Dengue virus infection: Prevention and treatment.

All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Feb 2018. | This topic last updated: Jan 05, 2018.
INTRODUCTION — Dengue is a febrile illness caused by a flavivirus transmitted
by Aedes aegypti or Aedes albopictus mosquitoes during 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 100 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 serotypes circulate simultaneously. Infection with
DENV provides long-term protection against disease caused by reinfection with that
particular type, supporting the feasibility of developing an effective vaccine. 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 — Dengue virus (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.
Endemic areas — Approaches for the prevention of DENV infection and disease in
endemic areas include mosquito control, personal protective measures, and
vaccination.
Mosquito control — Mosquito control is effective but is difficult to resource and sustain.
Approaches to mosquito control for prevention of DENV infection include:
●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 [7,8].
●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 [9], although this strategy is
difficult to apply in urban areas [10].
●Use of insecticide – Distribution of insecticide-treated curtains was successful in
reducing populations of A. aegypti mosquitoes for up to 18 months in several
studies [11,12] and was associated with reduced human and mosquito infections
with DENV in one region [11,12], 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 [7,13].
●Endosymbiotic control – A novel strategy consists of releasing mosquitoes
infected with the intracellular endosymbiotic bacterium Wolbachia [14,15]. Such
mosquitoes could reduce DENV transmission via several mechanisms, including
reducing mosquito lifespan and inhibiting viral replication; these effects could be
propagated into later generations of mosquitoes via ongoing transmission
of Wolbachia.
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 [7]. Lack
of funding and attention for these programs led to reemergence of A. aegypti and
corresponding reemergence of dengue.
Issues related to mosquito vector control are discussed further separately.
(See "Malaria: Epidemiology, prevention, and control", section on 'Mosquito control'.)
Personal protective measures — Issues related to personal protection for prevention of
mosquito bites are discussed separately. (See "Prevention of arthropod and insect
bites: Repellents and other measures".)
Vaccination — 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 [16].
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 [17]. Given that rate of clinically relevant third or fourth DENV
infection is low, it is unclear whether tetravalent immunity is required for efficacy [18].
A number of dengue vaccine candidates are in development [19,20]. One vaccine,
CYD-TDV (Dengvaxia), has been licensed in several countries in Latin America and
Southeast Asia (but not in the United States) [21]. CYD-TDV should be administered only
to individuals with history of previous dengue virus infection or laboratory evidence of
previous dengue virus infection.
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]. The basis for
licensure was two large phase III randomized controlled trials of CYD-TDV; results were
reported in 2014 to 2015 [23,24]. One trial was conducted in five countries in the
Asia-Pacific region and enrolled children aged 2 to 14 years [23]; the other trial was
conducted in five countries in Latin America and the Caribbean and enrolled children
aged 9 to 16 years [24]. 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 have confirmed limitations of the vaccine and
a safety signal in individuals who did have evidence of a previous dengue virus infection
prior to vaccination:
●An interim analysis published in 2015 noted that the vaccine was associated with
an elevated relative risk for dengue infection requiring hospitalization during the
third year of the trial (between one and two years after the last dose of the vaccine)
among children younger than nine years and particularly in children two to five
years of age [25]. The elevated risk has declined over successive years of
follow-up.
●In an analysis including 3736 study participants, 443 had asymptomatic dengue
infection (67 had virologically confirmed asymptomatic infection and 376 had
serologically confirmed infection) [26]. Vaccine efficacy against asymptomatic
dengue infection was 33 percent overall (38 among recipients ≥9 years of age and
9 percent among recipients 2 to 9 years of age).
●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 dengue prior to vaccination. In individuals with no
prior episode of dengue virus 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 dengue virus
infection forgo vaccination [27].
●In December 2017, the World Health Organization (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 [28].
The reason for the increased risk of severe dengue in seronegative individuals is
uncertain. Only a limited number of individuals underwent scheduled serologic
monitoring prior to and following vaccination, so analysis of the immune profiles
associated with various outcomes is not possible on a meaningful scale.
Travelers — The primary approach to prevention of dengue virus 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 [13]. 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 dengue virus 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.
TREATMENT APPROACH — There is no direct antiviral therapy available against the
dengue viruses (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 [29,30]. 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 — Dengue virus infection has three
phases: a febrile phase, a critical (plasma leakage) phase, and a convalescent
(reabsorption) phase [29]. 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 dengue virus infection are summarized separately
[29,31]. (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 [29].
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) [32].
(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 dengue virus 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 [29,30]; 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 [33-35]. 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 [35], 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 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 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.
In the absence of complications from prolonged hypotension, most patients with severe
dengue infection recover within a few days [36]. 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 menorrhagia 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 [37] 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, there is no role for prophylactic platelet transfusion in
patients with severe thrombocytopenia in the absence of active bleeding [29,38-41].
Administration of intravenous vitamin K is warranted for patients with severe liver
dysfunction or prolonged prothrombin time [30].
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 [29,30].
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 [42,43]:
●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 [44] and case series from
Singapore describing the clinical experience with institutional admissions guidelines
[45]. 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 [45,46].
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 [47]. 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 [48-51]. 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 [52-54],
intravenous immunoglobulins, pentoxifylline, or activated factor VII [55-57].
Several approaches are under investigation for specific treatment of dengue, including
direct viral inhibitors and modifiers of virus-host interactions [58,59]. 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 [60]. Several
agents have demonstrated reduction of viremia and levels of proinflammatory
cytokines in this model [61].
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 [62-64].
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 serotypes 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. The vaccine that is most advanced in development is CYD-TDV,
a formulation of four chimeric yellow fever 17D-dengue vaccine viruses. It has been
licensed in several countries in Latin America and Southeast Asia (but not the
United States). CYD-TDV should be administered only to individuals with history of
previous dengue virus infection or laboratory evidence of previous dengue virus
infection. (See 'Endemic areas' above.)
●Most travelers from nonendemic countries are at low risk for severe dengue in the
absence of prior dengue virus exposure; potential exceptions include frequent
international travelers, expatriates, frequently deploying military personnel, and
immigrants from endemic areas returning to their countries of origin.
(See '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 menorrhagia may be severe enough to warrant blood
transfusion. (See 'Management of fever' above and 'Management of
bleeding' above.)
©2018 UpToDate

