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Dengue fever is a mosquito-borne viral illness and the most prevalent arthropod-transmitted viral disease worldwide, representing a growing and persistent global public health challenge. Transmitted primarily by Aedes aegypti and Aedes albopictus mosquitoes, dengue affects millions annually, with a clinical spectrum ranging from asymptomatic infection to severe, life-threatening disease. Classically referred to as “breakbone fever,” this course details the clinical features of dengue fever, characterized by high fever, myalgias, arthralgias, headache, and rash, with severe forms involving plasma leakage, hemorrhage, and organ dysfunction as well as the expanding geographic distribution of dengue, driven by urbanization, climate change, and global travel, which has resulted in increasing incidence in tropical and subtropical regions, with periodic epidemics and rising disease burden. This activity reviews the virology and pathophysiology of dengue virus infection, emphasizing the mechanisms underlying disease severity and complications. Participants will gain an understanding of the clinical manifestations, diagnostic strategies, and evidence-based management of dengue fever and its severe forms. Risk stratification, warning signs, supportive care, and prevention strategies are also discussed. This activity for healthcare professionals is designed to enhance the learner's competence in identifying dengue virus infection, performing the recommended evaluation, and implementing an appropriate interprofessional approach when managing this condition, thereby optimizing patient outcomes and public health efforts. Objectives: Identify the clinical features of dengue virus infection across its full disease spectrum. Differentiate uncomplicated dengue from severe dengue using current diagnostic criteria. Implement evidence-based management strategies for patients with dengue infection. Collaborate effectively within the interprofessional healthcare team to optimize care coordination and outcomes in patients with dengue fever. Access free multiple choice questions on this topic.

Dengue fever is a mosquito-borne viral illness and the most common arthropod-borne viral disease worldwide, posing a growing public health burden. Transmitted primarily by Aedes aegypti and Aedes albopictus mosquitoes, dengue is endemic in large parts of the tropical and subtropical world, with ongoing geographic expansion driven by urbanization, climate change, and increased human mobility.[1][2] Most dengue virus infections are asymptomatic or mild, but a minority progress to severe disease characterized by plasma leakage, shock, bleeding, or organ dysfunction.[1][2] Clinically, dengue typically presents after an incubation period of 4 to 10 days with an abrupt onset of high fever, headache, myalgia, arthralgia, gastrointestinal symptoms, and rash, accompanied by laboratory abnormalities such as leukopenia and thrombocytopenia.[2][3] A subset of patients progress to severe dengue, most commonly during the critical phase around defervescence, due to increased capillary permeability.[2][3] Early recognition, accurate risk stratification, and appropriate supportive management are essential to reduce morbidity and mortality, particularly in resource-limited and outbreak settings.[2][4] Effective care and prevention require coordinated efforts by an interprofessional healthcare team that integrates clinical management, diagnostics, surveillance, and public health interventions.[5]

Dengue fever is caused by infection with dengue virus (DENV), a single-stranded, positive-sense RNA virus belonging to the genus Flavivirus within the family Flaviviridae. DENV exists as 4 antigenically distinct serotypes, designated DENV-1, DENV-2, DENV-3, and DENV-4, each capable of causing the full spectrum of clinical disease.[2] The 4 serotypes are genetically related but antigenically distinct.[2] Transmission to humans occurs primarily through the bite of infected female Aedes mosquitoes, most notably Aedes aegypti, with Aedes albopictus also contributing to transmission in some ecological settings.[1][2] These vectors thrive in urban and peri-urban environments and are well adapted to human habitation, facilitating sustained transmission in tropical and subtropical regions.[1][2] Environmental factors, eg, temperature, humidity, and rainfall, strongly influence vector density and transmission efficiency, with optimal viral transmission occurring at temperatures between 25 °C and 30 °C.[2] Although mosquito-borne transmission accounts for the vast majority of cases, rare alternative routes have been documented, including perinatal transmission, blood transfusion, organ transplantation, and, exceedingly rarely, sexual transmission.[2] Primary infection with a single DENV serotype confers long-lasting immunity to that specific serotype but only transient cross-protection against others. This immunologic feature contributes to an increased risk of severe disease during subsequent secondary infections with heterologous serotypes, a phenomenon known as antibody-dependent enhancement (ADE).[2][6][7]

