention. [48, 49, 50]
A 5year prospective study in Thai children examined the relative economic burden of dengue
infection in children on the local population. Most disabilityadjusted life years (DALYs) lost to
dengue resulted from longterm illness in children who had not been hospitalized. The infecting
serotype appeared to be the major determinant of DALYs lost, with DEN2 and DEN3
responsible for 59%. The mean cost of illness from dengue was significantly higher than that
from other febrile illnesses studied. [46]
A prospective study examined the direct and indirect costs of dengue infection in 1695 pediatric
and adult patients in 8 countries. The average illness lasted 11.9 days for ambulatory patients
and 11 days for hospitalized patients. Hospitalized students lost 5.6 days of school. Those at
work lost 9.9 work days. Overall mean costs were more than double (1394 international dollars
[I$]) for hospitalized cases. With an annual average of 594,000 cases the aggregate economic
cost was estimated to be at least I$587 million, without factoring in underreporting of disease
and dengue surveillance and vector control costs. This represents a significant global economic
burden in lowincome countries. [50]
Patient Education
Educate patients, especially those who have experienced prior dengue fever, to avoid mosquito
bites, including the use of appropriate mosquito repellants and peridomestic vector control,
when traveling to dengueendemic areas. Current evidence suggests that those with a history
of dengue fever are at highest risk for dengue hemorrhagic fever or dengue shock syndrome if
they are infected with a different dengue strain.
Information for reducing risk of contracting dengue while traveling, as well as current
information on dengue outbreaks, is available at the US Centers for Disease Control and
Prevention Travel & Dengue Outbreaks Web page. Information on dengue and alerts on current
outbreaks are also available through the World Health Organization Web site.
Clinical Presentation
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Media Gallery
Drawing of Aedes aegypti mosquito. Picture from the Centers for Disease Control and
Prevention (CDC) Web site.
Aedes aegypti mosquito. Picture from the Centers for Disease Control and Prevention
(CDC) Web site.
Aedes albopictus. From CDC Public Domain.
Worldwide distribution of dengue in 2000. Picture from the Centers for Disease Control
and Prevention (CDC) Web site.
Increasing rates of dengue infection by regions of the world. Graphs from the World
Health Organization (WHO) Web site.
Dengue transmission cycle. Illustration from the Centers for Disease Control and
Prevention (CDC) Web site.
Reinfestation by Aedes aegypti in the Americas after the 1970 (left) mosquito eradication
program and most recent distribution as of 2002 (right). Picture from the Centers for
Disease Control and Prevention (CDC) Web site.
A child with dengue hemorrhagic fever or dengue shock syndrome may present severely
hypotensive with disseminated intravascular coagulation (DIC), as this severely ill
pediatric ICU patient did. Crystalloid fluid resuscitation and standard DIC treatment are
critical to the child's survival.
Delayed capillary refill may be the first sign of intravascular volume depletion.
Hypotension usually is a late sign in children. This child's capillary refill at 6 seconds was
delayed well beyond a normal duration of 2 seconds.
Signs of early coagulopathy may be as subtle as a guaiac test that is positive for occult
blood in the stool. This test should be performed on all patients in whom dengue virus
infection is suspected.
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Contributor Information and Disclosures
Author
Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM Professor of Emergency
Medicine, Education Officer, Department of Emergency Medicine, Hospital of the University of
Pennsylvania; Director of Education and Research, PENN Travel Medicine; Medical Director,
Fast Track, Department of Emergency Medicine
Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM is a member of the following
medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American
Society of Tropical Medicine and Hygiene, International Society of Travel Medicine, Society for
Academic Emergency Medicine, Wilderness Medical Society
Disclosure: Nothing to disclose.
Chief Editor
Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of
Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine,
University of Oklahoma Health Science Center; Master of the American College of Physicians;
Fellow, Infectious Diseases Society of America
Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega
Alpha, American College of Physicians, American Medical Association, Association of
Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical
Association, Southern Society for Clinical Investigation
Additional Contributors
Patrick B Hinfey, MD Emergency Medicine Residency Director, Department of Emergency
Medicine, Newark Beth Israel Medical Center; Clinical Assistant Professor of Emergency
Medicine, New York College of Osteopathic Medicine
Patrick B Hinfey, MD is a member of the following medical societies: American Academy of
Emergency Medicine, Wilderness Medical Society, American College of Emergency
Physicians, Society for Academic Emergency Medicine
William H Shoff, MD, DTM&H Former Director, PENN Travel Medicine; Former Associate
Professor, Department of Emergency Medicine, Hospital of the University of Pennsylvania,
University of Pennsylvania School of Medicine
William H Shoff, MD, DTM&H is a member of the following medical societies: American College
of Physicians, American Society of Tropical Medicine and Hygiene, International Society of
Travel Medicine, Society for Academic Emergency Medicine, Wilderness Medical Society
Acknowledgements
Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology,
Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate
Medical University
Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega
Alpha, American Academy of Pediatrics, American Society for Microbiology, Infectious
Diseases Society of America, Pediatric Infectious Diseases Society, and Phi Beta Kappa
Hagop A Isnar, MD, FACEP Department of Emergency Medicine, Crouse Hospital
Hagop A Isnar, MD, FACEP is a member of the following medical societies: American College
of Emergency Physicians, American Medical Association, and Society for Academic
Emergency Medicine
Thomas M Kerkering, MD Chief of Infectious Diseases, Virginia Tech, Carilion School of
Medicine, Roanoke, Virginia
Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha,
American College of Physicians, American Public Health Association, American Society for
Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society
of America, Medical Society of Virginia, and Wilderness Medical Society
Deborah Sentochnik, MD Consulting Staff, Department of Internal Medicine, Division of
Infectious Disease, The Mary Imogene Bassett Hospital
Deborah Sentochnik, MD is a member of the following medical societies: American College of
Physicians, Infectious Diseases Society of America, and Medical Society of the State of New
York
Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's
Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of
Medicine
Russell W Steele, MD is a member of the following medical societies: American Academy of
Pediatrics, American Association of Immunologists, American Pediatric Society, American
Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical
Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern
Medical Association
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska
Medical Center College of Pharmacy; EditorinChief, Medscape Drug Reference
Disclosure: Medscape Reference Salary Employment
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center
College of Pharmacy; EditorinChief, Medscape Drug Reference

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