Dengue Virus Infection - Prevention and Treatment - UpToDate

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Dengue virus infection: Prevention and treatment

Authors: Stephen J Thomas, MD, Alan L Rothman, MD, Anon Srikiatkhachorn, MD, Siripen Kalayanarooj, MD
Section Editor: Martin S Hirsch, MD
Deputy Editor: Keri K Hall, MD, MS
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2022. | This topic last updated: Feb 24, 2022.
INTRODUCTION
Dengue is a febrile illness caused by a flavivirus transmitted by Aedes aegypti or Aedes

albopictus mosquitoes while taking a blood meal. There are four dengue virus (DENV) types
(DENV-1, DENV-2, DENV-3, and DENV-4), all of which are capable of inducing severe disease
(dengue hemorrhagic fever [DHF]/dengue shock syndrome [DSS]). Dengue is endemic in
more than 125 countries in tropical and subtropical regions and causes an estimated 390
million infections annually worldwide, of which 96 million are clinically apparent [1].
The likelihood for development of severe dengue is highest among individuals who are
infected a second time by a different DENV type from the first infection (known as secondary
or heterotypic infection) [2]. Thus, severe disease occurs primarily among individuals in
areas where multiple DENV types circulate simultaneously. Infection with DENV provides
long-term protection against disease caused by reinfection with that particular type.
However, infection provides only short-lived cross-protection to the other three DENV types.
There are numerous documents providing guidance on the optimal approaches to

managing dengue [3-6]. Data from well-designed randomized controlled trials are limited.
The guidance in this document largely agrees with published guidelines and is also based on
the contributors' clinical experience in management of complex DENV infections.
Measures to prevent DENV infection and supportive treatment following infection and the
development of disease will be reviewed here. The epidemiology, clinical manifestations, and
diagnosis of infection are discussed separately. (See "Dengue virus infection: Epidemiology"
and "Dengue virus infection: Clinical manifestations and diagnosis".)
PREVENTION
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DENV transmission occurs when susceptible hosts, DENVs, and mosquitoes capable of
transmission are co-located in space and time. Infection risk exists for anyone living in or
traveling in a dengue-endemic region, especially in tropical Asia, Central and South America,
and the Caribbean. In most of these regions, DENV transmission occurs year-round.
However, the greatest risk of infection tends to be seasonal or during a recognized outbreak.
In endemic areas — Approaches for the prevention of DENV infection and disease in

endemic areas include mosquito control, personal protective measures, and vaccination.
Personal protection from infection
Mosquito repellants — Issues related to personal protection for prevention of

mosquito bites are discussed separately. (See "Prevention of arthropod and insect bites:
Repellents and other measures".)
Insecticide spraying — Distribution of insecticide-treated curtains was successful in

reducing populations of A. aegypti mosquitoes for up to 18 months in several studies [7,8]
and was associated with reduced human and mosquito infections with DENV in one region
[7,8], although use of the curtains declined with time. Insecticide spraying in response to
dengue outbreaks is not highly effective, since A. aegypti mosquitoes frequently breed inside
houses [9,10].
Vaccine development — Infection with one DENV type provides long-term protection

against reinfection with that same type, supporting the feasibility of an effective dengue
vaccine. Following infection with one type, there is short-lived immunity and cross-protection
against disease caused by the other three DENV types [11].
In view of the association between previous exposure to DENV types and severe disease, and
the recognition that all four DENV types are capable of causing severe disease, ideally any
candidate vaccine should produce protective immunity against all four DENV types
(tetravalent immunity). Since waning immunity might also increase the risk for severe
disease in vaccine recipients, vaccine-induced protective immunity should be long lived [12].
Given that the rate of clinically relevant third or fourth DENV infection is low, it is unclear
whether tetravalent immunity is required for efficacy [13].
One vaccine, CYD-TDV (Dengvaxia), has been licensed in over 20 countries in Latin America
and Southeast Asia (first licensed in 2015) (see 'CYD-TDV (Dengvaxia)' below). Vaccines in
advanced clinical development include TAK-003 (Takeda) (see 'TAK-003' below) and a
tetravalent, live-virus vaccine attenuated through directed mutagenesis with a DENV-2/-4
chimeric strain (National Institute of Health, licensed to Bhutantan and Merck) [14-16].
CYD-TDV (Dengvaxia) — In 2018, the CYD-TDV (Dengaxia) vaccine was approved by