Dengue fever is the most prevalent arthropod-borne viral disease worldwide and remains a major and escalating global public health challenge. Over the past several decades, DENV transmission has expanded substantially in both geographic range and intensity, with sustained increases in incidence observed since the mid-20th century and continuing to the present day.[1][2][8][9] Dengue is now endemic in more than 100 countries, predominantly affecting tropical and subtropical regions of Southeast Asia, South Asia, the Western Pacific, Africa, and the Americas, with increasing reports of autochthonous transmission in temperate regions.[2][8][10] Although mosquitos are the predominant route of transmission, rare cases can occur through maternal-fetal transmission and various healthcare-associated routes including blood transfusion and needlestick injuries. [CDC. How Dengue Spreads. https://www.cdc.gov/dengue/transmission/index.html#:~:text=Key%20points,infects%20them%20with%20dengue%20virus.] Current estimates indicate that approximately 3.8 billion people—over half of the world’s population—live in areas suitable for dengue transmission.[2][8][10] Globally, dengue causes an estimated 100 to 400 million infections annually, of which approximately 58 to 59 million are symptomatic, with reported mortality ranging from 13,500 to more than 40,000 deaths per year.[1][2][8][11] The global burden of disease, measured in disability-adjusted life years (DALYs), has more than doubled since 1990, exceeding 2 million DALYs annually and reflecting both rising incidence and increasing disease severity.[2][11] Epidemiologically, dengue transmission occurs in 2 overlapping patterns: epidemic transmission and hyperendemic transmission. Epidemic transmission is characterized by explosive outbreaks following the introduction of a single DENV serotype into a largely susceptible population, whereas hyperendemic transmission involves the continuous circulation of multiple serotypes within the same geographic area.[9][10] Hyperendemicity is now common in large urban and peri-urban centers and is associated with high seroprevalence, increased risk of secondary infections, and a greater incidence of severe dengue.[2][9]

Epidemiologically, dengue transmission occurs in 2 overlapping patterns: epidemic transmission and hyperendemic transmission. Epidemic transmission is characterized by explosive outbreaks following the introduction of a single DENV serotype into a largely susceptible population, whereas hyperendemic transmission involves the continuous circulation of multiple serotypes within the same geographic area.[9][10] Hyperendemicity is now common in large urban and peri-urban centers and is associated with high seroprevalence, increased risk of secondary infections, and a greater incidence of severe dengue.[2][9] Marked regional and socioeconomic disparities exist in the dengue burden. The highest incidence and mortality rates are observed in Southeast Asia, South Asia, and tropical Latin America, where dengue is a leading cause of hospitalization and death, particularly among children.[2][9][11] However, the fastest relative growth in incidence has been observed in higher-income regions, reflecting the expanding geographic distribution of Aedes aegypti and Aedes albopictus mosquitoes.[2][12] Climate change, population growth, urban crowding, inadequate vector control, and increased international travel have collectively increased the global risk of dengue transmission by an estimated 10% to 46% since the mid-20th century.[2][8][12] Beyond its direct health impact, dengue imposes a substantial economic burden, with global costs estimated at approximately 8.9 billion dollars annually due to direct medical expenditures, productivity losses, and outbreak-related strain on healthcare systems.[2][9] Seasonal epidemics and large outbreaks can rapidly overwhelm healthcare infrastructure, particularly in resource-limited settings, underscoring the importance of sustained surveillance, vector control, and public health preparedness at both national and global levels.[2][9]

Following inoculation into the skin, DENV initially infects local immune cells, including dendritic cells, macrophages, mast cells, and dermal fibroblasts, before disseminating via the lymphatic system to regional lymph nodes and subsequently into the bloodstream, leading to systemic viremia.[2][6] Viral Replication and Dissemination DENV entry into host cells is mediated by binding of the viral envelope (E) glycoprotein to cell surface receptors, including heparan sulfate and C-type lectins, eg, DC-SIGN, followed by receptor-mediated endocytosis.[6] Acidification of the endosome induces conformational changes in the E protein, allowing fusion of viral and cellular membranes and release of viral RNA into the cytoplasm. Viral proteins are translated as a single polyprotein and cleaved into 3 structural and 7 nonstructural proteins, including NS1, NS3, and NS5, which are critical for viral replication and immune modulation.[2][6] Viremia typically becomes detectable shortly before symptom onset and persists for several days. Higher early viral loads correlate with increased risk of severe dengue and may reflect both viral and host determinants of immunopathology.[2][6] Host Immune Response and Immunopathogenesis Both innate and adaptive immune responses play central roles in dengue pathophysiology. Early innate immune responses include interferon production and natural killer cell activation, which contribute to viral control but may be partially inhibited by viral nonstructural proteins.[6] As infection progresses, adaptive immunity develops with activation of DENV-specific B and T lymphocytes.[2] Antibody responses are directed primarily against the E protein, precursor membrane (pre-M) protein, and NS1 protein. While neutralizing antibodies confer protection against homologous serotypes, subneutralizing antibodies can enhance viral entry into Fc receptor–bearing cells through ADE, a key mechanism implicated in severe disease during secondary heterologous infections.[2][6] T-cell responses further contribute to both viral clearance and immunopathology. Cross-reactive memory T cells generated during prior infection may produce excessive proinflammatory cytokines upon secondary infection, contributing to endothelial dysfunction, plasma leakage, and organ injury.[2][6] Endothelial Dysfunction and Plasma Leakage

