Prevention and treatment of dengue virus infection

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Official reprint from UpToDate

www.uptodate.com 2015 UpToDate

Prevention and treatment of dengue virus infection

Authors
Alan L Rothman, MD
Anon Srikiatkhachorn, MD
Siripen Kalayanarooj, MD

Section Editor
Martin S Hirsch, MD

Deputy Editor
Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2015. | This topic last updated: Jul 28, 2015.
INTRODUCTION Dengue is a febrile illness that is caused by any one of four serotypes of this flavivirus (DENV-1,
DENV-2, DENV-3, and DENV-4). It is endemic in more than 100 countries in tropical and subtropical regions of the
world and causes an estimated 50 million infections annually worldwide [1-3].
Mild dengue disease and dengue fever (DF) contributes more than half of the total public health burden of dengueassociated illness [4]. The more serious manifestations of dengue hemorrhagic fever (DHF) and dengue shock
syndrome (DSS) are the major impetus for efforts to prevent infection [5]. Epidemiologic studies have demonstrated
that the greatest risk factor for the development of DHF or DSS is secondary infection with a different dengue
serotype from the original infecting virus [6]. Thus, severe disease occurs primarily in patients who reside in
hyperendemic areas where multiple serotypes circulate simultaneously.
Dengue virus infection is a risk 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, dengue virus transmission occurs
year-round. However, the risk of infection tends to be seasonal and can be expected to be highest during a
recognized outbreak of dengue infections. The objectives of programs to prevent dengue infections differ depending
upon whether local residents or visitors are targeted. There is no direct therapy available against the dengue virus,
which increases the importance of prevention.
Measures to prevent dengue and supportive treatment for the different clinical features of dengue virus infection will
be reviewed here. The epidemiology, pathogenesis, clinical manifestations, and diagnosis of infection are discussed
separately. (See "Epidemiology of dengue virus infections" and "Pathogenesis of dengue virus infection" and
"Clinical manifestations and diagnosis of dengue virus infection".)
PREVENTION The greatest risk for dengue virus infection is among individuals residing in endemic areas, rather
than travelers.
Endemic areas Public health approaches for prevention of dengue infection in endemic areas include control of
Aedes mosquitoes (which transmit dengue virus) and development of vaccines.
Mosquito control Mosquito control is the most effective approach for prevention of dengue transmission.
Programs targeting the Aedes aegypti mosquito as a means to eliminate urban yellow fever in the Americas from the
1940s through 1970s were quite successful [7]. These programs were also effective at reducing dengue
transmission in the region. The approach was "top down" involving aggressive mosquito surveillance and insecticide
use. However, lack of attention and funding for these programs in the 1970s led to reemergence of A. aegypti
throughout its former region and the corresponding reemergence of dengue.
Insecticide spraying in response to dengue outbreaks is not highly effective against A. aegypti mosquitoes, which
frequently breed inside houses [7,8]. Community-based approaches involving education of the population in efforts
to reduce breeding sites, such as discarded tires and other containers that accumulate standing water, have shown
some promise [7].
In one study, a governmental control strategy consisting of the seeding water vessels with copepods that feed on
mosquito larvae was successful in eliminating A. aegypti and dengue transmission in 32 communities in rural areas

