Dengue virus infection: Prevention and treatment

INTRODUCTION — Dengue is a febrile illness caused by a flavivirus transmitted by Aedes aegypti or Aedes albopictus mosquitoes while taking a blood meal. There are four dengue virus (DENV) types (DENV-1, DENV-2, DENV-3, and DENV-4), all of which are capable of inducing severe disease (dengue hemorrhagic fever [DHF]/dengue shock syndrome [DSS]). Dengue is endemic in more than 125 countries in tropical and subtropical regions and causes an estimated 390 million infections annually worldwide, of which 96 million are clinically apparent [1].

The likelihood for development of severe dengue is highest among individuals who are infected a second time by a different DENV type from the first infection (known as secondary or heterotypic infection) [2]. Thus, severe disease occurs primarily among individuals in areas where multiple DENV types circulate simultaneously. Infection with DENV provides long-term protection against disease caused by reinfection with that particular type. However, infection provides only short-lived cross-protection to the other three DENV types.

There are numerous documents providing guidance on the optimal approaches to managing dengue [3-6]. Data from well-designed randomized controlled trials are limited. The guidance in this document largely agrees with published guidelines and is also based on the contributors' clinical experience in management of complex DENV infections.

Measures to prevent DENV infection and supportive treatment following infection and the development of disease will be reviewed here. The epidemiology, clinical manifestations, and diagnosis of infection are discussed separately. (See "Dengue virus infection: Epidemiology" and "Dengue virus infection: Clinical manifestations and diagnosis".)

PREVENTION — DENV transmission occurs when susceptible hosts, DENVs, and mosquitoes capable of transmission are co-located in space and time. Infection risk exists for anyone living in or traveling in a dengue-endemic region, especially in tropical Asia, Central and South America, and the Caribbean. In most of these regions, DENV transmission occurs year-round. However, the greatest risk of infection tends to be seasonal or during a recognized outbreak.

In endemic areas — Approaches for the prevention of DENV infection and disease in endemic areas include mosquito control, personal protective measures, and vaccination.

Personal protection from infection

Mosquito repellants — Issues related to personal protection for prevention of mosquito bites are discussed separately. (See "Prevention of arthropod and insect bites: Repellents and other measures".)

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

Vaccine development — Infection with one DENV type provides long-term protection against reinfection with that same type, supporting the feasibility of an effective dengue vaccine. Following infection with one type, there is short-lived immunity and cross-protection against disease caused by the other three DENV types [11].

In view of the association between previous exposure to DENV types and severe disease, and the recognition that all four DENV types are capable of causing severe disease, ideally any candidate vaccine should produce protective immunity against all four DENV types (tetravalent immunity). Since waning immunity might also increase the risk for severe disease in vaccine recipients, vaccine-induced protective immunity should be long lived [12]. Given that the rate of clinically relevant third or fourth DENV infection is low, it is unclear whether tetravalent immunity is required for efficacy [13].

One vaccine, CYD-TDV (Dengvaxia), has been licensed in over 20 countries in Latin America and Southeast Asia (first licensed in 2015) (see 'CYD-TDV (Dengvaxia)' below). Vaccines in advanced clinical development include TAK-003 (Takeda) (see 'TAK-003' below) and a tetravalent, live-virus vaccine attenuated through directed mutagenesis with a DENV-2/-4 chimeric strain (National Institute of Health, licensed to Bhutantan and Merck) [14-16].

CYD-TDV (Dengvaxia) — In 2018, the CYD-TDV (Dengaxia) vaccine was approved by European authorities and recommended by the World Health Organization (WHO) for persons aged 9 to 45 years with confirmed previous dengue infection who live in endemic areas [17-19]. In 2019, the United States Food and Drug Administration (FDA) approved the vaccine for use in endemic areas [20]. In 2021, the Advisory Committee on Immunization Practices (ACIP) of the United States Centers for Disease Control and Prevention (CDC) officially recommended the vaccine for children aged 9 to 16 who have serologic evidence of previous dengue infection and live in endemic US territories [21]. Among United States territories, dengue is endemic in Puerto Rico, American Samoa, and the US Virgin Islands. The vaccine is not approved for travelers visiting dengue-endemic areas and is not commercially available in the United States [17].

