Prevention and TX of Dengue

Official reprint from UpToDate

www.uptodate.com ©2015 UpToDate

AuthorsAlan L Rothman, MDAnon Srikiatkhachorn, MDSiripen Kalayanarooj, MD

Section EditorMartin S Hirsch, MD

Deputy EditorElinor L Baron, MD, DTMH

Prevention and treatment of dengue virus infection

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 dengue-

associated 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

®

®

Prevention and treatment of dengue virus infection http://www.uptodate.com.wdg.biblio.udg.mx:2048/contents/prevention-a...

1 de 11 11/08/2015 10:06 p.m.

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].

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

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.

●


2 de 11 11/08/2015 10:06 p.m.

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/mm or lower) is one of the clinical criteria for DHF and

usually precedes overt plasma leakage.

● 3

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

●


3 de 11 11/08/2015 10:06 p.m.

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:

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

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).

Blood pressure <90/60 mmHg●

Hematocrit >50 percent●

Platelet count <50,000/mm● 3

Evidence of bleeding other than petechiae●


4 de 11 11/08/2015 10:06 p.m.

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/mm ) 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 patient’s 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

3


5 de 11 11/08/2015 10:06 p.m.

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 5 to 6 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

10 to 12 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.)

SUMMARY

th th

th th

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

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●


6 de 11 11/08/2015 10:06 p.m.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

Kalayanarooj S, Vaughn DW, Nimmannitya S, et al. Early clinical and laboratory indicators of acute dengueillness. J Infect Dis 1997; 176:313.

1.

Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 1998; 11:480.2.

World Health Organization. Geneva: WHO, 2002.3.

Anderson KB, Chunsuttiwat S, Nisalak A, et al. Burden of symptomatic dengue infection in children at primaryschool in Thailand: a prospective study. Lancet 2007; 369:1452.

4.

Halstead SB. The XXth century dengue pandemic: need for surveillance and research. World Health Stat Q1992; 45:292.

5.

Burke DS, Nisalak A, Johnson DE, Scott RM. A prospective study of dengue infections in Bangkok. Am J TropMed Hyg 1988; 38:172.

6.

Gubler DJ. Aedes aegypti and Aedes aegypti-borne disease control in the 1990s: top down or bottom up.Charles Franklin Craig Lecture. Am J Trop Med Hyg 1989; 40:571.

7.

Halstead SB. Selective primary health care: strategies for control of disease in the developing world. XI.Dengue. Rev Infect Dis 1984; 6:251.

8.

Kay B, Vu SN. New strategy against Aedes aegypti in Vietnam. Lancet 2005; 365:613.9.

Hales S, van Panhuis W. A new strategy for dengue control. Lancet 2005; 365:551.10.

Monath TP. Dengue and yellow fever--challenges for the development and use of vaccines. N Engl J Med2007; 357:2222.

11.

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.)

●


7 de 11 11/08/2015 10:06 p.m.

Endy TP, Nisalak A, Chunsuttitwat S, et al. Relationship of preexisting dengue virus (DV) neutralizing antibodylevels to viremia and severity of disease in a prospective cohort study of DV infection in Thailand. J Infect Dis2004; 189:990.

12.

Pierson TC, Diamond MS. Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection.Expert Rev Mol Med 2008; 10:e12.

13.

Sukupolvi-Petty S, Austin SK, Purtha WE, et al. Type- and subcomplex-specific neutralizing antibodies againstdomain III of dengue virus type 2 envelope protein recognize adjacent epitopes. J Virol 2007; 81:12816.

14.

Durbin AP, Whitehead SS. Dengue vaccine candidates in development. Curr Top Microbiol Immunol 2010;338:129.

15.

Guirakhoo F, Pugachev K, Zhang Z, et al. Safety and efficacy of chimeric yellow Fever-dengue virustetravalent vaccine formulations in nonhuman primates. J Virol 2004; 78:4761.

16.

Capeding MR, Tran NH, Hadinegoro SR, et al. Clinical efficacy and safety of a novel tetravalent denguevaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet2014; 384:1358.

17.

Villar L, Dayan GH, Arredondo-García JL, et al. Efficacy of a tetravalent dengue vaccine in children in LatinAmerica. N Engl J Med 2015; 372:113.

18.

Sabchareon A, Wallace D, Sirivichayakul C, et al. Protective efficacy of the recombinant, live-attenuated, CYDtetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 2012;380:1559.

19.

Hadinegoro SR, Arredondo-García JL, Capeding MR, et al. Efficacy and Long-Term Safety of a DengueVaccine in Regions of Endemic Disease. N Engl J Med 2015.

20.

Dengue: guidelines for diagnosis, treatment, prevention and control - new edition. World Health Organization,Geneva 2009, p. 1.

21.

WHO Regional Office for Southeast Asia. Comprehensive guidelines for prevention and control of dengue anddengue haemorrhagic fever. Revised and expanded version. SEARO Technical Publication Series, New Delhi2011.

22.