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of Vietnam [9]. However, this strategy is difficult to apply in cities, where breeding sites are different and community
participation may be harder to sustain [10].
Vaccination Infection with dengue virus provides long-term protection against the particular serotype that
caused the disease, supporting the feasibility of a dengue vaccine. However, it provides only short-lived immunity to
the other three dengue virus serotypes. In view of the association of dengue hemorrhagic fever (DHF) with previous
exposure to dengue viruses and the recognition that all four serotypes are capable of inducing DHF, it is the general
consensus in the scientific and public health communities that any candidate vaccine should produce protective
immunity against all four serotypes. Since waning immunity might also increase the risk for DHF in vaccine
recipients, vaccine-induced protective immunity should also be long lived [11].
Animal studies indicate that protective immunity against dengue can be mediated by neutralizing antibodies,
especially those directed against the envelope (E) glycoprotein. However, natural dengue infection induces low
levels of cross-reactive antibodies that are detected in neutralization assays but do not prevent infection with the
other dengue serotypes [12]. Studies have elucidated the molecular basis for antibody neutralization of virus
infection [13,14]; however, cross-reactivity will continue to complicate the laboratory assessment of vaccine-induced
immunity until improved assays are available.
No licensed vaccine is available for preventing dengue [15,16]. The vaccine that is most advanced in development is
CYD-TDV, a formulation of four chimeric yellow fever 17D vaccine viruses, each one engineered to express the
surface envelope and membrane proteins from one of the four serotypes of dengue virus. Results of two large phase
III randomized, controlled vaccine trials were reported in 2014 [17,18].
In a phase 3 trial conducted among children aged 2 to 14 years in the Asia-Pacific region, CYD-TDV or placebo
was given at months 0, 6, and 12 [17]. In the primary per-protocol analysis, on the basis of 250 confirmed
cases that occurred between 28 days and 13 months after the third dose, vaccine efficacy was 57 percent
(95% CI 44 to 66 percent). Vaccine efficacy against dengue hemorrhagic fever was 80 percent (95% CI 53 to
92 percent) after one or more doses and 89 percent (95% CI 58 to 98 percent) after three doses. Efficacy was
higher in the older age cohorts compared with the younger cohorts (74 percent, 60 percent, and 34 percent in
subjects aged 12 to 14 years, 6 to 11 years, and 2 to 5 years at study entry, respectively). Vaccine efficacy
varied by serotype (50 percent for DENV-1, 35 percent for DENV-2 [not statistically significant compared with
placebo], 78 percent for DENV-3, 75 percent for DENV-4), a finding consistent with the results of an earlier
phase 2b clinical trial conducted in Thailand [19]. The safety profile was considered good, but one child
developed acute disseminated encephalomyelitis on day seven following the first vaccination.
In a phase 3 trial conducted among children aged 9 to 16 years in Latin America and the Caribbean, CYD-TDV
or placebo was given at months 0, 6, and 12 [18]. In the primary per-protocol analysis, on the basis of 397
confirmed cases that occurred between 28 days and 13 months after the third dose, vaccine efficacy was 61
percent (95% CI 52 to 68 percent). Vaccine efficacy against dengue hemorrhagic fever was 95 percent (95% CI
65 to 100 percent) after one or more doses and 90 percent (95% CI 11 to 100 percent) after three doses.
Vaccine efficacy varied by serotype (50 percent for DENV-1, 42 percent for DENV-2, 74 percent for DENV-3, 78
percent for DENV-4) but was statistically significant for all four serotypes. The frequency of serious adverse
events after vaccination was not significantly different from the placebo.
Overall, the results of these two large trials show that a three-dose series of CYD-TDV can provide moderate
protection against virologically confirmed dengue, the primary study endpoint, at least over the first year after
vaccination. Lower efficacy in the youngest age group studied (two to five year olds), against infection with DENV-2,
and in individuals who were seronegative at baseline (while based on secondary statistical analyses for which the
trials were not adequately powered), may limit the impact of this vaccine, although the efficacy against severe
infection, including dengue hemorrhagic fever, was substantial.
A follow-up report of the efficacy and long-term safety of three CYD-TDV trials [17-19], published in 2015 [20], noted
that the vaccine was associated with an elevated risk of hospitalization for dengue among children younger than
nine years in the setting of natural infection in the third year after vaccination. Further follow-up of participants in