European authorities and recommended by the World Health Organization (WHO) for
persons aged 9 to 45 years with confirmed previous dengue infection who live in endemic
areas [17-19]. In 2019, the United States Food and Drug Administration (FDA) approved the
vaccine for use in endemic areas [20]. In 2021, the Advisory Committee on Immunization
Practices (ACIP) of the United States Centers for Disease Control and Prevention (CDC)
officially recommended the vaccine for children aged 9 to 16 who have serologic evidence of
previous dengue infection and live in endemic US territories [21]. Among United States
territories, dengue is endemic in Puerto Rico, American Samoa, the US Virgin Islands, the
Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau.
The vaccine is not approved for travelers visiting dengue-endemic areas and is not
commercially available in the United States [17].
CYD-TDV is a formulation of four chimeric yellow fever 17D-dengue vaccine viruses, where
the premembrane and envelope proteins from each of the four DENV types replaces the
same proteins in a yellow fever 17D backbone virus [22,23]. The basis for licensure was two
large phase III randomized controlled trials of CYD-TDV; results were reported in 2014 to
2015 [24,25]. One trial was conducted in five countries in the Asia-Pacific region and enrolled
children aged 2 to 14 years [24]; the other trial was conducted in five countries in Latin
America and the Caribbean and enrolled children aged 9 to 16 years [25]. The age groups
were chosen based on likely target populations for vaccination and epidemiologic data of
clinical attack rates.
In both trials, the CYD-TDV vaccine was administered in three doses at months 0, 6, and 12.
Results from the two trials were comparable; in the primary per-protocol analysis, vaccine
efficacy was 57 and 61 percent against virologically confirmed dengue of any severity caused
by any DENV type that occurred between 28 days and 13 months after the third vaccine
dose. Vaccine efficacy was higher against dengue hemorrhagic fever or dengue infection
requiring hospitalization (80 to 95 percent). Vaccine efficacy varied by serotype and was
significantly higher for DENV-3 and DENV-4 (approximately 75 percent) than DENV-1 (50
percent) and DENV-2 (35 to 42 percent). Vaccine efficacy was lower (34 to 36 percent) in
children 2 to 5 years of age and in children who did not have detectable dengue-neutralizing
antibodies prior to vaccination. The safety profile was considered good, and there was no
indication of more severe dengue disease in breakthrough cases in vaccine recipients that
occurred over the 25 months of active case surveillance.
Follow-up analyses of these vaccine trials found significant limitations of the vaccine [26-28].
In a case-cohort study in which data from three vaccine efficacy trials were reanalyzed, the
vaccine was protective among children previously exposed to dengue but increased the risk
of hospitalization and severe illness among children who were not previously exposed [26].
Among dengue-seronegative children age 2 to 16 years, the cumulative incidence of
hospitalization for dengue among vaccine recipients and controls was 3.06 and 1.87 percent,
respectively (hazard ratio [HR] 1.75, 95% CI 1.14-2.70). Among dengue-seropositive children
age 2 to 16 years, the cumulative incidence of hospitalization for dengue among vaccine
recipients and controls was 0.75 and 2.47 percent, respectively (HR 0.32, 95% CI 0.23-0.45).
In November 2017, the vaccine manufacturer announced that, based on six years of clinical
data, the vaccine had a persistent beneficial effect in individuals who had been previously
infected with DENV prior to vaccination. In individuals with no prior episode of DENV
infection, however, vaccination was associated with an increased risk of severe disease and
hospitalization. Therefore, the manufacturer updated the label, advising that individuals with
no prior DENV infection forgo vaccination [29].
In December 2017, the WHO issued a statement indicating that the vaccine is protective
against severe dengue for individuals with dengue seropositivity at the time of first
vaccination but that the risk of severe dengue is significantly increased for individuals with
dengue seronegativity at the time of first vaccination [30].
The mechanisms for CYD-TDV vaccine efficacy in seropositive individuals and the increased
risk of severe dengue in seronegative individuals are uncertain. Only a subset of individuals
underwent scheduled serologic monitoring prior to and following vaccination, so analyses of
the immune profiles associated with various outcomes are limited. A statistical analysis
found that higher postvaccination titers of neutralizing antibodies were associated with a
significantly higher vaccine efficacy for all DENV types, baseline serostatus groups, and age
groups [31]. However, no absolute correlate of protection could be identified, indicating that
the relationship between vaccine-induced immune responses and efficacy is likely more
complex than any one single factor.
The vaccine sponsor also used measured (when values were available) or imputed (when
values missing) PRNT50 titers, with imputation conducted using covariates to include data
generated from study month 13 blood samples (on month after dose 3) tested with a newly
developed anti-non-structural protein 1 (NS1) assay. Because the vaccine construct does not
contain dengue NS1 protein, the absence of anti-NS1 antibodies from a study month 13
sample would indicate the individual had not experienced a natural DENV infection
(seronegative status at baseline) [26,32].
Overall, CYD demonstrated superior efficacy and clinical benefit in seropositive versus
seronegative vaccine recipients. There was also a trend of superior efficacy and beneficial
vaccine effect in older children, and these effects were noted against any dengue caused by
all DENV types as well as severe and hospitalized dengue. In contrast, there was a clear
safety signal in seronegative vaccine recipients especially in the younger age groups with
hospitalization and severe disease occurring with increased frequency in seronegative
vaccine recipients [33].

TAK-003 — TAK-003 is tetravalent vaccine based on an attenuated laboratory-

derived DENV-2 virus, DENV-2 primary dog kidney (PDK)–53, which provides the genetic
backbone for all four of the viruses in the vaccine [34-37]. The other three virus strains (TDV-
1, TDV-3, and TDV-4) are chimeras generated by replacing the premembrane and envelope
genes of TDV-2 with those from wild-type DENV-1, DENV-3, and DENV-4 strains.
Findings from a phase 2 trial among more than 1400 participants aged 2 to 17 years in three
countries with 48-month follow-up support a two-dose schedule administered three months
apart [35]. No serious adverse events or severe DENV disease were reported.
In a phase 3 clinical trial including more than 20,000 children 4 to 16 years of age in regions
of Asia and Latin America where DENV infection is endemic, individuals were randomly
assigned to receive two doses of vaccine or placebo three months apart [36,37].
● At 12 months of follow-up, fewer cases of DENV infection (confirmed via polymerase

chain reaction) were observed among vaccinated individuals than among those who
received placebo (0.5 versus 2.5 per 100-person years); the overall vaccine efficacy was
80.9 percent (95% CI 75.2-85.3) [36]. Approximately 5200 individuals (28 percent of the
per-protocol population) were seronegative at baseline; in this group, the vaccine
efficacy was 74.9 percent (95% CI 57.0-85.4). The incidence of serious adverse events
was similar in the vaccine group and placebo group (3.1 and 3.8 percent, respectively).
Efficacy varied according to DENV type; there was no efficacy against DENV-3, and data
were insufficient to evaluate efficacy against DENV-4.
● At 18 months of follow-up, overall vaccine efficacy (against any DENV type and any
disease severity) was 73.3 percent (95% CI 66.5-78.8) and overall efficacy against
hospitalized dengue was 90.4 percent (95% CI 82.6-94.7) [37]. Vaccine efficacy was
higher among baseline seropositive than seronegative individuals (76.1 versus 66.2
percent). Secondary vaccine efficacy endpoints by serotype were met for DENV-1 (69.8
percent, 95% CI 54.8-79.9), DENV-2 (95.1 percent, 95% CI 89.9-97.6), and DENV-3 (48.9
percent, 95% CI 27.2-64.1), but not DENV-4 (51.0 percent, 95% CI -69.4 to 85.8). Vaccine
efficacy against DENV-1 and DENV-2 was similar regardless of baseline serostatus; for
DENV-3, vaccine efficacy among seropositive individuals was 61.8 percent (43.0 to 74.4)
but vaccine efficacy was not observed among seronegative individuals (-68.2 percent,
95% CI -318.9 to 32.4).
Thus far, the available data suggest TAK-003 may be used in seropositive or seronegative
individuals, and the high efficacy against hospitalized dengue suggests that TAK-003 may be
a useful public health tool for reducing the burden of severe disease. However, further
efficacy and safety evaluation is needed, particularly for serotypes DENV-3 and DENV-4.

