EMERGING AND RE-EMERGING DISEASES

IN LATIN AMERICA 0891-5520/00 $15.00 + .OO

DENGUE AND DENGUE

HEMORRHAGIC FEVER IN LATIN
AMERICA AND THE CARIBBEAN
Rafil E. Istfuiz, MD, FACE Duane J. Gubler, ScD,
and Jose Brea del Castillo, MD

HISTORY AND EPIDEMIOLOGY

History

The first outbreaks of a disease compatible with classic dengue fever

(DF) in Latin America and the Caribbean occurred in the French West
Indies in 1635 and in Panama in 1699,144 years before the 1779 epidemic
of a dengue-like illness that is often reported as the first (Table l).13, 18, 44
In Panama, a 4- to 5-day illness characterized by fever, rash, headache,
ocular pain, bone and joint aches, nausea, vomiting, and prostration,
followed by prolonged convalescence and eventual recovery was proba-
bly dengue." Paralleling the Asian and Pacific epidemics, DF occurred
in the Caribbean Basin at the time of World War 11, but the isolation of
the DEN-2 serotype in Trinidad in 1953 notwithstanding, there is no
record of epidemic dengue from 1946 to 1963.13,18 This was likely because
of the success of the Aedes aegypti mosquito eradication programs carried

From the Departamento de Medicina, Centro Medico de Caracas, and Centro Medico
Docente La Trinidad, Caracas, Venezuela; and the Departement de Medecine Interne,
Groupe HBpitalier Bichat-Claude Bernard, Pans, France (REI);the Division of Vector-
Borne Infectious Diseases, National Center for Infectious Disease, Centers for Disease
Control and Prevention, Public Health Service, US Department of Health and Human
Services, Fort Collins, Colorado (DJG); and the Departamento de Pediatria, Centro
Medico, Universidad del Este, Santo Domingo, Repiiblica Dominicana @dC)

INFECTIOUS DISEASE CLINICS OF NORTH AMERICA

VOLUME 14 NUMBER 1 * MARCH 2000 121

Table 1. EPIDEMICS OF DENGUELIKE ILLNESS IN LATIN AMERICA AND THE
CARIBBEAN BEFORE LABORATORY CONFIRMATION WAS POSSIBLE
Years Geographic Area Concurrent Epidemics
1635 French West Indies
1699 Darien, Panama
1700 Lima, Peru
1779 Caribbean Islands; Colombia; Bermuda; Southern United States
Monterrey, Mexico
1837 Bermuda
1844-49 Rio de Janeiro, Brazil Africa, India, Egypt
1850-51 Havana, Cuba; Lima, Peru United States, Africa
187677 Lima, Peru Hong Kong
1897-99 Havana, Cuba; San Juan, Puerto Rico Australia, India, United States
1901-07 Havana, Cuba Asia, United States, Egypt
1914-18 San Juan, Puerto Rico; Rio Grande do Sul, Australia, China
Brazil; Buenos Aires, Argentina Sudan, Taiwan
1920-26 Niteroi, Brazil; Maracaibo, Venezuela Australia, China
1940-45 Caribbean basin Asia, Australia

Adapted from Gubler DJ: Dengue and dengue hemorrhagic fever: Its history and resurgence as a
global public health problem. In Gubler DJ, Kuno G (eds): Dengue and Dengue Hemorrhagic Fever.
London. CAB International. 1997, pp 1-22; with permission.

out by the Pan American Health Organization (PAHO) during the 1940s,
1950s, and 1960s to prevent urban epidemics of yellow fever.17,18
Eradication of Aedes aegypti was achieved in Argentina, Belize, Ber-
muda, Bolivia, Brazil, Cayman Islands, Chile, Colombia, Costa Rica,
Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Pan-
ama, Paraguay, Peru, and Uruguay, but the program was discontinued
in the early 1970s. Failure to eradicate the vector in most Caribbean
Islands, French Guiana, Guyana, Suriname, the United States, and Vene-
zuela, however, resulted in reinfestation of most countries in the region
and coincided with an increasing number of cases and epidemics of
dengue fever.17

Reemergence of Dengue Fever in the Americas

After 18 years with no epidemic dengue activity, major laboratory-

documented epidemics of classic DF affected the Caribbean and
Vene~uela.'~,l8 From 1963 to 1964, epidemics caused by DEN-3 occurred
in Jamaica and Puerto Rico, and from 1968 to 1969, epidemics caused
predominantly by DEN-2 occurred in several Caribbean i~1ands.I~ Dur-
ing the 1970s, these serotypes were responsible for two large epidemics
in Colombia, DEN-2 in 1971-72 and DEN-3 in 1975-77. It is estimated
that over half a million individuals became infected in that peri0d.4~
In 1977, DEN-1 was introduced to the Americas. After its initial
detection in Jamaica, it caused a devastating pandemic, with epidemics
that lasted until 1981 in virtually every Caribbean Island and many
countries of Central and South America? Spreading to the east and
 DENGUE AND DHF IN LATIN AMERICA AND THE CARIBBEAN 123

south, the pandemic affected Puerto Rico, Venezuela, Colombia, Guyana,

Suriname, and French Guiana; to the west, it affected Honduras, El
Salvador, Guatemala, and Belize; and later, in 1978, moving north, it
reached Mexico. In late 1980, Texas reported cases. Although over
700,000 cases of DF were reported to PAHO from 1977 to 1980, estimates
from Colombia, Cuba, and Venezuela suggest that over 5 million individ-
uals were infe~ted.4~ In Cuba alone, 42% of approximately 10 million
inhabitants were infected by DEN-1.4y
During the 1980s, the geographic expansion of dengue in Latin
America increased progressively. Brazil (1982 and 1986), Bolivia (1987),
Paraguay (1988), Ecuador (1988), and Peru (1990), countries free of
dengue for decades, experienced severe epidemics caused by DEN-1.
This strain continued to cause epidemic disease in Brazil, Ecuador, and
Peru in subsequent years.49In 1981, DEN-4 was introduced and, like
DEN-1, caused numerous outbreaks in the Caribbean, Central America,
northern South America, and DEN-4 was also isolated during
the 1982 DEN-1 outbreak in Brazil and in the 1990 outbreak in
Finally, in 1981, a new strain of DEN-2 was introduced into Cuba,
causing the first major dengue hemorrhagic fever (DHF) epidemic in the
Ameri~as.3~. 38 Although fewer than 240,000 cases were reported from the
affected American countries between 1986 and 1990, serologic studies
suggested millions of infections, and DHF/ dengue shock syndrome
(DSS) emerged as a major public health pr~blem.~, 15, 17, 25, 49
In the 1990s, DEN-1 continued its spread to the last two tropical
countries of Latin America, Costa Rica and Panama, that had been free
of DF for decades. Severe outbreaks occurred in 1993 and subsequent
years? In 1994, DEN-3 re-emerged in the Americas. It was first detected
in Nicaragua and Panama, and in 1995, the epidemic spread throughout
Central America to Mexico. The introduction of DEN-3 in Nicaragua in
1994 and in Mexico in 1995 coincided with increasing numbers of DHF
cases in those areas. Venezuela has reported increasing numbers of cases
since 1995.l
Over 250,000 cases of dengue were reported in the Latin American
and Caribbean regions in each of the years 1995 and 1996, 421,998 in
1997, and 736,986 in 1998. Analysis of the first weeks of 1999 suggests a
continuation of the upward trend.