CYD-TDV is a formulation of four chimeric yellow fever 17D-dengue vaccine viruses, where the premembrane and envelope proteins from each of the four DENV types replaces the same proteins in a yellow fever 17D backbone virus [22,23]. The basis for licensure was two large phase III randomized controlled trials of CYD-TDV; results were reported in 2014 to 2015 [24,25]. One trial was conducted in five countries in the Asia-Pacific region and enrolled children aged 2 to 14 years [24]; the other trial was conducted in five countries in Latin America and the Caribbean and enrolled children aged 9 to 16 years [25]. The age groups were chosen based on likely target populations for vaccination and epidemiologic data of clinical attack rates.

In both trials, the CYD-TDV vaccine was administered in three doses at months 0, 6, and 12. Results from the two trials were comparable; in the primary per-protocol analysis, vaccine efficacy was 57 and 61 percent against virologically confirmed dengue of any severity caused by any DENV type that occurred between 28 days and 13 months after the third vaccine dose. Vaccine efficacy was higher against dengue hemorrhagic fever or dengue infection requiring hospitalization (80 to 95 percent). Vaccine efficacy varied by serotype and was significantly higher for DENV-3 and DENV-4 (approximately 75 percent) than DENV-1 (50 percent) and DENV-2 (35 to 42 percent). Vaccine efficacy was lower (34 to 36 percent) in children 2 to 5 years of age and in children who did not have detectable dengue-neutralizing antibodies prior to vaccination. The safety profile was considered good, and there was no indication of more severe dengue disease in breakthrough cases in vaccine recipients that occurred over the 25 months of active case surveillance.

Follow-up analyses of these vaccine trials found significant limitations of the vaccine [26-28]. In a case-cohort study in which data from three vaccine efficacy trials were reanalyzed, the vaccine was protective among children previously exposed to dengue but increased the risk of hospitalization and severe illness among children who were not previously exposed [26]. Among dengue-seronegative children age 2 to 16 years, the cumulative incidence of hospitalization for dengue among vaccine recipients and controls was 3.06 and 1.87 percent, respectively (hazard ratio [HR] 1.75, 95% CI 1.14-2.70). Among dengue-seropositive children age 2 to 16 years, the cumulative incidence of hospitalization for dengue among vaccine recipients and controls was 0.75 and 2.47 percent, respectively (HR 0.32, 95% CI 0.23-0.45).

In November 2017, the vaccine manufacturer announced that, based on six years of clinical data, the vaccine had a persistent beneficial effect in individuals who had been previously infected with DENV prior to vaccination. In individuals with no prior episode of DENV infection, however, vaccination was associated with an increased risk of severe disease and hospitalization. Therefore, the manufacturer updated the label, advising that individuals with no prior DENV infection forgo vaccination [29].

In December 2017, the WHO issued a statement indicating that the vaccine is protective against severe dengue for individuals with dengue seropositivity at the time of first vaccination but that the risk of severe dengue is significantly increased for individuals with dengue seronegativity at the time of first vaccination [30].

The mechanisms for CYD-TDV vaccine efficacy in seropositive individuals and the increased risk of severe dengue in seronegative individuals are uncertain. Only a subset of individuals underwent scheduled serologic monitoring prior to and following vaccination, so analyses of the immune profiles associated with various outcomes are limited. A statistical analysis found that higher postvaccination titers of neutralizing antibodies were associated with a significantly higher vaccine efficacy for all DENV types, baseline serostatus groups, and age groups [31]. However, no absolute correlate of protection could be identified, indicating that the relationship between vaccine-induced immune responses and efficacy is likely more complex than any one single factor.

The vaccine sponsor also used measured (when values were available) or imputed (when values missing) PRNT50 titers, with imputation conducted using covariates to include data generated from study month 13 blood samples (on month after dose 3) tested with a newly developed anti-non-structural protein 1 (NS1) assay. Because the vaccine construct does not contain dengue NS1 protein, the absence of anti-NS1 antibodies from a study month 13 sample would indicate the individual had not experienced a natural DENV infection (seronegative status at baseline) [26,32].

Overall, CYD demonstrated superior efficacy and clinical benefit in seropositive versus seronegative vaccine recipients. There was also a trend of superior efficacy and beneficial vaccine effect in older children, and these effects were noted against any dengue caused by all DENV types as well as severe and hospitalized dengue. In contrast, there was a clear safety signal in seronegative vaccine recipients especially in the younger age groups with hospitalization and severe disease occurring with increased frequency in seronegative vaccine recipients [33].