Mosquito control — Mosquito control is effective but is difficult to resource and sustain.

Programs in the 1940s through 1970s targeting the A. aegypti mosquito via aggressive
surveillance and insecticide use for elimination of urban yellow fever in the Americas were
successful at reducing transmission of yellow fever as well as the DENVs [9]. Lack of funding
and attention for these programs led to reemergence of A. aegypti and corresponding re-
emergence of dengue.
Some approaches to mosquito control for prevention of DENV infection are described below.
Additional issues related to mosquito vector control are discussed further separately. (See
"Malaria: Epidemiology, prevention, and control", section on 'Mosquito control'.)
● Reducing breeding sites – Community-based education to reduce breeding sites that

accumulate standing water (such as discarded tires and other containers) have shown
some promise [9,38].
● Larva control – Seeding water vessels with copepods that feed on mosquito larvae was
successful in eliminating A. aegypti and dengue transmission in one study including 32
rural communities in Vietnam [39], although this strategy is difficult to apply in urban
areas [40].
● Endosymbiotic control – A novel dengue control strategy consists of releasing

mosquitoes infected with Wolbachia, an obligate intracellular bacterium [41-43]. A.
aegypti mosquitoes infected with Wolbachia are less susceptible to DENV infection than
wild-type A. aegypti [44].
This strategy was applied in a cluster-randomized controlled trial in Indonesia in which

24 geographic clusters were randomly assigned to receive deployments of Wolbachia-
infected A. aegypti mosquitoes (intervention) or no deployments (control) [45]. Among
more than 8000 participants age 3 to 45 years presenting with acute undifferentiated
fever during the two-year study period, the incidence of symptomatic dengue was
lower in the intervention cluster (2.3 versus 9.4 percent; odds ratio 0.23, 95% CI 0.15-
0.35). The efficacy of the intervention for protection against dengue infection was 77.1
percent (95% CI 65.3-84.9) and was similar for all four DENV serotypes; the efficacy for
protection against hospitalization was 86.2 percent (95% CI 66.2-94.3). Further study is
needed to evaluate the durability of protection afforded by Wolbachia-infected
mosquitoes and to reproduce these findings in other contexts.
Among travelers — The primary approach to prevention of DENV infections in travelers

consists of avoiding exposure to infected A. aegypti mosquitoes, which predominantly live in
urban areas (in and around houses) and are most active during the daytime as well as at
twilight [10]. Remaining in well-screened or air-conditioned buildings during the day can
reduce the risk of exposure. When outside during the day, individuals should wear clothing

that reduces the amount of exposed skin and should use an effective mosquito repellent,
such as N,N-diethyl-metatoluamide (DEET). (See "Prevention of arthropod and insect bites:
Repellents and other measures".)
Most travelers from nonendemic countries are at exceedingly low risk for severe dengue in
the absence of prior DENV exposure; potential exceptions include frequent international
travelers, expatriates, frequently deploying military personnel, and immigrants from
endemic areas returning to their countries of origin.
People with history of dengue infection need not avoid subsequent travel to dengue-
endemic regions. Severe dengue occurs in a small number of secondary infections (2 to 4
percent), so the risk of severe dengue in travelers is very low.
CYD-TDV (Dengvaxia) is not approved for travelers visiting dengue-endemic areas and is not
commercially available in the United States [17]. (See 'CYD-TDV (Dengvaxia)' above.)
TREATMENT APPROACH
There is no direct antiviral therapy available against the DENVs. Management is supportive,
which largely consists of maintaining adequate intravascular volume.
Treatment guidelines have been published by the World Health Organization (WHO; 2009)
and the WHO South-East Asia Regional Office (SEARO; 2011); there are variations between
these guidelines [5,46]. These are discussed in the following sections, which follow the
framework of the revised dengue case classification. Where relevant, significant differences
in the recommendations are noted in the discussion below. (See "Dengue virus infection:
Clinical manifestations and diagnosis".)
Thus far, there has been no prospective validation of the approaches summarized in the
WHO guidelines. The areas of greatest uncertainty are the sensitivity and specificity of the
criteria used for hospitalization and for initiation of fluid therapy. Some additional clinical
approaches that have been successful in endemic areas are discussed below. (See 'Additional
approaches to management' below.)
A definitive laboratory diagnosis of dengue is often not available at the point of care;
therefore, it is also important to consider other treatable diagnoses. (See "Dengue virus
infection: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)
Phases of infection and clinical assessment — DENV infection has three phases: a febrile
phase, a critical (plasma leakage) phase, and a convalescent (reabsorption) phase [5]. The
febrile phase is characterized by a sudden high-grade fever and dehydration typically lasting
two to seven days. The critical phase is characterized by plasma leakage, bleeding, shock,

and organ impairment; it usually starts around the time of defervescence (typically days 3 to
7 of infection) and lasts for 24 to 48 hours. The convalescent phase may be characterized by
fatigue that can last for days to weeks. (See "Dengue virus infection: Clinical manifestations
and diagnosis", section on 'Phases of infection'.)
The WHO classification schemes for DENV infection are summarized separately [4,5]. (See
"Dengue virus infection: Clinical manifestations and diagnosis", section on 'Classification
schemes'.)
Patients with suspected dengue should be assessed carefully and directed to the
appropriate care setting. Early recognition of progression to severe disease and patients at
increased risk for severe disease is essential, with prompt initiation of more aggressive
therapy when necessary.
Outpatient management is appropriate for patients with presumptive diagnosis of dengue