Emergence of Dengue Hemorrhagic Fever and Dengue

Shock Syndrome

Major outbreaks of DHF / DSS have been well documented in the

Americas. The first outbreak was associated with a new strain of DEN-
2 introduced to Cuba from South-East Asia in 1981, 4 years after DEN-
1 had caused a major epidemic on the island.37,% This was a dramatic
epidemic during which 344,203 cases of DF were reported, and 10,312
cases met the World Health Organization (WHO) case definition for
DHF/DSS. There were 158 deaths (101 children and 57 adults). In a 3-
month period, 116,143 persons were hospitalized for suspected DHF,
and at the peak of the epidemic, some 11,400 cases were reported in 1
day.43The social and economic consequences of this event, the most
important in the history of dengue in the region, are still incalculable.
After the Cuban epidemic in 1981, DHF/DSS began to expand geograph-
ically; cases have been reported in the region every year, except 1983,
and in 1999, the severe disease is endemic in most countries.
The second major American outbreak of DHF occurred in Venezuela
in 1989-90: between December 2, 1989, and April 17, 1990, when the
outbreak was declared over, 3108 cases and 73 deaths had been re-
ported? Another epidemic of DHF occurred later in 1990, and the disease
has been reported every year since. DEN-2 predominated in 1989-90
and was responsible for all fatal cases that were autopsied; DEN-1 and
DEN-4 were also recovered. This DEN-2 was the same genotype as the
strain thought to have caused the Cuban epidemic?] Epidemics of DHF
caused by this genotype of DEN-2 subsequently occurred in Colombia
in 1990, French Guiana in 1991, Brazil in 1992 and 1994, and Puerto Rico
in 1994.lSIn 1994, DEN-3 was re-introduced to the region from South-
East Asia." It caused a major epidemic of DF/DHF in Nicaragua and a
small DF outbreak in Panama in 1995. DF outbreaks with cases of DHF
have occurred in Aruba, Colombia, the Dominican Republic, El Salvador,
French Guiana, Guatemala, Honduras, Mexico, Nicaragua, Panama,
Puerto Rico, St. Lucia, Suriname, and the US Virgin Islands.18,l9 A large
proportion of the cases reported by Colombia and Mexico occurred
during 1995-96. DEN-2 re-emerged in Cuba in 1997 and was effectively
c0ntrolled.3~
Provisional figures indicate that from 1981 to the first 19 epidemio-
logic weeks of 1999, 67,362 cases of DHF and 894 fatalities have been
reported from countries in the Americas (PAHO, unpublished data,
1999). Of those, 25,042 cases of DHF and 312 fatalities represent data
received by PAHO since 1997 (PAHO, 1999, unpublished data) (Table 2).
DHF has become endemic in the region, with 24 countries reporting
confirmed cases.lS,*
The proportion of DF to DHF has varied widely from epidemic to
e~idemic.4~ The case-fatality rate also varies among countries. In 1995, it
ranged from 8.3% in Puerto Rico to 0.87% in and in 1998, it
was 22.2'70 in Honduras, 10.1% in Brazil, 5.2% in Puerto Rico, and 0.6%
in Venezuela. (PAHO, 1999, unpublished data). It should be noted,
however, that these rates may not be accurate because they are also
influenced by different surveillance systems and case definitions, and
suffer from marked underreporting practices. Making accurate assess-
ments of incidence and trends in the Americas and the Caribbean is
difficult; nevertheless, the widespread distribution of Aedes aegypti, the
introduction of South-East Asian strains of dengue viruses, the continu-
ous circulation of all four virus serotypes, and the persistence of large
numbers of cases of classic dengue all suggest a continued, increased
risk for epidemic DHF in the region.17,19,49
 DENGUE AND DHF IN LATIN AMERICA AND THE CARIBBEAN 125

VIROLOGY AND PATHOGENESIS

Dengue Viruses and Vectors

Dengue fever is caused by 40- to 50-mm single-stranded RNA

viruses belonging to the genus FZavivirus, family FZaviviridae.@ They are
spheric and have a lipid envelope derived from host cell membranes.
Three structural and seven nonstrudural proteins make up the infectious
genome of approximately 11,000 bases that can be translated in vitro.
Four species have been described, called serotypes: DEN-1, DEN-2,
DEN-3, and DEN-4.'" 19, 30, All flaviviruses, including yellow fever,
Japanese encephalitis, St. Louis encephalitis, West Nile, Murray Valley
encephalitis, Kayasanur Forest disease, and tick-borne encephalitis vi-
ruses, have common group epitopes on the envelope protein that result
in cross reactions in serologic tests." These make unequivocal serologic
diagnosis of infection by flaviviruses difficult. This is especially true
among the four dengue serotypes.16,19, 27, 31 Identification of serotypes is
possible by the use of serotype-specificmonoclonal antibodies.l9.23, 27, 31, 32
Extensive genetic variation of flavivirus strains has been docu-
mented by nucleotide sequence analysis.25,31, 51, 52 This technique pro-
vides a tool for the separation of viruses that belong to a single serotype
into several genetic subgroups designated genotypes. DEN-1 and DEN-
2 viruses have five genotypes, DEN-3 has four, and DEN-4 has two.",
51,52 The relationship between these genetic differences among the viruses
and epidemic transmission or disease expression is uncertain, but further
study may provide important epidemiologic and management clues in
the future.20,21.51, 52.55
Infection with one dengue virus serotype results in specific, lifelong
homotypic imm~nity,'~, 31 but cross-protective heterotypic immunity may
last 2 to 12 months, and exposed individuals can theoretically be infected
with all four serotypes.16,19,
The transmission of dengue viruses is determined by factors related
to the environment, the vector, the virus strain, and the susceptible
human pop~lation.'~ In most tropical countries, including Latin America
and the Caribbean, dengue viruses are transmitted in an endemic/
epidemic, human-mosquito-human, rural or urban cycle by the bite of
infected mosquito vectors of the Aedes family.16,l9 Althou h different
species have been implicated in other areas of the world, ti? e principal
vector in the American region is Aedes aegypti. The presence of Aedes
albopictus in several countries of the region and its possible role as a
vector requires further study. It is unlikely that lower primate species
play an important part as dengue virus hosts in this area.5oThe role of
vertical transmission in the maintenance of dengue viruses is
uncertain.l6fl9
Aedes aegypti is a very efficient vector of dengue viru~es.'~ This
species can be found between latitudes 30" north and 20" south9 and at
over 2200 meters above sea level. Transmission occurs in geographically
diverse areas, including subtropical and tropical cities at various alti-
 DENGUE AND DHF IN LATIN AMERICA AND THE CARIBBEAN 125