TAK-003 — TAK-003 is tetravalent vaccine based on an attenuated laboratory-derived DENV-2 virus, DENV-2 primary dog kidney (PDK)–53, which provides the genetic backbone for all four of the viruses in the vaccine [34-37]. The other three virus strains (TDV-1, TDV-3, and TDV-4) are chimeras generated by replacing the premembrane and envelope genes of TDV-2 with those from wild-type DENV-1, DENV-3, and DENV-4 strains.

Findings from a phase 2 trial among more than 1400 participants aged 2 to 17 years in three countries with 48-month follow-up support a two-dose schedule administered three months apart [35]. No serious adverse events or severe DENV disease were reported.

In a phase 3 clinical trial including more than 20,000 children 4 to 16 years of age in regions of Asia and Latin America where DENV infection is endemic, individuals were randomly assigned to receive two doses of vaccine or placebo three months apart [36,37].

●At 12 months of follow-up, fewer cases of DENV infection (confirmed via polymerase chain reaction) were observed among vaccinated individuals than among those who received placebo (0.5 versus 2.5 per 100-person years); the overall vaccine efficacy was 80.9 percent (95% CI 75.2-85.3) [36]. Approximately 5200 individuals (28 percent of the per-protocol population) were seronegative at baseline; in this group, the vaccine efficacy was 74.9 percent (95% CI 57.0-85.4). The incidence of serious adverse events was similar in the vaccine group and placebo group (3.1 and 3.8 percent, respectively). Efficacy varied according to DENV type; there was no efficacy against DENV-3, and data were insufficient to evaluate efficacy against DENV-4.

●At 18 months of follow-up, overall vaccine efficacy (against any DENV type and any disease severity) was 73.3 percent (95% CI 66.5-78.8) and overall efficacy against hospitalized dengue was 90.4 percent (95% CI 82.6-94.7) [37]. Vaccine efficacy was higher among baseline seropositive than seronegative individuals (76.1 versus 66.2 percent). Secondary vaccine efficacy endpoints by serotype were met for DENV-1 (69.8 percent, 95% CI 54.8-79.9), DENV-2 (95.1 percent, 95% CI 89.9-97.6), and DENV-3 (48.9 percent, 95% CI 27.2-64.1), but not DENV-4 (51.0 percent, 95% CI -69.4 to 85.8). Vaccine efficacy against DENV-1 and DENV-2 was similar regardless of baseline serostatus; for DENV-3, vaccine efficacy among seropositive individuals was 61.8 percent (43.0 to 74.4) but vaccine efficacy was not observed among seronegative individuals (-68.2 percent, 95% CI -318.9 to 32.4).

Thus far, the available data suggest TAK-003 may be used in seropositive or seronegative individuals, and the high efficacy against hospitalized dengue suggests that TAK-003 may be a useful public health tool for reducing the burden of severe disease. However, further efficacy and safety evaluation is needed, particularly for serotypes DENV-3 and DENV-4.

Mosquito control — Mosquito control is effective but is difficult to resource and sustain. Programs in the 1940s through 1970s targeting the A. aegypti mosquito via aggressive surveillance and insecticide use for elimination of urban yellow fever in the Americas were successful at reducing transmission of yellow fever as well as the DENVs [9]. Lack of funding and attention for these programs led to reemergence of A. aegypti and corresponding re-emergence of dengue.

Some approaches to mosquito control for prevention of DENV infection are described below. Additional issues related to mosquito vector control are discussed further separately. (See "Malaria: Epidemiology, prevention, and control", section on 'Mosquito control'.)

●Reducing breeding sites – Community-based education to reduce breeding sites that accumulate standing water (such as discarded tires and other containers) have shown some promise [9,38].

●Larva control – Seeding water vessels with copepods that feed on mosquito larvae was successful in eliminating A. aegypti and dengue transmission in one study including 32 rural communities in Vietnam [39], although this strategy is difficult to apply in urban areas [40].

●Endosymbiotic control – A novel dengue control strategy consists of releasing mosquitoes infected with Wolbachia, an obligate intracellular bacterium [41-43]. A. aegypti mosquitoes infected with Wolbachia are less susceptible to DENV infection than wild-type A. aegypti [44].