infection in the absence of warning signs or coexisting conditions (pregnancy, infancy, old
age, diabetes, renal failure, underlying hemolytic disease, obesity, or poor social situation);
such patients should be able to tolerate oral fluids, urinate at least once every six hours, and
have near normal blood counts [5].
Inpatient management is warranted for patients with dengue and warning signs of severe
infection, severe dengue infection, or dengue infection with coexisting conditions
( algorithm 1). Dramatic plasma leakage can develop suddenly; early identification of
patients at increased risk for shock and other complications is critical. The period of
maximum risk for shock is between the third and seventh day of illness, which typically
coincides with resolution of fever. In general, plasma leakage first becomes evident between
24 hours before and 24 hours after defervescence.
Laboratory abnormalities include derangements in blood counts and liver function tests. An
elevated hematocrit is an indication that plasma leakage has already occurred and that fluid
repletion is required. Confounding factors should be considered when interpreting the
hematocrit, including dehydration (associated with increased hematocrit) and hemorrhage
(associated with reduced hematocrit). Marked thrombocytopenia (≤100,000/mm3) is a
criteria for dengue hemorrhagic fever and usually precedes overt plasma leakage. Mild
elevations in serum transaminases are common in the setting of dengue infection;
transaminase levels are significantly elevated in patients with DHF. In addition, elevated
aspartate transaminase (AST) levels are common relatively early in the course of illness; in
one Thai study, a normal AST level was a strong negative predictor of DHF (negative
predictive value 0.96) [47]. (See "Dengue virus infection: Clinical manifestations and
diagnosis", section on 'Dengue hemorrhagic fever'.)

Outpatient management — Outpatient management is appropriate for patients with

presumptive diagnosis of dengue in the absence of warning signs or coexisting conditions
as summarized in the preceding section. Most patients with dengue do not develop severe
illness and can be safely managed in the outpatient setting. (See 'Phases of infection and
clinical assessment' above.)
Patients should be instructed regarding the warning signs of severe dengue infection and
the critical phase that follows defervescence (which lasts for 24 to 48 hours); during this
period, patients may deteriorate rapidly. During the febrile phase (lasting two to seven days)
and the subsequent critical phase (lasting one to two days), the patient should be evaluated
daily from the third day of illness through the end of the critical phase for signs of
dehydration and other warning signs of severe dengue. Serial blood counts should be
followed to evaluate for interval increases in hematocrit concurrent with rapid decrease in
platelet count, indicating presence of plasma leakage and increased risk of bleeding
complications.
Fever may be controlled with acetaminophen; nonsteroidal anti-inflammatory drugs and

aspirin-based products should not be used out of concern for their effect on platelet
function and the potential increased risk for bleeding. (See 'Management of fever' below.)
Patients should be instructed to take plenty of fluids and watch for signs of dehydration
(decrease in urination, few or no tears, dry mouth or lips, sunken eyes, listlessness or
confusion, cold or clammy extremities, sunken fontanel in an infant); these findings warrant
prompt clinical evaluation. As fever declines (three to eight days after onset of symptoms),
patients should be instructed to seek prompt attention for any of the following: severe
abdominal pain, persistent vomiting, skin rash, bleeding from nose or gums, vomiting blood,
dark stools, drowsiness or irritability, pale or cool skin, and difficulty breathing.
Patients in endemic areas should take measures to prevent DENV transmission. If possible,
all mosquitoes in the house should be eliminated, screens should be placed on windows and
doors to prevent mosquitoes from coming into the house, and containers holding standing
water should be emptied. To avoid infecting mosquitoes (which can in turn infect others in
the household), if possible, the patient should sleep under a bed net and use insect repellant
while ill.
Inpatient management — Inpatient management is warranted for patients with dengue

and warning signs of severe infection, severe dengue infection, or dengue infection with
coexisting conditions (pregnancy, infancy, diabetes, poor social situation, old age, or renal
failure). (See 'Phases of infection and clinical assessment' above.)
Patients warranting inpatient management should be assessed for signs of impending shock
( table 1). In the absence of shock, patients may be managed as summarized in the

algorithm ( algorithm 1) [3]. Most patients who present for medical attention before
profound shock develops and who receive appropriate fluid therapy recover quickly.
In setting of shock (normal systolic pressure but rising diastolic pressure with narrowing
pulse pressure), patients may be managed as summarized in the algorithm ( algorithm 2).
In the setting of profound or prolonged shock (hypotension, narrow pulse pressure [systolic
minus diastolic pressure ≤20 mmHg]), patients may be managed as summarized in the
algorithm ( algorithm 3).
Management of fever — Fever and myalgias should be managed with acetaminophen

(maximum 60 mg/kg/day in children; 4 g/day in adults). Aspirin or nonsteroidal anti-
inflammatory agents should be avoided because of the risk of bleeding complications and
because of the potential risk of Reye's syndrome in children. (See "Acute toxic-metabolic
encephalopathy in children", section on 'Reye syndrome'.)
Management of plasma leakage — Plasma leakage should be managed with intravascular

volume repletion to prevent or reverse hypovolemic shock ( algorithm 1). In mild cases,
particularly when medical attention is received early, oral rehydration may be sufficient.
Administration of intravenous fluid is warranted in patients with established intravascular
volume loss. Blood transfusion is appropriate in patients with significant bleeding or low
hematocrit and failure to improve with fluid resuscitation. Subsequent hematocrit
measurements must be interpreted with caution since it is critical to assess the adequacy of
both blood and fluid repletion; in complex cases, it can be challenging to distinguish
whether a decrease in hematocrit reflects volume repletion or blood loss.
Treatment of shock — Protocols for intravenous fluid therapy have been developed by the
World Health Organization [4,5,46] ; these are summarized in the algorithms ( algorithm 2
and algorithm 3). There are a number of acceptable approaches to management of shock
associated with dengue, and there are no clinical trial data favoring one approach over the
other. The process of frequent clinical assessment is critical to ensure judicious fluid
resuscitation and detection of hemorrhage if present.
Initial fluid resuscitation with crystalloid is appropriate; there is no clinical advantage of