VIROLOGY AND PATHOGENESIS

Dengue Viruses and Vectors

Dengue fever is caused by 40- to 50-mm single-stranded RNA

viruses belonging to the genus FZavivirus, family FZaviviridae.@ They are
spheric and have a lipid envelope derived from host cell membranes.
Three structural and seven nonstrudural proteins make up the infectious
genome of approximately 11,000 bases that can be translated in vitro.
Four species have been described, called serotypes: DEN-1, DEN-2,
DEN-3, and DEN-4.'" 19, 30, All flaviviruses, including yellow fever,
Japanese encephalitis, St. Louis encephalitis, West Nile, Murray Valley
encephalitis, Kayasanur Forest disease, and tick-borne encephalitis vi-
ruses, have common group epitopes on the envelope protein that result
in cross reactions in serologic tests." These make unequivocal serologic
diagnosis of infection by flaviviruses difficult. This is especially true
among the four dengue serotypes.16,19, 27, 31 Identification of serotypes is
possible by the use of serotype-specificmonoclonal antibodies.l9.23, 27, 31, 32
Extensive genetic variation of flavivirus strains has been docu-
mented by nucleotide sequence analysis.25,31, 51, 52 This technique pro-
vides a tool for the separation of viruses that belong to a single serotype
into several genetic subgroups designated genotypes. DEN-1 and DEN-
2 viruses have five genotypes, DEN-3 has four, and DEN-4 has two.",
51,52 The relationship between these genetic differences among the viruses
and epidemic transmission or disease expression is uncertain, but further
study may provide important epidemiologic and management clues in
the future.20,21.51, 52.55
Infection with one dengue virus serotype results in specific, lifelong
homotypic imm~nity,'~, 31 but cross-protective heterotypic immunity may
last 2 to 12 months, and exposed individuals can theoretically be infected
with all four serotypes.16,19,
The transmission of dengue viruses is determined by factors related
to the environment, the vector, the virus strain, and the susceptible
human pop~lation.'~ In most tropical countries, including Latin America
and the Caribbean, dengue viruses are transmitted in an endemic/
epidemic, human-mosquito-human, rural or urban cycle by the bite of
infected mosquito vectors of the Aedes family.16,l9 Althou h different
species have been implicated in other areas of the world, ti? e principal
vector in the American region is Aedes aegypti. The presence of Aedes
albopictus in several countries of the region and its possible role as a
vector requires further study. It is unlikely that lower primate species
play an important part as dengue virus hosts in this area.5oThe role of
vertical transmission in the maintenance of dengue viruses is
uncertain.l6fl9
Aedes aegypti is a very efficient vector of dengue viru~es.'~ This
species can be found between latitudes 30" north and 20" south9 and at
over 2200 meters above sea level. Transmission occurs in geographically
diverse areas, including subtropical and tropical cities at various alti-
 DENGUE AND DHF IN LATIN AMERICA AND THE CARIBBEAN 125

VIROLOGY AND PATHOGENESIS

Dengue Viruses and Vectors

Dengue fever is caused by 40- to 50-mm single-stranded RNA

viruses belonging to the genus FZavivirus, family FZaviviridae.@ They are
spheric and have a lipid envelope derived from host cell membranes.
Three structural and seven nonstrudural proteins make up the infectious
genome of approximately 11,000 bases that can be translated in vitro.
Four species have been described, called serotypes: DEN-1, DEN-2,
DEN-3, and DEN-4.'" 19, 30, All flaviviruses, including yellow fever,
Japanese encephalitis, St. Louis encephalitis, West Nile, Murray Valley
encephalitis, Kayasanur Forest disease, and tick-borne encephalitis vi-
ruses, have common group epitopes on the envelope protein that result
in cross reactions in serologic tests." These make unequivocal serologic
diagnosis of infection by flaviviruses difficult. This is especially true
among the four dengue serotypes.16,19, 27, 31 Identification of serotypes is
possible by the use of serotype-specificmonoclonal antibodies.l9.23, 27, 31, 32
Extensive genetic variation of flavivirus strains has been docu-
mented by nucleotide sequence analysis.25,31, 51, 52 This technique pro-
vides a tool for the separation of viruses that belong to a single serotype
into several genetic subgroups designated genotypes. DEN-1 and DEN-
2 viruses have five genotypes, DEN-3 has four, and DEN-4 has two.",
51,52 The relationship between these genetic differences among the viruses
and epidemic transmission or disease expression is uncertain, but further
study may provide important epidemiologic and management clues in
the future.20,21.51, 52.55
Infection with one dengue virus serotype results in specific, lifelong
homotypic imm~nity,'~, 31 but cross-protective heterotypic immunity may
last 2 to 12 months, and exposed individuals can theoretically be infected
with all four serotypes.16,19,
The transmission of dengue viruses is determined by factors related
to the environment, the vector, the virus strain, and the susceptible
human pop~lation.'~ In most tropical countries, including Latin America
and the Caribbean, dengue viruses are transmitted in an endemic/
epidemic, human-mosquito-human, rural or urban cycle by the bite of
infected mosquito vectors of the Aedes family.16,l9 Althou h different
species have been implicated in other areas of the world, ti? e principal
vector in the American region is Aedes aegypti. The presence of Aedes
albopictus in several countries of the region and its possible role as a
vector requires further study. It is unlikely that lower primate species
play an important part as dengue virus hosts in this area.5oThe role of
vertical transmission in the maintenance of dengue viruses is
uncertain.l6fl9
Aedes aegypti is a very efficient vector of dengue viru~es.'~ This
species can be found between latitudes 30" north and 20" south9 and at
over 2200 meters above sea level. Transmission occurs in geographically
diverse areas, including subtropical and tropical cities at various alti-
tudes. For example, epidemic transmission in Caracas, Venezuela, or
even Taxco, Mexico, cities located 960 and 1700 meters, respectively,
above sea level is well documented." 33 The mosquito is small and
exhibits characteristic black and white horizontal stripes on long thin
legs that account for its regional nickname "patas blancas." It is an
anthropophilic, highly domesticated vector that has adapted well to the
ample ranges of ambient temperature of the neotropical regions of Latin
America and the Caribbean. The female is predisposed to lay eggs in
man-made containers commonly found in and around homes.16,l9 Active
breeding sites include old automobile tires, flower vases, buckets, water-
storage containers, and any trash items that collect water. Some of
these recipients (e.g., tires) are inadvertent methods for long-distance
transportation of Aedes larvae. Rainfall and temperature variation may
also affect both mosquito proliferation and human behavior and thus
disease transmission patterns, but the mechanism by which dengue virus
circulation is maintained between epidemics is not fully understood.16,l9
Adult mosquitoes prefer to rest indoors and feed on humans during
daylight hours, with peaks of biting activity occurring in the early
morning for 3 to 4 hours after dawn, in the late afternoon for 3 to 4
hours before dusk, and on overcast days.'" l9 Mosquitoes are infected by
ingesting the virus when they take a blood meal. After 8 to 10 days, virus
replication within the salivary glands renders the mosquito infectious for
life.16,19Females have been described as very nervous feeders because
they often discontinue the feeding process and restart on the same or
another individual soon after; they may transmit dengue virus to multi-
ple persons over a short period of time.19 Several members of the same
household have become ill with DF within a period of 36 hours, sug-
gesting infection by a single mosquito.l6?l9

