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Prevention and treatment of dengue virus infection

Official reprint from UpToDate


www.uptodate.com 2014 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: Apr 2014. | This topic last updated: May 03, 2013.
INTRODUCTION Dengue is a febrile illness that is caused by any one of four serotypes of this flavivirus (DENV1, 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].
Although mild dengue disease and dengue fever (DF) contributes more than half of the total public health burden of
dengue-associated illness [4], the more serious manifestations of dengue hemorrhagic fever (DHF) and dengue
shock syndrome (DSS) provide 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 infections".)
PREVENTION The greatest risk for dengue virus infection is in individuals residing in endemic areas and not in
travelers.
Public health efforts in endemic areas Control of Aedes mosquitoes, which transmit dengue virus, and the
development of vaccines are two potential approaches in preventing dengue virus infections.
Mosquito control Mosquito control is the most effective approach to the 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. These programs were based on a "top down" approach involving aggressive mosquito
surveillance and insecticide use. However, lack of attention and funding of these programs in the 1970s led to reemergence of A. aegypti throughout its former region and the corresponding re-emergence 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].
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In one study, a comprehensive community and governmental control strategy, including the seeding of water
vessels with copepods that feed on mosquito larvae, was successful in eliminating A. aegypti and dengue
transmission in 32 communities in rural areas of Vietnam [9]. However, this strategy will be more 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 DENV 1-4. Since waning immunity might also increase the risk for DHF in vaccinees, vaccineinduced 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 shed light on the molecular basis for antibody neutralization of virus
infection [13,14]; however, until improved assays are available, the cross-reactivity will continue to complicate the
laboratory assessment of vaccine-induced immunity.
No licensed vaccine is yet available for preventing dengue, although several are in development [15,16]. In a phase 2
trial of CYD-TDV, a recombinant, live, attenuated tetravalent dengue vaccine based on the yellow fever 17D vaccine
strain, the vaccine reduced the risk of dengue infection by only 30 percent among 4000 children in Thailand [17].
For unclear reasons, the vaccine failed to protect against DENV-2, which was the prevalent serotype in the region
at the time of the study. The results of phase 3 trials of this vaccine underway in larger cohorts in Asia and the
Americas will be needed to provide clarification of the vaccines efficacy in different populations and epidemiologic
settings. The results cannot be extrapolated to the other dengue vaccines in development because the correlates of
protective immunity are not known.
Recommendations for travelers Most travelers from non-endemic countries are at exceedingly low risk for
DHF because they lack previous exposure to dengue viruses (see "Pathogenesis of dengue virus infection").
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.
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
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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 'Outpatient
management and early recognition of DHF/severe dengue' below.)
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 post transfusion 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 [18] and, in severe
cases, frank disseminated intravascular coagulation (see "Pathogenesis of dengue virus infection"). 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 [19,20].
Administration of intravenous vitamin K1 is recommended for patients with severe liver dysfunction or prolonged
prothrombin time [21].
Management of plasma leakage Plasma leakage in DHF is important to manage with intravascular volume
repletion to prevent or reverse hypovolemic shock [22]. 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) [19,21].
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, blinded trials have investigated the effect of different fluid regimens on outcome [23-25].
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 [25]. 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 above, 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 was
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
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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 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 [26]. 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 therapy for shock and/or bleeding 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 [27,28].
Other modalities, including intravenous immunoglobulins, pentoxifylline, and activated factor VII, have also been
proposed for use [29-31]. Thus far data are limited and not shown convincing benefit.
Unusual complications Encephalopathy and liver failure are uncommon manifestations of DHF, and are
associated with a high mortality rate [32]. While seizures or jaundice should always be regarded as indicative of
severe disease, no specific treatment is available.
Outpatient management and early recognition of DHF/severe dengue Because dramatic plasma
leakage can develop suddenly, substantial attention has been placed upon the 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.
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"Alarm signs"/Warning signs 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 [19,21]. 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 [33].
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 mg/mL) were predictive of
DHF in one study of Thai children with secondary dengue 2 virus infections [34]. Several assays for detection
of soluble dengue NS1 in serum have become commercially available outside the United States; however,
current 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 diseases, may increase the risk of severe dengue and/or
complicate management. Referral for hospitalization is recommended for such patients regardless of other
findings [19]. 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 [35].
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-poor 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 [36]. The assessment tool was derived from the
WHO/UNICEF "Integrated Management of Childhood Illness" algorithm designed for use in Africa and was modified
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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 [37-39]. Until these findings can
be externally validated in a prospective fashion, the use of any of these specific algorithms in clinical practice
cannot be recommended.
FUTURE DIRECTIONS A dengue mouse model has been validated and demonstrated to be a suitable test
system for antiviral drugs [40]. In one study, administration of an antiviral agent targeting dengue RNA-dependent
RNA polymerase to mice significantly reduced viremia and levels of proinflammatory cytokines [41]. 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 [42].
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 AND RECOMMENDATIONS
Dengue is a febrile illness that is caused by any 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
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.)
To date, there is no licensed vaccine available for preventing dengue. (See 'Vaccination' above.)
Most travelers from non-endemic 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 'Recommendations for travelers'
above.)
Patients with dengue should be cautioned to maintain their fluid intake to avoid dehydration and to take
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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 re-evaluation. (See 'Outpatient
management and early recognition of DHF/severe dengue' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
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11. Monath TP. Dengue and yellow fever--challenges for the development and use of vaccines. N Engl J Med
2007; 357:2222.
12. Endy TP, Nisalak A, Chunsuttitwat S, et al. Relationship of preexisting dengue virus (DV) neutralizing
antibody levels to viremia and severity of disease in a prospective cohort study of DV infection in Thailand. J
Infect Dis 2004; 189:990.
13. Pierson TC, Diamond MS. Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection.
Expert Rev Mol Med 2008; 10:e12.
14. Sukupolvi-Petty S, Austin SK, Purtha WE, et al. Type- and subcomplex-specific neutralizing antibodies
against domain III of dengue virus type 2 envelope protein recognize adjacent epitopes. J Virol 2007;
81:12816.
15. Durbin AP, Whitehead SS. Dengue vaccine candidates in development. Curr Top Microbiol Immunol 2010;
338:129.
16. Guirakhoo F, Pugachev K, Zhang Z, et al. Safety and efficacy of chimeric yellow Fever-dengue virus
tetravalent vaccine formulations in nonhuman primates. J Virol 2004; 78:4761.
17. Sabchareon A, Wallace D, Sirivichayakul C, et al. Protective efficacy of the recombinant, live-attenuated,
CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 2012;
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GRAPHICS
Algorithm for hypotensive shock and dengue fever

Isotonic crystalloid solutions include normal saline (0.9 percent ) and Ringer's lactate. 5 percent
albumin is the most commonly used colloid solution.
Reproduced with permission from: Dengue: Guidelines for diagnosis, treatment, prevention and control.
World Health Organization, Geneva, Switzerland, 2009. Copyright 2009 WHO. Available at:
http://www.who.int/tdr/publications/documents/dengue-diagnosis.pdf.
Graphic 82833 Version 2.0

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