colloid over crystalloid [48-50]. In one randomized trial including 512 Vietnamese children
with moderate dengue shock syndrome, outcomes were similar with Ringer's lactate, 6%
dextran 70, and 6% hydroxyethyl starch [50], establishing that Ringer's lactate is a safe,
effective, and inexpensive crystalloid solution for initial resuscitation of patients with
moderate shock. In patients with severe shock, dextran and starch performed similarly,
although dextran was associated with more hypersensitivity reactions.
Intravenous colloid solution is warranted for patients with intractable shock resistant to
crystalloid resuscitation; in such cases, we favor 10% dextran 40 in normal saline. Patients
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with persistent hypoperfusion and falling hematocrit require blood transfusion and should
be evaluated for occult or overt bleeding. Other possible complications (such as acidosis,
hypoglycemia, and hypocalcemia) should be investigated and corrected as needed. (See
"Treatment of severe hypovolemia or hypovolemic shock in adults" and "Hypovolemic shock
in children: Initial evaluation and management".)
Once hemodynamic stability has been restored, intravenous fluids should be continued with
gradual reduction of the infusion rate over the next 24 to 48 hours. There have been no
controlled comparisons of infusion regimens; we typically reduce the infusion rate as
follows: 10 mL/kg over the first hour, then 7 mL/kg/hour for 1 to 2 hours, 5 mL/kg/hour for 4
to 6 hours, and 3 mL/kg/hour for 6 to 12 hours. This gradual reduction is intended to
minimize the risk of recurrent shock and volume overload. The patient's clinical status
(including vital signs, urine output, and hematocrit) should be evaluated prior to each
infusion rate adjustment.
Close clinical observation is essential even after restoration of normovolemia; the 24 hours
following initial resuscitation is a period of increased vascular permeability, and patients can
develop recurrent shock during this period. Fluid lost into potential spaces (pleura,
peritoneum) during the period of plasma leakage is reabsorbed rapidly. Therefore,
intravenous fluid supplementation should be discontinued following the period of increased
vascular permeability; excessive fluid administration after this point can precipitate
hypervolemia and pulmonary edema.
Monitoring of volume status by other means, such as serial ultrasonographic measurements

of the inferior vena cava, may be useful, but conclusive evidence for the use of these
techniques in the clinical monitoring of dengue is still lacking [51,52].
In the absence of complications from prolonged hypotension, most patients with severe
dengue infection recover within a few days [53]. Discharge from the hospital is appropriate
when patients have been afebrile for at least 24 hours or have passed two days after an
episode of shock, are clinically well, and have normal appetite, urine output, and hematocrit.
Management of bleeding — Gastrointestinal bleeding, epistaxis, or heavy menstrual

bleeding may be severe enough to warrant blood transfusion. Significant internal bleeding
should be suspected in patients with signs of intravascular hypovolemia without elevation of
hematocrit. In these circumstances, blood transfusion should be performed (5 mL/kg of
packed red blood cells or 10 mL/kg whole blood in children; 1 unit of packed red blood cells
or whole blood in adults). The clinical response and posttransfusion hematocrit should be
monitored. (See "Approach to acute upper gastrointestinal bleeding in adults" and
"Approach to acute lower gastrointestinal bleeding in adults".)

Factors that contribute to bleeding include thrombocytopenia due to decreased platelet

survival [54] and, in severe cases, prolonged prothrombin time (international normalized
ratio >1.3) and frank disseminated intravascular coagulation due to liver failure. Platelet
transfusion has not been shown to be effective at preventing or controlling hemorrhage but
may be warranted in patients with severe thrombocytopenia (<10,000/mm3) and active
bleeding. In general, the preponderance of data does not support a role for prophylactic
platelet transfusion in patients with severe thrombocytopenia in the absence of active
bleeding [5,55-60]. Administration of intravenous vitamin K is warranted for patients with
severe liver dysfunction or prolonged prothrombin time [46].
ADDITIONAL APPROACHES TO MANAGEMENT
Treatment guidelines have been published by the World Health Organization (WHO; 2009)
and the WHO South-East Asia Regional Office (SEARO; 2011); there are variations between
these guidelines [4,5,47].
Clinical practice is informed by the above guidelines as well as clinical experiences with
managing dengue in different populations. There have been no rigorous trials comparing
clinical approaches or establishing endpoints (clinical or laboratory based) for management
of severe disease.
The following indications for inpatient admission have been used at the Queen Sirikit
National Institute for Child Health in Bangkok, Thailand, since 1999 [61,62]:
● Shock or impending shock
● Leukopenia (white blood cell count 5000 cells/mm3 or lower) and/or thrombocytopenia
(platelet count 100,000 cells/mm3 or lower), especially in high-risk patients (infants,
older adults, pregnancy, patients with comorbidities)
● Clinical deterioration or lack of clinical improvement with defervescence
● Significant bleeding (epistaxis, hematemesis, melena, hematuria, or excessive

menstrual bleeding)
● Altered consciousness
● Difficulty with follow-up
● Family concern/anxiety
Published experience with systematic application of more restrictive criteria for admission of
patients with suspected dengue is limited. This includes an uncontrolled study in Malaysia

conducted over a two-month period [63] and case series from Singapore describing the
clinical experience with institutional admissions guidelines [64]. The major criteria for
hospitalization in those sites included:
● Blood pressure <90/60 mmHg