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these trials will be important to assess the durability of vaccine-induced protective immunity.
Travelers Most travelers from nonendemic countries are at exceedingly low risk for DHF because they lack
previous exposure to dengue viruses. Possible exceptions include immigrants from endemic areas subsequently
returning to their countries of origin and frequent international travelers. Regardless of the risk for DHF, most
travelers will wish to avoid the morbidity of dengue fever.
Avoidance of exposure to infected A. aegypti mosquitoes is the primary approach to prevention of dengue virus
infections in travelers. These mosquitoes predominantly live in urban areas in and around houses [8]. Thus, travelers
to major cities are at risk for exposure to A. aegypti. Bed netting is of little use since the mosquitoes are most active
during the daytime. Remaining in well-screened or air-conditioned buildings during the day can reduce the risk of
exposure but many travelers are unwilling or unable to comply. When outside during the day, travelers wishing to
avoid dengue should wear clothing that reduces the amount of exposed skin and should use an effective mosquito
repellent, such as N,N-diethyl-metatoluamide (DEET).
THERAPY Since, as noted above, there is no specific therapy available for dengue virus infections, it is important
to exclude other treatable diagnoses. Patients at risk for dengue can acquire other diseases with similar clinical
features, such as malaria, typhoid fever, and leptospirosis. Symptoms in patients with dengue virus infections
resolve in five to seven days.
Supportive treatments are available for the specific disease manifestations of dengue virus infection.
Early recognition of DHF/severe dengue Dramatic plasma leakage can develop suddenly; therefore,
substantial attention has been placed on early identification of patients at higher risk for shock and other
complications. The following clinical features are helpful in this determination:
Duration of illness The period of maximum risk for shock is between the third and seventh day of illness. This
tends to coincide with resolution of fever. Plasma leakage generally first becomes evident between 24 hours
before and 24 hours after defervescence.
"Warning signs" World Health Organization (WHO) guidelines recommend attention to clinical warning signs
for severe dengue, including severe abdominal pain or tenderness, persistent vomiting, lethargy or
restlessness, abrupt change from fever to hypothermia, bleeding, pallor, cold/clammy extremities, liver
enlargement on physical exam, or abnormal mental status [21,22]. These recommendations were based on the
judgment of expert clinicians and have not been rigorously evaluated in prospective studies. In one study, these
signs were noted in a minority of patients with severe dengue and, in most cases, developed less than one day
prior to hospitalization [23].
Hematocrit An elevation of the hematocrit is an indication that plasma leakage has already occurred and that
fluid repletion is urgently required.
Platelet count Severe thrombocytopenia (100,000/mm3 or lower) is one of the clinical criteria for DHF and
usually precedes overt plasma leakage.
Serum aspartate transaminase (AST) Mild elevations in serum transaminases are common in both dengue
fever and DHF. However, levels are significantly higher in patients with DHF, and elevated AST levels are noted
earlier in illness than the other signs listed above. In one study conducted in Thailand, a normal AST level was
a strong negative predictor of DHF (negative predictive value 0.96) even in the first three days of illness [1].
Soluble dengue NS1 protein Blood levels of soluble dengue NS1 protein (>600 ng/mL) were predictive of
DHF in one study of Thai children with secondary dengue 2 virus infections [24]. Several assays for detection
of soluble dengue NS1 in serum have become commercially available outside the United States; however, the
assays do not provide a quantitative measurement of soluble dengue NS1 protein levels.
Other considerations Coexisting medical conditions, such as pregnancy, infancy, old age, obesity, diabetes
mellitus, renal failure, and chronic hemolytic disease may increase the risk of severe dengue and/or complicate