Pathogenesis

After introduction through the skin by the bite of an infected mos-

quito, the virus undergoes an incubation period that averages 4 to 7
days, after which the patient may or may not experience symptoms,
depending on virus strain, age, immune status, and other factors.*9,29, 34
Symptoms may range from mild to severe, occasionally with a fatal
outcome. This extreme clinical variability has not been satisfactorily
explained and is probably multifactorial. Viremia may range in titer
from lo3 to 108.5mosquito infectious doses (MIDJO)per milliliter, with a
tendency to be higher in primary infection~.'~ It peaks around the time
of onset of symptoms and may last 2 to 12 days.19 In some secondary
infections, viremia may not be detected because the virus can be com-
plexed with heterologous antibody, making it undetectable by some
isolation techniques. The principal site of replication of dengue virus in
man is thought to be cells of mononuclear phagocyte 29 Viral

antigens have been detected in monocytes obtained from kidney, skin,

liver, spleen, thymus, lung, and in saliva in a case of sialitis associated
 DENGUE AND DHF IN LATIN AMERICA AND THE CARIBBEAN 129

with DF by reverse transcription polymerase chain reaction (J. Torres,

personal communication, 1999). Dengue virus has been isolated from
peripheral blood leukocytes and from autopsy tissue from liver, spleen,
lymph node, bone marrow, thymus, heart, kidney, stomach, lung,30and
56
possibly brain, suggesting blood-brain barrier
Epidemiologic and laboratory evidence obtained from the Cuban
outbreak of 1981 can be interpreted to support both the antibody-depen-
dent enhancement and the increased viral virulence hypotheses, to ex-
plain the pathogenesis of DHF and DSS. The former hypothesis main-
tains that preexisting, nonneutralizing heterologous dengue antibodies,
developed as a consequence of prior infection or acquired transplacen-
tally, enhance the infection and replication of a second virus in mononu-
clear cells. The resulting increased number of infected cells results in
increased production of the cytokines and other chemical mediators
responsible for increased vascular permeability, hypovolemia, shock,
and hemostatic abnormalities.28, 29, The latter hypothesis assumes that
dengue viruses submitted to appropriate selective pressures as they
replicate in their vertebrate or invertebrate hosts develop genomic varia-
tions that confer increased virulence and epidemic p~tential.'~, 55 Excel-
lent reviews covering the pathogenesis of DHF and DSS have been
recently published.34, 50, 57
Common gross pathologic findings include petechial hemorrhages
and ecchymoses, serous pleural and peritoneal effusions, and pulmonary
edema. Vasculitis of small vessels in visceral and soft tissues is found
on microscopy as well as focal midzonal hepatic necrosis and subendo-
cardial left ventricle and gastric mucosal hemorrhages.

CLINICAL MANIFESTATIONS AND DIAGNOSIS

Although, from the epidemiologic standpoint, dengue comprises

four diseases, from the clinical perspective, it is but one, with five
different presentations: nonspecific febrile illness, classic DF, DHF, DSS,
and other severe dengue syndromes.
The incubation period after inoculation of the virus by the mosquito
ranges from 2 to 14 days, during which the patient has no ~ymptoms.'~
Rarely, transplacental infection and neonatal dengue has been recorded.
Dengue is characterized by clinical variability. Presentation may include
asymptomatic seroconversion, mild undifferentiated febrile illness, or
severe and fatal hemorrhagic disease. Variations in clinical characteristics
may be at least partially explained by the strain of virus, age, sex, race,
nutritional and immunologic differences among the affected individuals,
and chronic preexisting comorbidities.8The three clinical presentations
most commonly observed in Latin America are undifferentiated febrile
illness, DF, also referred to as classic dengue, and DHF, with or with-
out DSS.
Classic Dengue

Commonly a disease of older children and adults, classic DF usually

starts suddenly. As described for influenza, the patient often remembers
the moment of onset of the first symptom. Fever, malaise, and a discrete
macular rash are nonspecific complaints that make the clinical differenti-
ation from other self-limiting diseases difficult. These cases are often
managed symptomatically by family members, and the diagnosis of
dengue is missed, remaining unreported. The typical case of DF is more
severe, to the point of being incapacitating. The patient experiences high
fever, which in the first 2 days may be preceded by erythematous
mottling and chills and may last for 5 to 7 days. Concomitantly, a severe
frontal and retroorbital headache, myalgias, especially lower back, arm,
and leg pains, arthralgias, especially in shoulders and knees, a prostrat-
ing weakness, and anorexia are clinical corn plaint^.^^ An evanescent
macular or maculopapular rash appears around the third day over the
thorax, face, and flexure joint surfaces and lasts 2 to 3 days. Altered
taste sensation, mild sore throat, cough, facial flushing, and conjunctival
injection have been described less frequently. Defervescence may be
heralded by intense erythematous burning or itching sensation of palmar
and plantar surfaces, which may be followed by desquamation. Around
the time when the temperature falls (a recurrence of fever has been
described with bradycardia, but rarely observed in Venezuela), hemor-
rhagic manifestations may appear. They range from mild to life-threaten-
ing and include petechiae, purpura, gingivorrhagia, epistaxis, metrorrha-
gia, and gastrointestinal bleeding. In classic DF, a severe gastrointestinal
hemorrhage has caused death in this stage.58Hematuria is infrequent.
The tourniquet test (see box) can be positive in the absence of DHF.35A
convalescent state ensues, which may take several weeks to resolve and
is characterized by weakness, attention deficit, and depression. Most
patients recover without sequelae. During pregnancy, preliminary data
suggest no evidence of teratogenicity, with the debatable exception of
possible neural tube defects,*Oabortion, or intrauterine growth abnormal-
ities.
In younger children, the disease tends to have minimal or nonspe-
cific manifestations; a biphasic temperature curve with paradoxic brady-
cardia during fever is more commonly observed, and syncope has been

The Tourniquet Test

Method
Inflate blood pressure cuff to median BP (average of systolic and dia-
stolic) in the patient's extremity for up to 5 minutes, or until positive.
Interpretation
Test is positive when 3 or more petechiae per square centimeter or 20
per square inch appear. Profound shock subestimates the test.
 DENGUE AND DHF IN LATIN AMERICA AND THE CARIBBEAN 131

described. Convalescence is benign. Newborn dengue can present with

varied severity, even mortality?
Recovery of appetite and 2 to 3 days without fever and complica-
tions are good prognostic signs in all clinical syndromes associated
with dengue.
Neutropenia, typical or atypical lymphocytosis, mild thrombocyto-
penia, and elevation of alanine and aspartate aminotransferases are
frequent clinical laboratory findings." 12, 14, 30