● Hematocrit >50 percent
● Platelet count <50,000/mm3
● Evidence of bleeding other than petechiae
Additional criteria for hospitalization in the Singapore study included pulse ≥100
beats/minute, severe abdominal pain, persistent vomiting, and older adult patients with
comorbidities. Both groups reported successful management with no complications
resulting from outpatient care; however, the studies involved only adults, and the number of
cases of severe dengue/dengue hemorrhagic fever (DHF) was relatively small (28 in Malaysia
and 148 in Singapore). In case series in Thailand and Singapore, the WHO criteria for dengue
with warning signs of severe infection would have led to an excess of hospitalizations and/or
treatment relative to local clinical practice [64,65].
Routine laboratory testing is not readily available in many resource-limited settings where
dengue is endemic. One study including 1250 children aged 2 months to 10 years in
southern Vietnam evaluated whether an assessment tool using only clinical signs could
appropriately guide management of acute illness [66]. The assessment tool was derived
from the WHO/United Nations Children's Emergency Fund (UNICEF) "Integrated
Management of Childhood Illness" algorithm designed for use in Africa and was modified to
include common signs and symptoms of DHF. The 20 children who presented with dengue
shock syndrome were correctly identified as requiring urgent hospitalization, although
classification of less severe DHF was imperfect, and reevaluation within one to two days was
needed to detect children who developed shock.
Several studies have applied decision-tree analysis to develop algorithms for early
management of patients with suspected dengue, although the study populations and
conclusions have differed [67-70]. Until these findings can be externally validated in a
prospective fashion, the use of any of these algorithms in clinical practice cannot be
recommended.
FUTURE DIRECTIONS
Thus far, data do not support a role for corticosteroids [71-73], intravenous
immunoglobulins, pentoxifylline, or activated factor VII [74-76].

Several approaches are under investigation for specific treatment of dengue, including direct
viral inhibitors and modifiers of virus-host interactions [77,78]. Direct-acting agents have
included small molecule inhibitors of essential viral enzymes (NS2B-3 protease, NS3 helicase,
NS5 methyltransferase, the NS5 polymerase) or small molecule or antibody inhibitors of viral
entry/fusion. A dengue mouse model has been validated and demonstrated to be a suitable
test system for direct viral inhibitors [79]. Several agents have demonstrated reduction of
viremia and levels of proinflammatory cytokines in this model [80].
Randomized trials of chloroquine, lovastatin, balapiravir (a polymerase inhibitor), and

celgosivir (an alpha-glucosidase inhibitor) among adults with dengue have not noted a
significant benefit on viremia, NS1 antigenemia, or fever [81-83].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Dengue virus".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Dengue fever (The Basics)")
SUMMARY
● Dengue is a febrile illness that is caused by one of four dengue virus (DENV) types
(DEN-1, DEN-2, DEN-3, and DEN-4). The likelihood for development of severe dengue is
highest among individuals who develop a second dengue infection caused by a
different virus type from the first infection. Thus, severe disease occurs primarily
among individuals in areas where multiple DENV types circulate simultaneously. (See
'Introduction' above and 'Prevention' above.)
● Approaches for prevention of dengue infection in endemic areas include mosquito

control and vaccine development. Mosquito control is effective but is difficult to
sustain. A single vaccine, CYD-TDV, has been licensed in several countries in Latin
America, Southeast Asia, Europe, and the United States. CYD-TDV should be
administered only to individuals with history of previous DENV infection or laboratory
evidence of previous DENV infection. (See 'In endemic areas' above.)
● Most travelers from nonendemic countries are at low risk for severe dengue in the
absence of prior DENV exposure; potential exceptions include frequent international
travelers, expatriates, frequently deploying military personnel, and immigrants from
endemic areas returning to their countries of origin. (See 'Among travelers' above.)
● Patients with suspected dengue should be assessed carefully and directed to the
appropriate care setting. Early recognition of severe disease and patients at increased
risk for severe disease are essential, with prompt initiation of more aggressive therapy
when necessary. (See 'Phases of infection and clinical assessment' above.)
● Outpatient management is appropriate for patients with presumptive diagnosis of

dengue in the absence of warning signs or coexisting condition (pregnancy, infancy, old
age, diabetes, renal failure, underlying hemolytic disease, obesity, or poor social
situation). Patients should be instructed to take plenty of fluids and watch for signs of
dehydration. Inpatient management is warranted for patients with dengue and
warning signs of severe infection, severe dengue infection, or dengue infection with
coexisting conditions. (See 'Outpatient management' above and 'Inpatient
management' above.)
● Patients warranting inpatient management should be assessed for signs of shock

( table 1). In the absence of shock, patients may be managed as summarized in the
algorithm ( algorithm 1). In the setting of shock (normal systolic pressure but rising
diastolic pressure with narrowing pulse pressure), patients may be managed as
summarized in the algorithm ( algorithm 2). In the setting of profound or prolonged
shock, patients may be managed as summarized in the algorithm ( algorithm 3). (See
'Management of plasma leakage' above and 'Treatment of shock' above.)
● Fever and myalgias should be managed with acetaminophen; aspirin or nonsteroidal

anti-inflammatory agents should be avoided. Gastrointestinal bleeding, epistaxis, or
heavy menstrual bleeding may be severe enough to warrant blood transfusion. (See
'Management of fever' above and 'Management of bleeding' above.)

Use of UpToDate is subject to the Terms of Use.
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Topic 3030 Version 48.0

GRAPHICS
An approach to inpatient management of dengue infection with plasma leak