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

Among travelers — The primary approach to prevention of DENV infections in travelers consists of avoiding exposure to infected A. aegypti mosquitoes, which predominantly live in urban areas (in and around houses) and are most active during the daytime as well as at twilight [10]. Remaining in well-screened or air-conditioned buildings during the day can reduce the risk of exposure. When outside during the day, individuals should wear clothing that reduces the amount of exposed skin and should use an effective mosquito repellent, such as N,N-diethyl-metatoluamide (DEET). (See "Prevention of arthropod and insect bites: Repellents and other measures".)

Most travelers from nonendemic countries are at exceedingly low risk for severe dengue in the absence of prior DENV exposure; potential exceptions include frequent international travelers, expatriates, frequently deploying military personnel, and immigrants from endemic areas returning to their countries of origin.

People with history of dengue infection need not avoid subsequent travel to dengue-endemic regions. Severe dengue occurs in a small number of secondary infections (2 to 4 percent), so the risk of severe dengue in travelers is very low.

CYD-TDV (Dengvaxia) is not approved for travelers visiting dengue-endemic areas and is not commercially available in the United States [17]. (See 'CYD-TDV (Dengvaxia)' above.)

TREATMENT APPROACH — There is no direct antiviral therapy available against the DENVs. Management is supportive, which largely consists of maintaining adequate intravascular volume.

Treatment guidelines have been published by the World Health Organization (WHO; 2009) and the WHO South-East Asia Regional Office (SEARO; 2011); there are variations between these guidelines [5,46]. These are discussed in the following sections, which follow the framework of the revised dengue case classification. Where relevant, significant differences in the recommendations are noted in the discussion below. (See "Dengue virus infection: Clinical manifestations and diagnosis".)

Thus far, there has been no prospective validation of the approaches summarized in the WHO guidelines. The areas of greatest uncertainty are the sensitivity and specificity of the criteria used for hospitalization and for initiation of fluid therapy. Some additional clinical approaches that have been successful in endemic areas are discussed below. (See 'Additional approaches to management' below.)

A definitive laboratory diagnosis of dengue is often not available at the point of care; therefore, it is also important to consider other treatable diagnoses. (See "Dengue virus infection: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

Phases of infection and clinical assessment — DENV infection has three phases: a febrile phase, a critical (plasma leakage) phase, and a convalescent (reabsorption) phase [5]. The febrile phase is characterized by a sudden high-grade fever and dehydration typically lasting two to seven days. The critical phase is characterized by plasma leakage, bleeding, shock, and organ impairment; it usually starts around the time of defervescence (typically days 3 to 7 of infection) and lasts for 24 to 48 hours. The convalescent phase may be characterized by fatigue that can last for days to weeks. (See "Dengue virus infection: Clinical manifestations and diagnosis", section on 'Phases of infection'.)

The WHO classification schemes for DENV infection are summarized separately [4,5]. (See "Dengue virus infection: Clinical manifestations and diagnosis", section on 'Classification schemes'.)

Patients with suspected dengue should be assessed carefully and directed to the appropriate care setting. Early recognition of progression to severe disease and patients at increased risk for severe disease is essential, with prompt initiation of more aggressive therapy when necessary.

Outpatient management is appropriate for patients with presumptive diagnosis of dengue infection in the absence of warning signs or coexisting conditions (pregnancy, infancy, old age, diabetes, renal failure, underlying hemolytic disease, obesity, or poor social situation); such patients should be able to tolerate oral fluids, urinate at least once every six hours, and have near normal blood counts [5].

Inpatient management is warranted for patients with dengue and warning signs of severe infection, severe dengue infection, or dengue infection with coexisting conditions (algorithm 1). Dramatic plasma leakage can develop suddenly; early identification of patients at increased risk for shock and other complications is critical. The period of maximum risk for shock is between the third and seventh day of illness, which typically coincides with resolution of fever. In general, plasma leakage first becomes evident between 24 hours before and 24 hours after defervescence.

Laboratory abnormalities include derangements in blood counts and liver function tests. An elevated hematocrit is an indication that plasma leakage has already occurred and that fluid repletion is required. Confounding factors should be considered when interpreting the hematocrit, including dehydration (associated with increased hematocrit) and hemorrhage (associated with reduced hematocrit). Marked thrombocytopenia (≤100,000/mm³) is a criteria for dengue hemorrhagic fever and usually precedes overt plasma leakage. Mild elevations in serum transaminases are common in the setting of dengue infection; transaminase levels are significantly elevated in patients with DHF. In addition, elevated aspartate transaminase (AST) levels are common relatively early in the course of illness; in one Thai study, a normal AST level was a strong negative predictor of DHF (negative predictive value 0.96) [47]. (See "Dengue virus infection: Clinical manifestations and diagnosis", section on 'Dengue hemorrhagic fever'.)