Dengue Hemorrhagic Fever

In Latin America and the Caribbean, DHF shows similar clinical

features in all age groups, but incidence is higher in the group under
age 15.6,l2 DHF is defined as an acute febrile illness with evidence of
bleeding, thrombocytopenia (<lo5/ kL), and evidence of plasma extrava-
sation, manifested by hemoconcentration (20% increase over base hema-
tocrit or 20% decrease after rehydration), polyserositis, or hypoproteine-
mia."
DHF starts with a sudden elevation of temperature in a manner
similar to what was described for DF.& Temperature is frequently high
(39" to 41°C) and persistent for 2 to 7 days, after which it returns to
normal or subnormal, coinciding with the development of hemorrhagic
manifestations (DHF) or shock (DSS).4 7, A fall in platelet count associ-
ated with a rising hematocrit suggests the development of DHF and
the possibility of DSS. Febrile seizures have been reported in children.
Epigastralgia, right upper quadrant tenderness, and generalized abdomi-
nal pain are frequent features. Sonography shows peritoneal fluid accu-
mulation, acalculous cholecystitis, and hepatic ptosis, which may be
misdiagnosed at the bedside as hepatomegaly. The tourniquet test (see
previous box) is positive in over 50% of patients. Hemorrhagic manifes-
tations can be minimal or can dominate the clinical picture. They include
petechiae and venipuncture site subcutaneous hemorrhage, purpura,
ecchymoses, epistaxis, gingivorrhagia, gastrointestinal bleeding, and less
commonly hematuria. Vascular leakage may be mild and clinically inap-
parent or excessive and can cause polyserositis, expressed by symptom-
atic pleural effusions, typically on the right side, ascites, and pericardial
effusions.
Four worsening levels of severity have been defined by the WHO
that are useful for epidemiologic and clinical purposes (Table 3)."
Warning signs for DSS have also been described%and are presented in
the following list:
Alarm signals for DSS
Clinical
Severe abdominal pain
Prolonged and/or large volume vomiting
 Abrupt change from fever to hypothermia, at times with syncope
Change in the level of consciousness (irritability, somnolence, or
both)
Sentinels of increased probability of shock
Laboratory
Progressively rising hematocrit
Progressively decreasing platelet count
Recovery is hastened by appropriate fluid and electrolyte replacement
but also occurs 7, 46
Leukopenia and lymphocytosis are common, and aminotransferases
may be elevated. Varying degrees of thrombocytopenia and hemo-
concentration are constant findings. Thrombin, prothrombin, and partial
thromboplastin times (TT, PT, and PTT) may be prolonged. Fibrinogen
levels decrease and fibrin degradation products may increase.

Dengue Shock Syndrome

Criteria fulfilling the diagnosis of DHF plus signs of circulatory

failure, including narrowing of pulse pressure ( 5 20 mm Hg), hypoten-
sion, or shock, are diagnostic of DSS." ', 46 The circulatory failure may
develop rapidly and may progress to profound shock and death in 12
to 24 hours. The duration of shock may be brief, but recurrent shock,
defined as the reappearance of circulatory failure after improvement,
complicated by metabolic acidosis and hemorrhage of the gastrointesti-
nal tract, carries a poor prognosis.
Signs of poor prognosis in DHFDSS
Profound shock
Recurrent shock
Respiratory failure
High level leukocytosis in the absence of secondary bacterial infection

Table 3. LEVELS OF SEVERITY OF DHF/DSS. DEFINITIONS OF THE PAN AMERICAN

HEALTH ORGANIZATION AND WHO
Grade I Fever + nonspecific constitutional symptoms + positive tourniquet
test
Grade I1 Grade I + spontaneous bleeding, usually skin other sites
Grade I11 Circulatory failure manifested by rapid and weak pulse, narrowing of
pulse pressure (20 rnm Hg or less), or hypotension with the
presence of cold, clammy skin and restlessness or agitation
Grade IV Profound shock with undetectable blood pressure and pulse
* The presence of hemoconcentration + thrombocytopenia differentiates DHF from DF
and other hemorrhagic fevers
- Grades I11 and IV constitute DSS

From the Organizaadn Panamericana de la Salud. 1997

 DENGUE AND DHF IN LATIN AMERICA AND THE CARIBBEAN 133

Mortality may be significant and usually occurs on the fourth to fifth

day of illness. After recovery from the acute disease, convalescence of
DHF and DSS is rapid and uneventful.
Clinical laboratory information is similar to that described for DHF,
but the severity of the abnormalities tends to be worse. Dilutional
hyponatremia and hypoproteinemia correlate with disease severity.

Other Dengue Syndromes

Encephalopathy associated with dengue has been recognized in
children and adults.22, 59 Neurologic manifestations may be mild to
severe, acute or delayed, and include severe headache, seizures, stupor,
and coma. They may be accompanied by signs of meningeal irritation
but lack of inflammatory response in the cerebrospinal fluid examina-
tion. The pathophysiology is largely undefined and may involve vascu-
lar leak, metabolic consequences, and actual neural tissue invasion by
dengue virus.14,41, 56 Most resolve without sequelae.
Cardiomyopathy clinically expressed by sinus tachycardia during
the febrile phase, and sinus bradycardia with varying degrees of conduc-
tion defects have been noted.14 Myocarditis and heart failure are rare.
Pericardial effusions are commonly documented by echocardiography
during the vascular leak phase.
Microscopic or macroscopic hematuria develop during dengue in-
fection. More severe renal involvement is likely related to parenchemal
hypoperfusion, but acute glomerulonephritis has been associated with
dengue. Thickening of the gallbladder wall, splenic enlargement, and
ascites are detected by sonography or physical e~amination.’~

Differential Diagnosis
The diagnosis of DF is primarily clinical, but the disease may be
confused with a number of other viral, bacterial, and parasitic infections
that cause similar febrile illnesses, especially if other epidemics coexist.
The abrupt onset and myalgias resemble influenza; the rashes resemble
those of rubella, measles, and meningococcemia; headache, prostration,
and paradoxic bradycardia resemble typhoid fever; the preceding rigors
resemble malaria; leukopenia and thrombocytopenia resemble mono-
cytic and granulocytic ehrlichiosis; and aminotransferase elevation may
suggest viral hepatitis or leptospirosis. DHF may also be misdiagnosed
as other Latin American hemorrhagic fevers and yellow fever.