the absence of shock (WHO DHF Grades I and II)*¶


WHO: World Health Organization; DHF: dengue hemorrhagic fever; DSS: dengue shock syndrome.
* Inpatient management is warranted for patients high-risk patients (infants, pregnant women, elderly,
diabetes, renal failure, neurologic signs), patients with significant bleeding, patients with leukopenia (wh
blood cell count ≤5,000 cells/mcL), patients with thrombocytopenia (platelet count ≤100,00 cells/mcL), a
patients with warning signs of severe dengue (as defined in Box B above).
¶ The WHO has established a grading for severity of DHF. DHF Grade I refers to fever and hemorrhagic
manifestation (positive tourniquet test) and evidence of plasma leakage. DHF Grade II refers to Grade I p
spontaneous bleeding. DHF Grade III refers to Grade I or Grade II plus circulatory failure, and DHF Grade
refers to Grade III plus profound shock with undetectable blood pressure and pulse. DSS consists of DHF
III and DHF Grade IV. Shock refers to normal systolic pressure but rising diastolic pressure with narrowin
pulse pressure.
Δ The baseline hematocrit may be the patient’s hematocrit obtained prior to acute illness, the initial hem
obtained in the absence of evidence of plasma leakage, shock, severe dehydration, or hemorrhage, or ag
sex matched normal values. In the absence of shock, the rate of fluid repletion depends on the degree o
hemoconcentration, adjusted to the body weight. If the hematocrit increases by less than 20% and the p
can drink, no intravenous fluid is needed; in case of poor oral intake, we administer half-maintenance
intravenous fluid (1.5 mL/kg/hour for children and 40 mL/hour for adults). If the hematocrit increases by
25%, we administer maintenance intravenous fluids (3 mL/kg/hour for children and 80 mL/hour for adul
the hematocrit rises by more than 25%, we administer intravenous fluids at 7 to 10 mL/kg/hour (for child
and 100 to 500 mL/hour (for adults).
◊ Criteria for clinical stability include: blood pressure rising or normalized, heart rate decreasing, pulse
pressure widening, respiratory rate decreasing, skin warm with turgor intact.
§ Criteria for clinical instability include: blood pressure decreasing, heart rate increasing, pulse pressure
narrowing, respiratory rate increasing, skin cool and clammy with diminshed turgor.
¥ No other colloid formulations (such as albumin) should be used for management of dengue. If 10% de
40 in normal saline is not available, crystalloid should be used.
‡ The patient's clinical status (including vital signs, urine output, and hematocrit) should be evaluated pr
each infusion rate adjustment.
Data from:
1. World Health Organization. Dengue: Guidelines for diagnosis, treatment, prevention and control. WHO, Geneva 2009.
2. World Health Organization Regional Office for Southeast Asia. Comprehensive guidelines for prevention and control of den
dengue haemorrhagic fever. Revised and expanded version. SEARO Technical Publications Series, New Delhi 2011.
Graphic 109849 Version 3.0

Dengue hemodynamic assessment
Prolonged/profound
Shock (DHF
Stable circulation shock (DHF Grade
Grade III)*¶
IV)*¶
Heart rate Normal Tachycardia Severe tachycardia or

bradycardia
Blood pressure Normal Normal systolic Severe hypotension or

pressure but rising undetectable blood
diastolic pressure pressure
(narrowing pulse
pressureΔ )
Postural hypotension
Respiratory rate Normal Tachypnea Hyperpnea or Kussmaul

respirations
Urine output Normal Reducing trend Oliguria or anuria
Consciousness level Clear, lucid Clear, lucid Restless, combative
Capillary refill Brisk (≤2 seconds) Prolonged (>2 Very prolonged

seconds)
Extremities Warm, pink Cool Cold, clammy, mottled

skin
Peripheral pulse Good volume Weak, thready Feeble or absent

volume
DHF: dengue hemorrhagic fever.
* The World Health Organization has established the following grading system for severity of
dengue hemorrhagic fever:
DHF Grade I – Fever, hemorrhagic manifestation (positive tourniquet test), and evidence of
plasma leakage.
DHF Grade II – DHF Grade I plus spontaneous bleeding.
DHF Grade III – DHF Grade I or DHF Grade II plus narrowing pulse pressure or
hypotension.
DHF Grade IV – DHF Grade III plus profound shock with undetectable blood pressure and
pulse.
Dengue shock syndrome consists of DHF Grade III and DHF Grade IV.
¶ Shock due to plasma leakage often presents with a narrow pulse pressure or elevated diastolic
pressure with preserved systolic pressure, whereas shock due to bleeding often presents with
hypotension or low systolic pressure. Other causes of shock must also be considered (such as
hypoglycemia, excessive vomiting, or bacterial coinfection).
Δ Pulse pressure is systolic pressure minus diastolic pressure.

Modified from: Centers for Disease Control and Prevention. Dengue case management. Available at:
http://www.cdc.gov/dengue/resources/dengue-clinician-guide_508.pdf (Accessed on September 15, 2016).

An approach to management of dengue infection in the setting of shock, na

hypotension (WHO DHF Grade III)*¶
WHO: World Health Organization; DHF: dengue hemorrhagic fever.
* The WHO has established a grading for severity of dengue hemorrhagic fever:
DHF Grade I – Fever, hemorrhagic manifestation (positive tourniquet test), and evidence of plasma
DHF Grade III – DHF Grade I or DHF Grade II plus circulatory failure.
DHF Grade IV – DHF Grade III plus profound shock with undetectable blood pressure and pulse.

¶ Shock refers to normal systolic pressure but rising diastolic pressure with narrowing pulse pressure. P
hypotension and narrow pulse pressure (systolic minus diastolic pressure ≤20 mmHg).
Δ Criteria for clinical improvement include blood pressure rising or normalized, heart rate decreasing, pu
rate decreasing, skin warm with turgor intact, or sensorium clear.
◊ Criteria for lack of clinical improvement include blood pressure decreasing, heart rate increasing, puls
rate increasing, skin cool and clammy with diminished turgor, mental confusion, or restlessness.

§ No other colloid formulations (such as albumin) should be used for management of dengue. If 10% de
available, crystalloid should be used.
¥ The patient's clinical status (including vital signs, urine output, and hematocrit) should be evaluated pr
adjustment.
Data from:
1. World Health Organization. Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic F

An approach to management of dengue infection in the setting of profound

(WHO DHF Grade IV)*¶
WHO: World Health Organization; DHF: dengue hemorrhagic fever.
* The WHO has established a grading for severity of dengue hemorrhagic fever
DHF Grade I – Fever, hemorrhagic manifestation (positive tourniquet test), and evidence of plasma
DHF Grade III – DHF Grade I or DHF Grade II plus circulatory failure.
DHF Grade IV – DHF Grade III plus profound shock with undetectable blood pressure and pulse.
¶ Shock refers to normal systolic pressure but rising diastolic pressure with narrowing pulse pressure. P
hypotension and narrow pulse pressure (systolic minus diastolic pressure ≤20 mmHg).