Outpatient management — Outpatient management is appropriate for patients with presumptive diagnosis of dengue in the absence of warning signs or coexisting conditions as summarized in the preceding section. Most patients with dengue do not develop severe illness and can be safely managed in the outpatient setting. (See 'Phases of infection and clinical assessment' above.)

Patients should be instructed regarding the warning signs of severe dengue infection and the critical phase that follows defervescence (which lasts for 24 to 48 hours); during this period, patients may deteriorate rapidly. During the febrile phase (lasting two to seven days) and the subsequent critical phase (lasting one to two days), the patient should be evaluated daily from the third day of illness through the end of the critical phase for signs of dehydration and other warning signs of severe dengue. Serial blood counts should be followed to evaluate for interval increases in hematocrit concurrent with rapid decrease in platelet count, indicating presence of plasma leakage and increased risk of bleeding complications.

Fever may be controlled with acetaminophen; nonsteroidal anti-inflammatory drugs and aspirin-based products should not be used out of concern for their effect on platelet function and the potential increased risk for bleeding. (See 'Management of fever' below.)

Patients should be instructed to take plenty of fluids and watch for signs of dehydration (decrease in urination, few or no tears, dry mouth or lips, sunken eyes, listlessness or confusion, cold or clammy extremities, sunken fontanel in an infant); these findings warrant prompt clinical evaluation. As fever declines (three to eight days after onset of symptoms), patients should be instructed to seek prompt attention for any of the following: severe abdominal pain, persistent vomiting, skin rash, bleeding from nose or gums, vomiting blood, dark stools, drowsiness or irritability, pale or cool skin, and difficulty breathing.

Patients in endemic areas should take measures to prevent DENV transmission. If possible, all mosquitoes in the house should be eliminated, screens should be placed on windows and doors to prevent mosquitoes from coming into the house, and containers holding standing water should be emptied. To avoid infecting mosquitoes (which can in turn infect others in the household), if possible, the patient should sleep under a bed net and use insect repellant while ill.

Inpatient management — Inpatient management is warranted for patients with dengue and warning signs of severe infection, severe dengue infection, or dengue infection with coexisting conditions (pregnancy, infancy, diabetes, poor social situation, old age, or renal failure). (See 'Phases of infection and clinical assessment' above.)

Patients warranting inpatient management should be assessed for signs of impending shock (table 1). In the absence of shock, patients may be managed as summarized in the algorithm (algorithm 1) [3]. Most patients who present for medical attention before profound shock develops and who receive appropriate fluid therapy recover quickly.

In setting of shock (normal systolic pressure but rising diastolic pressure with narrowing pulse pressure), patients may be managed as summarized in the algorithm (algorithm 2). In the setting of profound or prolonged shock (hypotension, narrow pulse pressure [systolic minus diastolic pressure ≤20 mmHg]), patients may be managed as summarized in the algorithm (algorithm 3).

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

Management of plasma leakage — Plasma leakage should be managed with intravascular volume repletion to prevent or reverse hypovolemic shock (algorithm 1). In mild cases, particularly when medical attention is received early, oral rehydration may be sufficient. Administration of intravenous fluid is warranted in patients with established intravascular volume loss. Blood transfusion is appropriate in patients with significant bleeding or low hematocrit and failure to improve with fluid resuscitation. Subsequent hematocrit measurements must be interpreted with caution since it is critical to assess the adequacy of both blood and fluid repletion; in complex cases, it can be challenging to distinguish whether a decrease in hematocrit reflects volume repletion or blood loss.

Treatment of shock — Protocols for intravenous fluid therapy have been developed by the World Health Organization [4,5,46] ; these are summarized in the algorithms (algorithm 2 and algorithm 3). There are a number of acceptable approaches to management of shock associated with dengue, and there are no clinical trial data favoring one approach over the other. The process of frequent clinical assessment is critical to ensure judicious fluid resuscitation and detection of hemorrhage if present.