T-cell responses further contribute to both viral clearance and immunopathology. Cross-reactive memory T cells generated during prior infection may produce excessive proinflammatory cytokines upon secondary infection, contributing to endothelial dysfunction, plasma leakage, and organ injury.[2][6] Endothelial Dysfunction and Plasma Leakage The hallmark of severe dengue is transient but profound plasma leakage resulting from increased capillary permeability rather than direct endothelial cell destruction.[2][3][6] Histopathological studies demonstrate widened endothelial tight junctions with minimal structural damage, consistent with functional endothelial dysfunction rather than cytolysis.[6] This process is mediated by a complex interplay of immune mechanisms, including cytokine release (eg, TNF-α, IFN-γ, IL-2, IL-8), complement activation, and vasoactive mediators, eg, vascular endothelial growth factor (VEGF).[6] The secreted viral nonstructural protein NS1 plays a critical role in endothelial injury by disrupting the endothelial glycocalyx, activating Toll-like receptor 4 signaling, and promoting complement-mediated damage.[2][6] Plasma leakage typically peaks during the critical phase of illness, coinciding with defervescence and declining viremia.[3] Hematologic and Coagulation Abnormalities Hematologic abnormalities are common in dengue and include leukopenia, thrombocytopenia, and varying degrees of coagulopathy.[2][3] Bone marrow suppression occurs early in infection, leading to reduced hematopoiesis, while peripheral platelet destruction—mediated by immune complexes, complement activation, and direct viral effects—contributes to thrombocytopenia.[3][6] Bleeding manifestations arise from a combination of thrombocytopenia, endothelial dysfunction, platelet activation, and disturbances in coagulation and fibrinolysis. Severe hemorrhage is uncommon but may occur in advanced disease, particularly in the context of shock or multiorgan dysfunction.[3][6][13] Organ Involvement DENV infection can involve multiple organ systems, particularly in severe disease. Hepatic involvement is common and ranges from mild elevations in transaminases to severe hepatitis. Liver injury results from both direct viral infection of hepatocytes and immune-mediated inflammatory damage.[2][3][6]

Bleeding manifestations arise from a combination of thrombocytopenia, endothelial dysfunction, platelet activation, and disturbances in coagulation and fibrinolysis. Severe hemorrhage is uncommon but may occur in advanced disease, particularly in the context of shock or multiorgan dysfunction.[3][6][13] Organ Involvement DENV infection can involve multiple organ systems, particularly in severe disease. Hepatic involvement is common and ranges from mild elevations in transaminases to severe hepatitis. Liver injury results from both direct viral infection of hepatocytes and immune-mediated inflammatory damage.[2][3][6] Cardiac involvement may manifest as myocarditis, pericarditis, or pericardial effusion. Histopathological findings include myocardial fiber destruction, loss of cross-striations, and nuclear depletion, consistent with myocarditis.[14] The pathogenesis of dengue-associated cardiac injury is multifactorial and includes: Direct viral effects: Viral replication has been demonstrated in cardiac myocytes and endothelial cells. Inflammatory and immune-mediated injury: Elevated cytokines and neutrophil-derived myeloperoxidase (MPO) correlate with impaired cardiac function, reduced cardiac output, and decreased stroke volume in severe cases. Oxidative stress and leukocyte infiltration: These processes contribute to myocardial inflammation and tissue damage. Autonomic and metabolic disturbances: Altered autonomic tone, abnormalities in electrolyte and calcium homeostasis, and immune-mediated mechanisms further exacerbate myocardial dysfunction. Collectively, these mechanisms may lead to arrhythmias (including bradyarrhythmias, tachyarrhythmias, and nonspecific ST-T changes), reduced myocardial contractility, and hemodynamic compromise.[15][16][17][18] Neurologic involvement is uncommon but well recognized in severe dengue and includes encephalopathy and encephalitis.[3][6] Neurologic injury is thought to occur through several overlapping mechanisms, including: Direct neurotropism: DENV can infect glial and endothelial cells in the central nervous system, as evidenced by the detection of viral antigens in fatal cases.[18] Immune-mediated injury: Excessive cytokine production (eg, IL-2, IFN-γ, TNF-α) and complement activation promote endothelial dysfunction, increased vascular permeability, and perivascular inflammation.[18][13]