Δ Intravenous crystalloid solutions include normal saline or Ringer's lactate. Colloid solution includes blo
dextran 40 in normal saline; no other colloid formulations (such as albumin) should be used for manage
dextran should not be used for initial resuscitation. If 10% dextran 40 in normal saline is not available, cr
used.
◊ Criteria for clinical improvement include blood pressure rising or normalized, heart rate decreasing, p
respiratory rate decreasing, skin warm with turgor intact, or sensorium clear.
§ The patient's clinical status (including vital signs, urine output, and hematocrit) should be evaluated pr
adjustment.
¥ Criteria for lack of clinical improvement include blood pressure decreasing, heart rate increasing, pulse
respiratory rate increasing, skin cool and clammy with diminished turgor, mental confusion, or restlessn
‡ Additional interventions include dialysis or plasmapheresis; the clinical approach depends on locally av
clinical expertise.
Data from:
1. World Health Organization. Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic F

Contributor Disclosures
Stephen J Thomas, MD Patent Holder: USG/Army [Pan-flavivirus, chikungunya, Zika virus].
Grant/Research/Clinical Trial Support: Congressionally Directed Medical Research Programs [Dengue
human infection model]; Department of Defense [Dengue human infection model]; Janssen [Dengue
antiviral study]; Merck [Dengue patient reported outcome]; National Institute on Drug Abuse [Heroin
vaccine study]; National Institutes of Health P01 [Dengue]; Pfizer [Influenza vaccine trial]; Pfizer [COVID
vaccine trial].
Consultant/Advisory Boards: Clover [COVID]; EdJen [Vaccines]; Isosavax [COVID]; Merck
[Dengue]; Moderna [Zika]; Pfizer [Vaccines]; PrimeVax [Dengue]; Rheonix [Chief Medical Officer, Board
of Directors]; Sanofi Pasteur [Vaccines]; Takeda [Dengue]; Vaxxinity [COVID].
Other Financial Interest:
Cormac Life Sciences, LLC [Veteran-owned small business]; Phairify [Director of Strategy & Cofounder].
All of the relevant financial relationships listed have been mitigated. Alan L Rothman,
MD Consultant/Advisory Boards: Merck [Prevention and treatment of dengue virus infections];
Moderna [Prevention and treatment of dengue virus infections].
All of the relevant financial
relationships listed have been mitigated. Anon Srikiatkhachorn, MD No relevant financial
relationship(s) with ineligible companies to disclose. Siripen Kalayanarooj, MD No relevant financial
relationship(s) with ineligible companies to disclose. Martin S Hirsch, MD No relevant financial
relationship(s) with ineligible companies to disclose. Keri K Hall, MD, MS No relevant financial
relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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21/09/2022 21:32 Dengue virus infection: Prevention and treatment - UpToDate

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Dengue virus infection: Prevention and treatment

Dengue is a febrile illness caused by a flavivirus transmitted by Aedes aegypti or Aedes

There are numerous documents providing guidance on the optimal approaches to

In endemic areas — Approaches for the prevention of DENV infection and disease in

Personal protection from infection

Mosquito repellants — Issues related to personal protection for prevention of

Insecticide spraying — Distribution of insecticide-treated curtains was successful in

Vaccine development — Infection with one DENV type provides long-term protection

CYD-TDV (Dengvaxia) — In 2018, the CYD-TDV (Dengaxia) vaccine was approved by

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TAK-003 — TAK-003 is tetravalent vaccine based on an attenuated laboratory-

● At 12 months of follow-up, fewer cases of DENV infection (confirmed via polymerase

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Mosquito control — Mosquito control is effective but is difficult to resource and sustain.

● Reducing breeding sites – Community-based education to reduce breeding sites that

● Endosymbiotic control – A novel dengue control strategy consists of releasing

This strategy was applied in a cluster-randomized controlled trial in Indonesia in which

Among travelers — The primary approach to prevention of DENV infections in travelers

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Outpatient management is appropriate for patients with presumptive diagnosis of dengue

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Outpatient management — Outpatient management is appropriate for patients with

Fever may be controlled with acetaminophen; nonsteroidal anti-inflammatory drugs and

Inpatient management — Inpatient management is warranted for patients with dengue

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Management of fever — Fever and myalgias should be managed with acetaminophen

Management of plasma leakage — Plasma leakage should be managed with intravascular

Initial fluid resuscitation with crystalloid is appropriate; there is no clinical advantage of

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Monitoring of volume status by other means, such as serial ultrasonographic measurements

Management of bleeding — Gastrointestinal bleeding, epistaxis, or heavy menstrual

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Factors that contribute to bleeding include thrombocytopenia due to decreased platelet

ADDITIONAL APPROACHES TO MANAGEMENT

● Shock or impending shock

● Clinical deterioration or lack of clinical improvement with defervescence

● Significant bleeding (epistaxis, hematemesis, melena, hematuria, or excessive

● Difficulty with follow-up

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● Blood pressure <90/60 mmHg

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Randomized trials of chloroquine, lovastatin, balapiravir (a polymerase inhibitor), and

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topic (see "Patient education: Dengue fever (The Basics)")

● Approaches for prevention of dengue infection in endemic areas include mosquito

● Outpatient management is appropriate for patients with presumptive diagnosis of

● Patients warranting inpatient management should be assessed for signs of shock

● Fever and myalgias should be managed with acetaminophen; aspirin or nonsteroidal

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Use of UpToDate is subject to the Terms of Use.

2. Mizumoto K, Ejima K, Yamamoto T, Nishiura H. On the risk of severe dengue during

4. World Health Organization. Dengue haemorrhagic fever: Diagnosis, treatment, preventi

7. Vanlerberghe V, Villegas E, Oviedo M, et al. Evaluation of the effectiveness of insecticide

8. Loroño-Pino MA, García-Rejón JE, Machain-Williams C, et al. Towards a Casa Segura: a

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28. Olivera-Botello G, Coudeville L, Fanouillere K, et al. Tetravalent Dengue Vaccine Reduces

33. Dengvaxia. Tetravalent, Live-Attenuated Viral Vaccine against Dengue Serotypes 1, 2, 3 a

35. Tricou V, Sáez-Llorens X, Yu D, et al. Safety and immunogenicity of a tetravalent dengue

37. Biswal S, Borja-Tabora C, Martinez Vargas L, et al. Efficacy of a tetravalent dengue