Rigau-Pérez JG, Laufer MK. Dengue-related deaths in Puerto Rico, 1992-1996: diagnosis and clinical alarmsignals. Clin Infect Dis 2006; 42:1241.

23.

Libraty DH, Young PR, Pickering D, et al. High circulating levels of the dengue virus nonstructural protein NS1early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis 2002;186:1165.

24.

Chin CK, Kang BH, Liew BK, et al. Protocol for out-patient management of dengue illness in young adults. JTrop Med Hyg 1993; 96:259.

25.

Cao XT, Ngo TN, Kneen R, et al. Evaluation of an algorithm for integrated management of childhood illness inan area of Vietnam with dengue transmission. Trop Med Int Health 2004; 9:573.

26.

Tanner L, Schreiber M, Low JG, et al. Decision tree algorithms predict the diagnosis and outcome of denguefever in the early phase of illness. PLoS Negl Trop Dis 2008; 2:e196.

27.

Lee VJ, Lye DC, Sun Y, Leo YS. Decision tree algorithm in deciding hospitalization for adult patients withdengue haemorrhagic fever in Singapore. Trop Med Int Health 2009; 14:1154.

28.

Potts JA, Gibbons RV, Rothman AL, et al. Prediction of dengue disease severity among pediatric Thai patientsusing early clinical laboratory indicators. PLoS Negl Trop Dis 2010; 4:e769.

29.

Mitrakul C, Poshyachinda M, Futrakul P, et al. Hemostatic and platelet kinetic studies in dengue hemorrhagicfever. Am J Trop Med Hyg 1977; 26:975.

30.

Thomas L, Kaidomar S, Kerob-Bauchet B, et al. Prospective observational study of low thresholds for platelettransfusion in adult dengue patients. Transfusion 2009; 49:1400.

31.

Nimmannitya S. Dengue hemorrhagic fever: Diagnosis and management. In: Dengue and DengueHemorrhagic Fever, Gubler DJ, Kuno G (Eds), CAB International, Wallingford 1997. p.133.

32.

Ngo NT, Cao XT, Kneen R, et al. Acute management of dengue shock syndrome: a randomized double-blindcomparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis 2001; 32:204.

33.


8 de 11 11/08/2015 10:06 p.m.

Dung NM, Day NP, Tam DT, et al. Fluid replacement in dengue shock syndrome: a randomized, double-blindcomparison of four intravenous-fluid regimens. Clin Infect Dis 1999; 29:787.

34.

Wills BA, Nguyen MD, Ha TL, et al. Comparison of three fluid solutions for resuscitation in dengue shocksyndrome. N Engl J Med 2005; 353:877.

35.

Lam PK, Tam DT, Diet TV, et al. Clinical characteristics of Dengue shock syndrome in Vietnamese children: a10-year prospective study in a single hospital. Clin Infect Dis 2013; 57:1577.

36.

Panpanich R, Sornchai P, Kanjanaratanakorn K. Corticosteroids for treating dengue shock syndrome.

Cochrane Database Syst Rev 2006; :CD003488.

37.

Tam DT, Ngoc TV, Tien NT, et al. Effects of short-course oral corticosteroid therapy in early dengue infection inVietnamese patients: a randomized, placebo-controlled trial. Clin Infect Dis 2012; 55:1216.

38.

Zhang F, Kramer CV. Corticosteroids for dengue infection. Cochrane Database Syst Rev 2014; 7:CD003488.39.

Dimaano EM, Saito M, Honda S, et al. Lack of efficacy of high-dose intravenous immunoglobulin treatment ofsevere thrombocytopenia in patients with secondary dengue virus infection. Am J Trop Med Hyg 2007;77:1135.

40.

Chuansumrit A, Wangruangsatid S, Lektrakul Y, et al. Control of bleeding in children with Dengue hemorrhagicfever using recombinant activated factor VII: a randomized, double-blind, placebo-controlled study. BloodCoagul Fibrinolysis 2005; 16:549.

41.

Salgado D, Zabaleta TE, Hatch S, et al. Use of pentoxifylline in treatment of children with dengue hemorrhagicfever. Pediatr Infect Dis J 2012; 31:771.

42.

Johnson AJ, Roehrig JT. New mouse model for dengue virus vaccine testing. J Virol 1999; 73:783.43.

Schul W, Liu W, Xu HY, et al. A dengue fever viremia model in mice shows reduction in viral replication andsuppression of the inflammatory response after treatment with antiviral drugs. J Infect Dis 2007; 195:665.

44.

Nguyen NM, Tran CN, Phung LK, et al. A randomized, double-blind placebo controlled trial of balapiravir, apolymerase inhibitor, in adult dengue patients. J Infect Dis 2013; 207:1442.

45.

Topic 3030 Version 23.0


9 de 11 11/08/2015 10:06 p.m.

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


10 de 11 11/08/2015 10:06 p.m.

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, MDNothing 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 amulti-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content isrequired of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

Disclosures


11 de 11 11/08/2015 10:06 p.m.

Prevention and TX of Dengue

Documents

Transcript of Prevention and TX of Dengue