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management. Referral for hospitalization is recommended for such patients, regardless of other findings [21].
Additionally, hospitalization should be considered for patients who may have difficulties with outpatient
follow-up or with timely self-referral should complications develop (eg, patients who live alone or who live far
from a healthcare facility without a reliable means of transport).
Patients with suspected dengue who do not have any of the above indicators probably can be safely managed as
outpatients, as long as close clinical observation is assured. Daily outpatient visits may be needed to permit serial
assessment of blood pressure, hematocrit, and platelet count.
Prospective validation of strategies for management and triage of suspected dengue cases is lacking. One study in
Malaysia over a two-month period tested a standard treatment protocol for patients with suspected dengue [25].
Daily outpatient visits were conducted and referral for hospitalization was made only for one of the following signs:
Blood pressure <90/60 mmHg
Hematocrit >50 percent
Platelet count <50,000/mm3
Evidence of bleeding other than petechiae
There were no deaths among 162 adults studied (average age 27 years), of whom 28 (17 percent) had DHF; the
overall hospitalization rate was 44 percent. All of the subjects with DHF either were hospitalized or qualified for
hospitalization according to the protocol, whereas 89 (66 percent) of the subjects without DHF were managed
without hospitalization.
For many resource-limited dengue endemic countries, routine laboratory testing is not readily available. One study of
1250 children aged 2 months to 10 years presenting to a pediatric hospital in southern Vietnam evaluated whether
an assessment tool designed for first-level healthcare workers, using only clinical signs, could appropriately classify
and guide management of acute illnesses in an endemic area [26]. The assessment tool was derived from the
WHO/UNICEF "Integrated Management of Childhood Illness" algorithm designed for use in Africa and was modified
to include common signs and symptoms of DHF. Although the 20 children with established dengue shock syndrome
were correctly identified as requiring urgent hospitalization, 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 [27-29]. Until these findings can be
externally validated in a prospective fashion, the use of any of these algorithms in clinical practice cannot be
recommended.
Management of fever Patients with dengue fever should be cautioned to maintain intake of oral fluid to avoid
dehydration. Fever and myalgias can be managed with acetaminophen (maximum 60 mg/kg/day in children or 4
g/day in adults). Aspirin or nonsteroidal antiinflammatory agents should generally be avoided because of the risk of
bleeding complications and in children because of the potential risk of Reye's syndrome. The most important
measure to assist the patient with suspected dengue fever is to carefully evaluate the patient for impending
complications or early evidence of dengue hemorrhagic fever (DHF), as described below. (See 'Early recognition of
DHF/severe dengue' above.)
Management of significant bleeding Gastrointestinal bleeding, epistaxis, or menorrhagia in patients with DHF
(and occasionally in patients with dengue fever) can be severe enough to require blood transfusion. Significant
internal bleeding should be suspected in patients with signs of intravascular hypovolemia without elevation of
hematocrit. In these circumstances, blood replacement should be performed with 5 mL/kg of packed red blood cells
(or 10 mL/kg whole blood). The clinical response and posttransfusion hematocrit should be monitored. Use of a
histamine H2 receptor antagonist or proton pump inhibitor is reasonable in patients with gastrointestinal bleeding,
although there is no evidence of benefit.
Factors that contribute to bleeding include thrombocytopenia due to decreased platelet survival [30] and, in severe