MANAGEMENT
DF is generally self-limiting.Treatment in most cases is symptomatic
and supportive. Patients require rest, fluids, and relief of fever and
pains with drugs such as acetaminophen (paracetamol). Aspirin, other
salicylates, and nonsteroidal anti-inflammatory agents are not used so
that platelet function is not impaired, precipitation of Reye’s syndrome
is avoided, and gastrointestinal mucosal toxicity is prevented.
Although there is no need to hospitalize most patients with dengue,
all should be observed carefully. The prognosis of patients with DHF/
DSS depends on early recognition and appropriate therapy for shock.
Adults and children who present with high or rising hematocrit, other
objective evidence of vascular leakage, low or rapidly decreasing platelet
counts, a positive tourniquet test, any spontaneous hemorrhage other
than petechiae, or any sign or symptom of shock should be hospitalized,
especially if comorbidities exist. A reliable peripheral intravenous line is
placed, and monitoring of blood pressure, hematocrit, platelet count,
hemorrhagic manifestations, urinary output, and level of consciousness
is established and continued for at least 24 hours after defervescence if
the clinical situation permits.& Patient-to-patient variability notwith-
standing, the most dangerous period is the time of vascular leakage,
which can progress very rapidly but is usually of short duration. Massive
plasma leakage into serous and interstitial spaces may occur for 12 to 48
hours, during which time vigorous but very judicious volume replace-
ment is essential to maintain effective circulation while avoiding fluid
overload. Assuming normal renal function and absence of abnormal
water losses and electrolyte or acid-base abnormalities, the required
amount of fluids frequently approximates the volume needed to treat
mild isotonic dehydration (= 5% deficit).&In adults, isotonic electrolyte
solutions such as 0.9% NaCl and Ringer’s lactate are administered as
maintenance; 10 to 20 mL/kg boluses are given every 30 to 60 minutes
according to vital signs (followed every 1 to 2 hours), hematocrit (every
2 to 4 hours), and hourly urinary output to prevent impending hypoper-
fusion or to treat established shock. The volume for children is also
administered with maintenance solutions calculated as 1500 to 2000 mL
per square meter of body surface per day; 5% dextrose in 0.45% NaC1,
5% dextrose in 0.30% NaC1, and the preparations listed for adults are
amply used by pediatricians in diverse Latin American hospitals. Bo-
luses of 400 mL per square meter are given every 4 to 8 hours for
prevention and therapy for shock.
Patients not responding promptly are treated in an intensive care
setting where, if necessary, insertion of central venous and peripheral
arterial lines can be performed by an expert.” They are especially useful
when 60 mL/kg (adults) or 1200 mL/m2 (children) of fluids has been
administered in bolus without improvement or if the patient’s clinical
condition is deteriorating. A urinary catheter may be needed to assess
fluid balance. Further plasma loss in patients with massive leakage can
be treated with colloidal fluids. Patients with persistent shock and a
declining hematocrit may have inadvertent bleeding and may benefit
from blood transfusion. Prompt detection and treatment of electrolyte
and acid-base disturbances, most commonly hyponatremia and meta-
bolic acidosis, is essential. Hypocalcemia and hypoglycemia are less
 DENGUE AND DHF IN LATIN AMERICA AND THE CARIBBEAN 135

frequent complications. In all severe cases, coagulation tests must be

performed, followed, and acted upon as needed.&
To avoid hypervolemia and acute congestive heart failure, intrave-
nous fluids are tapered at 1- to 2-hour intervals until the hematocrit
drops by approximately 40% and vital signs are stable. Despite all
precautions, however, some patients do develop fluid overload, massive
effusions, and respiratory failure, requiring more invasive treatment and
diuretics.
Corticosteroids and carbazochrome sodium sulfonate (AC-17) have
not provided benefit in recent studies.60, 61 Platelet transfusions may be
indicated prophylactically for severe thrombocytopenia, especially when
the rate of decline is very fast, and therapeutically for bleeding associ-
ated with any degree of thrombocytopenia. Fresh frozen plasma is indi-
cated in some cases when consumption coagulopathy may be responsi-
ble for bleeding. Whole blood is the product of choice for replacement
of losses in patients with significant bleeding.

LABORATORY DIAGNOSIS

Because all currently available diagnostic tests have limitations,

their bedside usefulness in the clinical setting is limited. The diagnosis
of dengue and the decisions concerning hospitalization and monitoring
to guide the physician about the initiation of appropriate therapeutic
measures should rely on clinical judgment.19Because the disease can be
life-threatening, it is important that physicians practicing in temperate
areas consider dengue in their differential diagnosis of a febrile disease
in all patients with a history of travel to Latin America, the Caribbean,
and other tropical areas. A detailed description of the laboratory meth-
ods to diagnose dengue virus infection is beyond the scope of this
article, and excellent reviews have been published recently.23,27 A brief
review of diagnostic technologies is presented as a guide for the practic-
ing physician.
Virus isolation can be carried out in special laboratories by four
systems as follows: (1)intracerebral inoculation of 1- to 3-day-old baby
mice-a very time consuming, slow, insensitive, and expensive method,
(2) mammalian cell culture, with the same caveats as baby mice, (3)
mosquito inoculation, the most sensitive method, is the method of choice
for virologic confirmation of severe and fatal cases caused by many
dengue virus strains; however, it is slow, labor intensive, and requires
an insectary, and (4) culture in mosquito cell lines, the best compromise
between sensitivity, convenience, and cost-effectiveness. Proper handling
and storing of the specimens, the level of viremia, and the isolation
system used influence the success of isolation.23Once isolated, the vi-
ruses are detected and identified by direct or indirect fluorescent anti-
body techniques.
Serologic diagnosis depends on the detection of IgM antibody or
significant rise in IgG antibody titer in paired samples. Although several
tests, such as hemagglutination-inhibition (HI), complement fixation
(CF), neutralization test (NT), and indirect IgG enzyme-linked immuno-
sorbent assay (ELISA) have been routinely used in the past, the more
recent IgM capture enzyme-linked immunosorbent assay (MAC-ELISA)
has become the most widely used. It is simple and requires little sophisti-
cated equipment. The rapidity with which IgM antibody develops varies
considerably among patients. For example, in Puerto Rico, 80% had
detectable antibodies by this technique at day 5 of illness, 93% 6 to 10
days after the onset of symptoms, and 99% 10 to 20 days after
IgM can be detected for an average of approximately 2 months. In the
last few years, less expensive kits that do not require specialized training
for the measurement of antibody against dengue virus have been widely
commercialized in Latin America for use in clinical laboratories.a These
include an ELISA microtitre, a dipstick format, and a rapid dot-blot test.
Their sensitivity and specificity are being evaluated. Positive samples
are interpreted as probable dengue. That negative results on acute phase
samples do not rule out dengue cannot be overemphasized.19
The measurement of IgG antibody to dengue viruses has been
highly reliable for epidemiologic studies, but the diagnosis of current
infection requires paired serum samples taken during acute and conva-
lescent phases of the disease, making their clinical application less useful
than IgM measurement. A fourfold or greater rise in IgG antibodies can
be interpreted as a confirmed case, provided no other flaviruses are
transmitted in the area. Because of the cross-reactions among the anti-
genic determinants of all four dengue viruses and other members of the
flavivirus family, the antigen battery for most serologic tests should
include all the dengue serotypes, another flavivirus, a nonflavivirus
virus, and ideally an uninfected tissue A rapid, sensitive,
simple, and economic test that detects antigen early in the clinical period
is needed.

PREVENTIONANDCONTROL

There are two approaches to prevention and control of dengue and

DHF: vaccines and mosquito control. Unfortunately, vaccines for these
viruses have not yet been developed, and mosquito control has been
completely ineffective in most dengue endemic countries of the world
in the past 30 years.