Initial fluid resuscitation with crystalloid is appropriate; there is no clinical advantage of colloid over crystalloid [48-50]. In one randomized trial including 512 Vietnamese children with moderate dengue shock syndrome, outcomes were similar with Ringer's lactate, 6% dextran 70, and 6% hydroxyethyl starch [50], establishing that Ringer's lactate is a safe, effective, and inexpensive crystalloid solution for initial resuscitation of patients with moderate shock. In patients with severe shock, dextran and starch performed similarly, although dextran was associated with more hypersensitivity reactions.

Intravenous colloid solution is warranted for patients with intractable shock resistant to crystalloid resuscitation; in such cases, we favor 10% dextran 40 in normal saline. Patients with persistent hypoperfusion and falling hematocrit require blood transfusion and should be evaluated for occult or overt bleeding. Other possible complications (such as acidosis, hypoglycemia, and hypocalcemia) should be investigated and corrected as needed. (See "Treatment of severe hypovolemia or hypovolemic shock in adults" and "Hypovolemic shock in children in resource-abundant settings: Initial evaluation and management".)

Once hemodynamic stability has been restored, intravenous fluids should be continued with gradual reduction of the infusion rate over the next 24 to 48 hours. There have been no controlled comparisons of infusion regimens; we typically reduce the infusion rate as follows: 10 mL/kg over the first hour, then 7 mL/kg/hour for 1 to 2 hours, 5 mL/kg/hour for 4 to 6 hours, and 3 mL/kg/hour for 6 to 12 hours. This gradual reduction is intended to minimize the risk of recurrent shock and volume overload. The patient's clinical status (including vital signs, urine output, and hematocrit) should be evaluated prior to each infusion rate adjustment.

Close clinical observation is essential even after restoration of normovolemia; the 24 hours following initial resuscitation is a period of increased vascular permeability, and patients can develop recurrent shock during this period. Fluid lost into potential spaces (pleura, peritoneum) during the period of plasma leakage is reabsorbed rapidly. Therefore, intravenous fluid supplementation should be discontinued following the period of increased vascular permeability; excessive fluid administration after this point can precipitate hypervolemia and pulmonary edema.

Monitoring of volume status by other means, such as serial ultrasonographic measurements of the inferior vena cava, may be useful, but conclusive evidence for the use of these techniques in the clinical monitoring of dengue is still lacking [51,52].

In the absence of complications from prolonged hypotension, most patients with severe dengue infection recover within a few days [53]. Discharge from the hospital is appropriate when patients have been afebrile for at least 24 hours or have passed two days after an episode of shock, are clinically well, and have normal appetite, urine output, and hematocrit.

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

Factors that contribute to bleeding include thrombocytopenia due to decreased platelet survival [54] and, in severe cases, prolonged prothrombin time (international normalized ratio >1.3) and frank disseminated intravascular coagulation due to liver failure. Platelet transfusion has not been shown to be effective at preventing or controlling hemorrhage but may be warranted in patients with severe thrombocytopenia (<10,000/mm³) and active bleeding. In general, the preponderance of data does not support a role for prophylactic platelet transfusion in patients with severe thrombocytopenia in the absence of active bleeding [5,55-60]. Administration of intravenous vitamin K is warranted for patients with severe liver dysfunction or prolonged prothrombin time [46].

ADDITIONAL APPROACHES TO MANAGEMENT — Treatment guidelines have been published by the World Health Organization (WHO; 2009) and the WHO South-East Asia Regional Office (SEARO; 2011); there are variations between these guidelines [4,5,47].

Clinical practice is informed by the above guidelines as well as clinical experiences with managing dengue in different populations. There have been no rigorous trials comparing clinical approaches or establishing endpoints (clinical or laboratory based) for management of severe disease.

The following indications for inpatient admission have been used at the Queen Sirikit National Institute for Child Health in Bangkok, Thailand, since 1999 [61,62]:

●Shock or impending shock

●Leukopenia (white blood cell count 5000 cells/mm³ or lower) and/or thrombocytopenia (platelet count 100,000 cells/mm³ or lower), especially in high-risk patients (infants, older adults, pregnancy, patients with comorbidities)

●Clinical deterioration or lack of clinical improvement with defervescence

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

●Altered consciousness

●Difficulty with follow-up

●Family concern/anxiety

Published experience with systematic application of more restrictive criteria for admission of patients with suspected dengue is limited. This includes an uncontrolled study in Malaysia conducted over a two-month period [63] and case series from Singapore describing the clinical experience with institutional admissions guidelines [64]. The major criteria for hospitalization in those sites included:

●Blood pressure <90/60 mmHg

●Hematocrit >50 percent

●Platelet count <50,000/mm³

●Evidence of bleeding other than petechiae

Additional criteria for hospitalization in the Singapore study included pulse ≥100 beats/minute, severe abdominal pain, persistent vomiting, and older adult patients with comorbidities. Both groups reported successful management with no complications resulting from outpatient care; however, the studies involved only adults, and the number of cases of severe dengue/dengue hemorrhagic fever (DHF) was relatively small (28 in Malaysia and 148 in Singapore). In case series in Thailand and Singapore, the WHO criteria for dengue with warning signs of severe infection would have led to an excess of hospitalizations and/or treatment relative to local clinical practice [64,65].

Routine laboratory testing is not readily available in many resource-limited settings where dengue is endemic. One study including 1250 children aged 2 months to 10 years in southern Vietnam evaluated whether an assessment tool using only clinical signs could appropriately guide management of acute illness [66]. The assessment tool was derived from the WHO/United Nations Children's Emergency Fund (UNICEF) "Integrated Management of Childhood Illness" algorithm designed for use in Africa and was modified to include common signs and symptoms of DHF. The 20 children who presented with dengue shock syndrome were correctly identified as requiring urgent hospitalization, although classification of less severe DHF was imperfect, and reevaluation within one to two days was needed to detect children who developed shock.

Several studies have applied decision-tree analysis to develop algorithms for early management of patients with suspected dengue, although the study populations and conclusions have differed [67-70]. Until these findings can be externally validated in a prospective fashion, the use of any of these algorithms in clinical practice cannot be recommended.

FUTURE DIRECTIONS — Thus far, data do not support a role for corticosteroids [71-73], intravenous immunoglobulins, pentoxifylline, or activated factor VII [74-76].

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

Randomized trials of chloroquine, lovastatin, balapiravir (a polymerase inhibitor), and celgosivir (an alpha-glucosidase inhibitor) among adults with dengue have not noted a significant benefit on viremia, NS1 antigenemia, or fever [81-83].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dengue virus".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th 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^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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

SUMMARY

●Dengue is a febrile illness that is caused by one of four dengue virus (DENV) types (DEN-1, DEN-2, DEN-3, and DEN-4). The likelihood for development of severe dengue is highest among individuals who develop a second dengue infection caused by a different virus type from the first infection. Thus, severe disease occurs primarily among individuals in areas where multiple DENV types circulate simultaneously. (See 'Introduction' above and 'Prevention' above.)

●Approaches for prevention of dengue infection in endemic areas include mosquito control and vaccine development. Mosquito control is effective but is difficult to sustain. A single vaccine, CYD-TDV, has been licensed in several countries in Latin America, Southeast Asia, Europe, and the United States. CYD-TDV should be administered only to individuals with history of previous DENV infection or laboratory evidence of previous DENV infection. (See 'In endemic areas' above.)

●Most travelers from nonendemic countries are at low risk for severe dengue in the absence of prior DENV exposure; potential exceptions include frequent international travelers, expatriates, frequently deploying military personnel, and immigrants from endemic areas returning to their countries of origin. (See 'Among travelers' above.)

●Patients with suspected dengue should be assessed carefully and directed to the appropriate care setting. Early recognition of severe disease and patients at increased risk for severe disease are essential, with prompt initiation of more aggressive therapy when necessary. (See 'Phases of infection and clinical assessment' above.)

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

●Patients warranting inpatient management should be assessed for signs of shock (table 1). In the absence of shock, patients may be managed as summarized in the algorithm (algorithm 1). In the setting of shock (normal systolic pressure but rising diastolic pressure with narrowing pulse pressure), patients may be managed as summarized in the algorithm (algorithm 2). In the setting of profound or prolonged shock, patients may be managed as summarized in the algorithm (algorithm 3). (See 'Management of plasma leakage' above and 'Treatment of shock' above.)

●Fever and myalgias should be managed with acetaminophen; aspirin or nonsteroidal anti-inflammatory agents should be avoided. Gastrointestinal bleeding, epistaxis, or heavy menstrual bleeding may be severe enough to warrant blood transfusion. (See 'Management of fever' above and 'Management of bleeding' above.)