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cases, frank disseminated intravascular coagulation. Platelet transfusions have 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. Prophylactic platelet transfusions in patients with severe thrombocytopenia but
without active bleeding are generally not recommended [21,31]. Administration of intravenous vitamin K1 is
recommended for patients with severe liver dysfunction or prolonged prothrombin time [22].
Management of plasma leakage Plasma leakage in DHF is important to manage with intravascular volume
repletion to prevent or reverse hypovolemic shock [32]. In mild cases, particularly when medical attention is received
early, oral rehydration may be sufficient. However, in patients with established intravascular volume loss, intravenous
fluid administration is recommended. Blood transfusion is appropriate in patients with significant bleeding or those
who have low hematocrit and fail to improve despite 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 (WHO) based upon clinical experience mainly in children from Southeast Asia (algorithm 1) [21,22]. For
patients with shock, initial resuscitation with normal saline or Ringer's lactate (10 mL per kg of body weight for
children or 500 mL for adults), preferably with 5 percent dextrose, is recommended, either as an infusion over the
first hour or as a bolus (infused over 10 to 15 minutes) for patients in profound shock. A second infusion of an equal
volume is recommended in patients who remain in shock.
There has been debate as to whether crystalloids or colloids should be used for volume replacement in critically ill
patients. Three randomized trials have investigated the effect of different fluid regimens on outcome [33-35]. The
largest of these studies was a double-blind randomized comparison of three fluids for initial resuscitation of 512
Vietnamese children with dengue shock syndrome [35]. Three hundred eighty-three patients with moderate shock
were assigned to Ringer's lactate or one of two different colloid solutions: 6 percent dextran 70 or 6 percent
hydroxyethyl starch. One hundred twenty-nine patients with severe shock were randomized to receive one of the two
colloids. The treatment regimen closely followed the WHO protocol, with 15 mL/kg administered over the first hour
and 10 mL/kg over the second hour. Only one patient died. This trial established that Ringer's lactate is a safe,
effective, and inexpensive alternative in 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.
In patients who remain in shock despite the two initial boluses of crystalloid, we switch to a colloid solution (10 mg/kg
over the next hour); we favor 10 percent dextran 40 in normal saline as the colloid of choice. Switching to a colloid
solution is also appropriate in patients who have signs of fluid overload (eg, puffy eyelids, distended abdomen,
tachypnea, or dyspnea). As noted above, patients who have persistent hypoperfusion with falling hematocrit require
blood transfusion. Other possible complications, such as acidosis, hypoglycemia, or hypocalcemia, should also be
investigated and corrected as needed.
Once blood pressure has been restored, intravenous fluids should be continued but the infusion rate should be
gradually reduced over the next 24 to 36 hours. The patients clinical condition, including vital signs, urine output,
and hematocrit, should be checked prior to each reduction in the infusion rate. There have been no controlled
comparisons of infusion regimens; however, we typically use the following progression in the infusion rate: 10 mL/kg
over the first hour, then 7 mL/kg/hour for one to two hours, 5 mL/kg/hour for four to six hours, and 3 mL/kg/hour for
four to six hours. This gradual reduction is intended to minimize the risks of both recurrent shock and volume
overload.
The adequacy of fluid repletion should be assessed by serial physical examinations and measurements of
hematocrit, blood pressure, pulse rate, and urine output. Patients with shock on presentation should initially have
vital signs measured at least every 15 minutes until stable and hematocrit measured every four to six hours.
Narrowing of the pulse pressure is an indication of hypovolemia even with a normal systolic blood pressure.
Normalization of the hematocrit is an important goal of early fluid repletion; however, a normal or low hematocrit may
be misleading in patients with overt bleeding and severe hypovolemia. Suspected bleeding in the gastrointestinal

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tract should be treated with blood transfusions. (See "Treatment of severe hypovolemia or hypovolemic shock in
adults".)
Close clinical observation is essential, even after normal blood volume is restored, because patients can develop
recurrent shock over the 24 hours after the initial resuscitation, which represents the period of increased vascular
permeability in DHF. Most patients who present for medical attention before profound shock develops and who
receive appropriate fluid therapy will recover quickly.
The fluids that are lost into potential spaces (eg, pleura, peritoneum) during the period of plasma leakage are rapidly
reabsorbed. Thus, intravenous fluid supplementation should be discontinued once patients have passed the period
of plasma leakage. Usually no more than 48 hours of intravenous fluid therapy are required. Excessive fluid
administration after this point can precipitate hypervolemia and pulmonary edema.
In the absence of complications from prolonged hypotension or from medical interventions, most patients with DHF
recover within a few days of admission [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.
Adjunctive therapies The basis of DHF pathogenesis is hypothesized to be immunologic, which has led to
interest in immunomodulatory drugs for therapy. (See "Pathogenesis of dengue virus infection".)
Several trials have demonstrated that corticosteroids are no more effective than placebo in reducing death, need for
blood transfusion, or serious complications [37-39].
Other modalities, including intravenous immunoglobulins, pentoxifylline, and activated factor VII, have also been
proposed for use [40-42]. Thus far, data are limited and have not shown convincing benefit.
FUTURE DIRECTIONS A dengue mouse model has been validated and demonstrated to be a suitable test
system for antiviral drugs [43]. In one study, administration of an antiviral agent targeting dengue RNA-dependent
RNA polymerase to mice significantly reduced viremia and levels of proinflammatory cytokines [44]. These results
suggest that lowering viremia may ameliorate the severity of dengue fever symptoms and possibly reduce the risk of
progression to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS).
A randomized trial of balapiravir (a polymerase inhibitor) among adults with dengue noted that the drug did not
reduce viremia, NS1 antigenemia, fever clearance time, or plasma cytokine concentrations [45].
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 information: Dengue fever (The Basics)")
SUMMARY
Dengue is a febrile illness that is caused by one of four serotypes of this flavivirus (DEN-1, DEN-2, DEN-3, and
DEN-4). It is endemic in more than 100 countries in tropical and subtropical regions of the world and causes an
estimated 50 million infections annually worldwide. (See 'Introduction' above.)
Epidemiologic studies have demonstrated that the greatest risk factor for the development of dengue