Dengue hemodynamic assessment

Prolonged/profound
Shock (DHF Grade
Stable circulation shock (DHF Grade
III)* ¶
IV)* ¶

Heart rate Normal Tachycardia Severe tachycardia or

bradycardia

Blood pressure Normal Normal systolic pressure but Severe hypotension or

rising diastolic pressure undetectable blood pressure
(narrowing pulse pressure Δ)
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 seconds) Very prolonged

Extremities Warm, pink Cool Cold, clammy, mottled skin

Peripheral pulse volume Good volume Weak, thready Feeble or absent

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).

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An approach to inpatient management of dengue infection with plasma leakage in the absence of shock (WHO DHF Grades I and II)* ¶

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 leakage.
DHF Grade II – DHF Grade I plus spontaneous bleeding.
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.
Dengue shock syndrome consists of DHF Grade III and DHF Grade IV. Shock refers to normal systolic pressure but rising diastolic pressure with narrowing pulse pressure.
¶ Inpatient management is warranted for high-risk patients (infants, pregnant women, older adults, obese, diabetes, renal failure, neurologic signs), patients with significant bleeding, patients with
leukopenia (white blood cell count ≤5000 cells/mcL), patients with thrombocytopenia (platelet count ≤10,000 cells/mcL), and patients with warning signs of severe dengue (as defined in Box D above).
Δ Criteria for clinical stability include blood pressure rising or normalized, heart rate decreasing, pulse pressure widening, respiratory rate decreasing, or skin warm with turgor intact.
◊ Criteria for clinical instability include blood pressure decreasing, heart rate increasing, pulse pressure narrowing, respiratory rate increasing, or skin cool and clammy with diminished turgor.
§ No other colloid formulations (such as albumin) should be used for management of dengue. If 10% dextran 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 prior to each infusion rate adjustment.

Data from:
1. World Health Organization. Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever. WHO, New Delhi 2011.
2. World Health Organization. Dengue: Guidelines for diagnosis, treatment, prevention and control. WHO, Geneva 2009.

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An approach to management of dengue infection in the setting of shock, narrowed pulse pressure, or 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 leakage.
DHF Grade II – DHF Grade I plus spontaneous bleeding.
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.
Dengue shock syndrome consists of DHF Grade III and DHF Grade IV.
¶ Shock refers to normal systolic pressure but rising diastolic pressure with narrowing pulse pressure. Profound shock refers to 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, pulse pressure widening, respiratory rate decreasing, skin warm with turgor
intact, or sensorium clear.
◊ Criteria for lack of clinical improvement include blood pressure decreasing, heart rate increasing, pulse pressure narrowing, respiratory 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% dextran 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 prior to each infusion rate adjustment.

Data from:
1. World Health Organization. Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever. WHO, New Delhi 2011.
2. World Health Organization. Dengue: Guidelines for diagnosis, treatment, prevention and control. WHO, Geneva 2009.

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An approach to management of dengue infection in the setting of profound or prolonged shock (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 leakage.
DHF Grade II – DHF Grade I plus spontaneous bleeding.
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.
Dengue shock syndrome consists of DHF Grade III and DHF Grade IV.
¶ Shock refers to normal systolic pressure but rising diastolic pressure with narrowing pulse pressure. Profound shock refers to 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 blood products or 10% dextran 40 in normal saline; no other
colloid formulations (such as albumin) should be used for management of dengue, and dextran should not be used for initial resuscitation. If 10% dextran 40 in
normal saline is not available, crystalloid should be used.
◊ Criteria for clinical improvement include blood pressure rising or normalized, heart rate decreasing, pulse pressure widening, 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 prior to each infusion rate adjustment.
¥ Criteria for lack of clinical improvement include blood pressure decreasing, heart rate increasing, pulse pressure narrowing, respiratory rate increasing, skin cool and
clammy with diminished turgor, mental confusion, or restlessness.
‡ Additional interventions include dialysis or plasmapheresis; the clinical approach depends on locally available resources and clinical expertise.

Data from:
1. World Health Organization. Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever. WHO, New Delhi 2011.
2. World Health Organization. Dengue: Guidelines for diagnosis, treatment, prevention and control. WHO, Geneva 2009.

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