Etiology

Dengue infection is caused by dengue virus (DENV), which is a single-stranded 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 type-specific virus is
yellow fever.
The dengue virus has 4 related but antigenically distinct serotypes: DENV-1, DENV-2, DENV-3,
and DENV-4. 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. [3, 29] 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. [10, 30, 31, 32, 33]
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, dengue occurs principally in travelers returning from endemic areas. During
20062008, an average of 244 confirmed and probable travel-associated dengue cases were
reported in the United States, according to the US Centers for Disease Control and Prevention
(CDC).[34] 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.[35]
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 year-round in southern Florida.
The last dengue epidemic in Florida (in the Tampa and Miami areas) occurred in 1934-1935 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 2009-2010, however,
with 27 locally acquired cases in Key West. [35] 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.[35]
International statistics
Each year, an estimated 50-100 million cases of dengue fever and 500,000 cases of dengue
hemorrhagic fever occur worldwide, with 22,000 deaths (mainly in children). [36,

37, 38]

An

estimated 2.5-3 billion people (approximately 40% of the worlds population) in approximately
112 tropical and subtropical countries worldwide are at risk for dengue infection. The only
continents that do not experience dengue transmission are Europe and Antarctica (see the images
below).
Worldwide distribution of dengue in 2000. Picture from the Centers for Disease Control
and Prevention (CDC) Web site. Worldwide distribution of dengue in 2003. Picture from the
Centers

for

Disease

Control

and

Prevention

(CDC)

Web

site.

Worldwide distribution of dengue in

2005. Picture from the Centers for Disease Control and Prevention (CDC) Web site.
According to the World Health Organization, dengue ranks as the most important mosquitoborne viral disease in the world. In the last 50 years, the incidence of dengue has increased 30fold worldwide.[38] 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.

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, [39] 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 5-year prospective study in Thai children examined the relative economic burden of dengue
infection in children on the local population. Most disability-adjusted life years (DALYs) lost to
dengue resulted from long-duration illness in children who had not been hospitalized. The
infecting serotype appeared to be a determining factor of DALYs lost, with DENV-2 and DENV3 responsible for 30% and 29%, respectively. The mean cost of illness from dengue was
significantly higher than that from other febrile illnesses.[40]
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 sub-Saharan 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 low-level 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 age-related 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, self-limited, 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 self-limiting disease with a mortality rate of less than 1%. When
treated, dengue hemorrhagic fever has a mortality rate of 2-5%. 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 dengue shock syndrome varies by country, from 12-44%. In a
1997 Cuban epidemic, the fatality rate in patients who met criteria for dengue hemorrhagic fever
or dengue shock syndrome 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[41] :

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 20-30% 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[36] ; 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.[42, 43, 44]

A 5-year prospective study in Thai children examined the relative economic burden of dengue
infection in children on the local population. Most disability-adjusted life years (DALYs) lost to
dengue resulted from long-term illness in children who had not been hospitalized. The infecting
serotype appeared to be the major determinant of DALYs lost, with DEN-2 and DEN-3
responsible for 59%. The mean cost of illness from dengue was significantly higher than that
from other febrile illnesses studied.[40]
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
low-income countries.[44]