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hemorrhagic fever (DHF) or dengue shock syndrome (DSS) is secondary infection with a different dengue
serotype from the original infecting virus. Thus, severe disease occurs primarily in patients who reside in
hyperendemic areas where multiple serotypes circulate simultaneously. (See 'Introduction' above.)
The greatest risk for dengue virus infection is among individuals residing in endemic areas. (See 'Prevention'
above.)
Mosquito control is the most effective approach to the prevention of dengue transmission. (See 'Mosquito
control' above.)
There is no licensed vaccine available for preventing dengue. (See 'Vaccination' above.)
Most travelers from nonendemic countries are at exceedingly low risk for DHF because they lack previous
exposure to dengue viruses. Possible exceptions include immigrants from endemic areas subsequently
returning to their countries of origin and frequent international travelers. (See 'Travelers' above.)
Patients with dengue should be cautioned to maintain their fluid intake to avoid dehydration and to take
acetaminophen as needed for fevers and myalgias. Aspirin or nonsteroidal antiinflammatory agents should
generally be avoided. (See 'Management of fever' above.)
It is important to manage plasma leakage in DHF with intravascular volume repletion to prevent or reverse
hypovolemic shock. Blood transfusion is appropriate in patients with significant bleeding. The adequacy of fluid
repletion should be assessed by serial determination of hematocrit, blood pressure, pulse, and urine output.
(See 'Management of plasma leakage' above.)
Early identification of patients at higher risk for shock and other complications of dengue is important. Patients
with suspected dengue who have none of the warning signs for more severe illness and can maintain their fluid
intake can be managed as outpatients but may need daily reevaluation. (See 'Early recognition of DHF/severe
dengue' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 3030 Version 23.0

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GRAPHICS
Volume replacement for patients with dengue shock syndrome

DHF: dengue hemorrhagic fever; IV: intravenous.

* In case with prolonged/profound shock (DHF grade IV) rate is 20 mL/kg/hour for 10 to 15
minutes or until blood pressure is restored, then reduce the rate to 10 mL/kg/hour.
Reproduced with permission from: Comprehensive Guidelines for Prevention and Control of
Dengue and Dengue Haemorrhagic Fever. New Delhi, World Health Organization, 2011.
Copyright 2011 World Health Organization.
Graphic 82833 Version 4.0

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Disclosures
Disclosures: Alan L Rothman, MD Consultant/Advisory Boards: Sanofi Pasteur [Prevention and treatment of dengue virus infections
(Tetravalent live-attenuated dengue vaccine Chimerivax-DEN)]. Anon Srikiatkhachorn, MD Nothing to disclose. Siripen Kalayanarooj, MD
Nothing to disclose. Martin S Hirsch, MD Nothing to disclose. Elinor L Baron, MD, DTMH Nothing 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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