Progress in Developing Dengue Vaccine

It has been 22 years since the WHO made the decision to recom-
mend development of a vaccine for dengue viruses. Progress was slowed
by the need to develop a tetravalent vaccine that was effective against
all four virus serotypes. Although live attenuated vaccine candidates
have been developed for all four serotypes, there have been formulation
 DENGUE AND DHF IN LATIN AMERICA AND THE CARIBBEAN 137

problems that have prevented cornmercializati~n.~ Results of recent trials

in Thailand of various formulations of these candidate vaccines are not
yet available.
There has been progress in developing dengue vaccines using mo-
lecular technology.62The most promising approach appears to be using
infectious cDNA technology to construct chimeric viruses using the
DEN-2 PDK-53 and the 17-D yellow fever vaccine viruses as backbones.
Naked DNA vaccine candidate vaccines have also been constructed. The
timeline for these candidate vaccines to be used in human trials, how-
ever, is uncertain. It is unlikely that a safe and effective vaccine for
dengue viruses will be available in the near future.

Mosquito Control
Currently, the most effective way to prevent epidemics of dengue/
DHF is to control the principal mosquito vector, Aedes ~egypti.'~,Mos-
quito control in the past 20 years in the American region has relied on
adult mosquito control using insecticidal space sprays.17Unfortunately,
this approach has been completely ineffective. Moreover, it has misled
both citizens of the community and government officials, making them
think that the mosquitoes had been controlled when they were
The only documented method to effectively control A. aegypti mos-
quitoes is source reduction by eliminating or controlling the principal
mosquito breeding sites in the domestic environment. Most mosquito
breeding and dengue transmission occurs in and around the home in
large urban centers of the tropics. Effective control of these principal
mosquito breeding sites is simple and economical but requires the help
of the persons living in the houses, simply because there are too many
houses for health officials to deal with effectively. Sustainable A. aegypti
control will require a partnership effort between the community and
government agencies. A comprehensive discussion of this topic is be-
yond the scope of this article, but the subject of A. aegypti control has
been recently reviewed.l7s 53

References
1. Republica de Venezuela Ministerio de Sauidad y Aristeucia Social Organizacion Pan-
americano de la Salud OPS Normas tecnicas y operativas para la prevencion del
dengue y el control del Aedes aegypti en Venezuela. Organizacion Mundial de la Salud
OMS, Caracas, Venezuela, 1997, pp 3-7
2. Anonymous: Dengue in the Caribbean, 1977. Proceedings of a Workshop Held in
Montego Bay, Jamaica (May 8-11,1978). Scientific Publication No. 375, Pan American
Health Organization, 1979
3. Anonymous: Dengue hemorrhagic fever in Venezuela. Epidemiol Bull 11:7, 1990
4. Anonymous: Dengue fever in Costa Rica and Panama. Epidemiol Bull 15:9, 1994
5. Anonymous: Dengue y dengue hemorragico en las Americas: Guias para su prevencion
y control. No 548. Washington, DC, Organizacion Panamericana de la Salud, 1997, p 3
6. Anonymous: Dengue haemorrhagic fever: Diagnosis, treatment, prevention and con-
trol, ed 2. Geneva, Switzerland, World Health Organization, 1997
 7. Bhamarapravati N, Yoksan S Live Attenuated Tetravalent Dengue Vaccine. In Gubler
DJ, Kuno G (eds):Dengue and Dengue HemorrhagicFever. London, CAB International,
1997, pp 367-377
8. Bravo JR, Kouri G, Guzman MG Why dengue hemorrhagic fever in Cuba? I. Individ-
ual risk factors for dengue hemorrhagic feverldengue shock syndrome (DHF/DSS).
Trans R SOCTrop Med Hyg 81:816, 1987
9. Cheong L L The vectors of dengue and dengue hemorrhagic fever in Malaysia. In
Rudnick A, Lin TW (eds): Dengue fever studies in Malaysia. Kuala Lumpur, Malaysia:
Institute of Medical Research, 1986, Bulletin 23
10. Chong KY, Lin KC: A preliminary report of the fetal effects of dengue infection in
pregnancy. Kao Hsiung I Hsueh KO Hsueh Tsa Chih 531,1989
11. Centers for Disease Control and Prevention: Imported dengueunited States, 1993
and 1994. MMWR Morb Mortal Wkly Rep 44:353-356, 1995
12. Dietz V, Gubler DJ, Ortiz S, et al: The 1986 dengue and dengue hemorrhagic fever
epidemic in Puerto Rico: Epidemiology and clinical observations. P. R. Health Sci J
15:201, 1996
13. Ehrenkranz NJ, Ventura AK, Cuadrado RR, et a 1 Pandemic dengue in the Caribbean
countries and the southern United States-past, present and potential problems. N
Engl J Med 2851460,1971
14. George R, Lum LCS Clinical Spectrum of Dengue Infection. In Gubler DJ, Kuno G
(eds): Dengue and dengue hemorrhagic fever. London, CAB International, 1997, p 89
15. Gubler DJ: Dengue and dengue hemorrhagic fever in the Americas. P.R. Hlth S a J
6107-111, 1987
16. Gubler DJ: Dengue. In Monath RP (ed): Epidemiology of Arthropod-Borne Viral
Disease, vol2. Boca Raton, FL, CRC Press, 1988, pp 223-260
17. Gubler DJ: Aedes uegypti and Aedes uegypti-borne disease control in the 1990s: Top
down or bottom up. Am J Trop Med Hyg 40571, 1989
18. Gubler DJ: Dengue and Dengue Hemorrhagic Fever: Its History and Resurgence as a
Global Public Health Problem. In Gubler DJ, Kuno G (eds): Dengue and Dengue
Hemorrhagic Fever. London, CAB International, 1997, p 1
19. Gubler DJ: Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 11:480, 1988
20. Gubler DJ, Reed D, Rosen L, et al: Epidemiologic, clinical and virologic observations
on dengue in the Kingdom of Tonga. Am J Trop Med Hyg 27581-589,1978
21. Gubler DJ, Suharyono, Lubis I, et al: Epidemic dengue 3 in Central Java associated
with low viremia. Am J Trop Med Hyg 30109P1099, 1981
22. Gubler DJ, Kuno G, Waterman SH, et al: Neurologic disorders associated with dengue
infection. In Proceedings of an International Conference on Dengue/Dengue Hemor-
rhagic Fever. Kuala Lumpur, Malaysia, September, 1983, pp 290-301
23. Gubler DJ, Sather G E Laboratory diagnosis of dengue and dengue hemorrhagic fever.
In Homma A, Cunha JF (eds): Proceedings of the International Symposium on Yellow
Fever and Dengue, 1988, p 291
24. Gubler DJ, Casta-Velez A: A program for prevention and control of epidemic dengue
and dengue hemorrhagic fever in Puerto Rico and the U.S. Virgin Islands. Bull Pan
Am Health Organ 25:237-247, 1991
25. Gubler DJ, Trent DW. Emergence of epidemic dengue/dengue hemorrhagic fever as a
public health problem in the Americas. Infect Agents Dis 2383, 1994
26. Gubler DJ, Clark GG: Community involvement in the control of Aedes uegypti. Ada
Trop 61:169-179, 1996
27. Guzman MG, Kouri G: Advances in dengue diagnosis. Clin Diagn Lab Immunol
3:621, 1996
28. Halstead SB: Dengue hemorrhagic fever: A public health problem and a field for
research. Bull World Health Organ 58:1, 1980
29. Halstead SB: The pathogenesis of dengue. Am J Epidemiol 114632, 1981
30. Hayes EB, Gubler DJ: Dengue and dengue hemorrhagic fever. Pediatr Infect Dis J
11:311, 1992
31. Henchal EA, Putnak J R The dengue viruses. Clin Microbiol Rev 3:376, 1990
32. Henchal EA, Gentry MK, McCown JM, et al: Dengue virus specific and flavivirus
 DENGUE AND DHF IN LATIN AMERICA AND THE CARIBBEAN 139

group determinants identified with monoclonal antibodies by direct immunofluores-

cence. Am J Trop Med Hyg 31530, 1982
33. Herrera E, Prevots DR, Zarate ML, et al: First reported outbreak of classical dengue
fever at 1700 meters above sea level in Guerrero State, Mexico, June 1988. Am J Trop
Med Hyg 46649,1992
34. Innis BL: Dengue and Dengue Hemorrhagic Fever. In Porterfield JS (ed): Exotic Viral
Infections-1995. London, Chapman & Hall, 1995, pp 10S-146
35. Kalayanarooj J, Vaughn DW, Nimmannitya S, et al: Early clinical and laboratory
indicators of acute dengue illness. J Infect Dis 176313, 1997
36. Kautner I, Robinson MJ, Kuhnle U Dengue virus infection: Epidemiology, pathogene-
sis, clinical presentation, diagnosis and prevention. J Pediatr 131:516, 1997
37. Kouri G, et al: Hemorrhagic dengue in Cuba: History of an epidemic. Bull Pan Am
Health Organ 20:24, 1986
38. Kouri GP, Guzman MG, Bravo JR, et al: Dengue hemorrhagic fever/dengue shock
syndrome: Lessons from the Cuban epidemic. Bull World Health Organ 67375, 1989
39. Kouri G, Guzman MG, Valdes L, et al: Reemergence of dengue in Cuba: A 1997
epidemic in Santiago de Cuba. Emerg Infect Dis 4:89-92, 1998
40. Kurane L, Ennis FA Immunopathogenesis of dengue virus infections. In Gubler DJ,
Kuno G (eds): Dengue and Dengue Hemorrhagic Fever. London, CAB International,
1997, p 273
41. Lum tSC, Lam SK, Choy IS, et al: Dengue encephalitis: A true entity? Am J Trop Med
Hve; 54:526, 1996
42. L&s JA, Chang GJ, Lanuotti RS, et al: Phylogeneticrelationships of dengue-2 viruses.
Virology 197216, 1993
43. Martinez E: El Problema. In Dengue y Dengue Hemorragico. Universidad Nacional de
Quilmes, Buenos Aires, Gallo, 1998, p 27
44. McSherry JA Some medical aspectsbf the Darien scheme: Was it dengue? Scott Med
1 2793,1982
45. Meltzer MI, Rigau-Perez JG, Clark GG, et a1 Using disability-adjusted life years to
assess the economic impact of dengue in Puerto Rico: 1984-1994. Am J Trop Med Hyg
59:265-271, 1998
46. Nimmannitya S: Dengue Hemorrhagic Fever: Diagnosis and Management. In Gubler
DJ, Kuno G (eds):Dengue and Dengue HemorrhagicFever. London, CAB International,
1997, p 133
47. Osanai CH: Surto de dengue em Boa Vista, Roraima. Nota previa. Rev Inst Med Trop
Sao Paul0 25:53, 1983
48. Phillips I: First documented outbreak of dengue in the Peruvian Amazon region. Bull
Pan Am Health Organ 26201, 1992
49. Pinheiro FP, Corber.SJ: Global situation of dengue and dengue hemorrhagic fever, and
its emergence in the Americas. World Health Stat Q 50:161, 1997
50. Ramirez-Ronda CH, Garcia C Dengue in the Western Hemisphere. Infect Dis Clin
North Am 8107,1994
51. Rico-Hesse R Molecular evolution and distribution of dengue viruses type 1 and 2 in
nature. Virology 174479493, 1990
52. Rico-Hesse R, Harrison L, Salas R, et al: Origins of dengue type 2 viruses associated
with increased pathogenicity in the Americas. Virology 230:244-251, 1997
53. Reiter P, Gubler DJ: Surveillance and Control of Urban Dengue Vectors. In Gubler DJ,
Kuno G (eds): Dengue and Dengue Hemorrhagic Fever. London, CAB International,
1997, pp 425-462
54. Rigau-Perez JG, Clark GG, Gubler DJ, et al: Dengue and dengue hemorrhagic fever.
Lancet 352971, 1998
55. Rosen L: The Emperor’s new clothes revisited, or reflections on the pathogenesis of
dengue hemorrhagic fever. Am J Trop Med Hyg 26:337-343, 1977
56. Rosen L, Mi MK, Tin U. Recovery of virus from the liver of children with fatal dengue:
Reflections on the pathogenesis of the disease and its possible analogy with that of
yellow fever. Res Virol 140:351-360, 1989
57. Rothman AL: Viral Pathogenesis of Dengue Infections. In Gubler DJ, Kuno G (eds):
Dengue and Dengue Hemorrhagic Fever. London, CAB International, 1997, p 245
58. Sumarmo, Wulur H, Jahja E, et ak Encephalopathy associated with dengue infection.
Lancet M49-450, 1978
59. Sumarmo SPS,Wulur H, Jahja E, et ak Clinical observations on virologically confirmed
fatal dengue infectionsin Jakarta, Indonesia. Bull World Health Organ 61:693-701,1983
60. Tassniyom S, Vasanawathana S, Chirawatkul A, et ak Failure of high dose methylpred-
nisolone in established dengue shock syndrome: A placebo-controlled, double-blind
study. Pediatrics 92111, 1993
61. Tassniyom S, Vasanawathana S, Dhiensiri T, et a1 Failure of carbazochrome sodium
sulfonate (AC-17) to prevent dengue vascular permeability or shock: A randomized
controlled trial. J Pediatr 131:525,1997
62. Trent DW, Kinney RM, Huang CY-H Recombinant Dengue Virus Vaccines. In Gubler
DJ, Kuno G (eds):Dengue and Dengue Hemorrhagic Fever. London, CAB International,
1997, pp 379-404
63. Vomdam V, Kuno G Laboratory diagnosis of dengue virus infections. In Gubler DJ,
Kuno G (eds): Dengue and Dengue Hemorrhagic Fever. London, CAB International,
1997, p 313
64. Westaway EG, Blok J: Taxonomy and evolutionary relationships of flaviviruses. In
Gubler DJ, Kuno G (eds): Dengue and Dengue Hemorrhagic Fever. London, CAB
International, 1997, p 147
65. Winter PE, Nantapanich S, Nisalak A Recurrence of epidemic dengue hemorrhagic
fever in an insular setting. Am J Trop Med Hyg 18:573, 1969
Address reprint requests to
Rafd E. Ishlriz, MD, FACP
BItiment INSERM EPI 9933
H6pital Bichat-Claude Bernard
46, Rue Henri Huchard
75877 Paris Cedex 18, France

e-mail: ul3@bichat.inserm.fr