Direct neurotropism: DENV can infect glial and endothelial cells in the central nervous system, as evidenced by the detection of viral antigens in fatal cases.[18] Immune-mediated injury: Excessive cytokine production (eg, IL-2, IFN-γ, TNF-α) and complement activation promote endothelial dysfunction, increased vascular permeability, and perivascular inflammation.[18][13] Vascular and coagulopathic complications: Thrombocytopenia, coagulopathy, and vasculitis may result in cerebral hemorrhage, infarction, or ischemic stroke.[13][19] Histopathological findings: These findings include neuronal damage (chromatolysis, pyknotic nuclei), microglial hyperplasia, demyelination, vasogenic edema, vascular congestion, and occasional meningitis or hemorrhage.[18] Immune signaling dysregulation: Altered interferon responses and upregulation of interferon regulatory factor-2 (IRF2) may further modulate central nervous system injury.[18] Systemic contributors: Hypotension, shock, and metabolic derangements can precipitate encephalopathy and secondary brain injury.[13][19]

Clinical History Patients with DENV infection typically present after an incubation period of 4 to 10 days following the bite of an infected Aedes mosquito.[2][5][20] A careful epidemiologic history is essential and should include recent travel to or residence in endemic or outbreak regions, exposure to mosquito-prone environments, and local dengue activity.[3][5] The illness characteristically begins with the abrupt onset of high-grade fever (≥101.3 °F [38.5 °C]), often accompanied by severe headache, retro-orbital pain, marked myalgia, arthralgia, fatigue, and anorexia.[3][5] Gastrointestinal symptoms (eg, nausea, vomiting, anorexia, abdominal pain, diarrhea) are common and may predominate, especially in children and in patients who later develop severe disease.[2][3][21] A transient macular or maculopapular rash typically appears 2 to 6 days after fever onset or during early convalescence and may be pruritic.[3][5] Minor mucocutaneous bleeding manifestations, eg, petechiae, easy bruising, epistaxis, or gingival bleeding, may be reported, whereas major hemorrhage is uncommon in uncomplicated dengue.[2][3][21] A biphasic (“saddleback”) fever pattern has been described in a minority of cases and should raise clinical suspicion in endemic settings.[5] As the disease progresses, some patients—particularly those with secondary heterologous infection, comorbidities, extremes of age, or elevated body mass index—develop warning signs that herald progression to severe dengue.[2][7][21] These include persistent vomiting, severe or worsening abdominal pain, lethargy or restlessness, mucosal bleeding, an increase in hematocrit (due to hemoconcentration), and clinical evidence of fluid accumulation.[3][21] Importantly, this transition often occurs around the time of defervescence (days 4–6 of illness), when patients may appear to be clinically improving despite ongoing plasma leakage.[3][21] Physical Examination Physical findings in dengue vary by disease phase and severity. During the febrile phase, patients often appear acutely ill with high fever, facial flushing, and generalized malaise.[3][5] Common examination findings include conjunctival injection, pharyngeal erythema, lymphadenopathy, and diffuse muscle and joint tenderness.[3][5]

Physical findings in dengue vary by disease phase and severity. During the febrile phase, patients often appear acutely ill with high fever, facial flushing, and generalized malaise.[3][5] Common examination findings include conjunctival injection, pharyngeal erythema, lymphadenopathy, and diffuse muscle and joint tenderness.[3][5] Cutaneous findings range from diffuse erythema to macular, maculopapular, or petechial rashes, which may involve the face, trunk, and extremities.[3][5] Petechiae, particularly at venipuncture sites, and ecchymoses may be observed. The tourniquet test, which assesses capillary fragility, may be positive and supports the diagnosis in appropriate clinical and epidemiologic contexts, although diagnostic accuracy is limited.[3][5] Between days 3 and 7 of illness, careful examination for signs of plasma leakage and evolving shock is critical. Hepatomegaly, often tender, may be present and is a recognized warning sign.[3][21] Progressive tachycardia, narrowing pulse pressure, delayed capillary refill, cool extremities, and postural hypotension may indicate early circulatory compromise despite preserved systolic blood pressure.[2][5] Respiratory examination may reveal decreased breath sounds or basal crackles due to pleural effusions, while abdominal examination may demonstrate ascites.[3][21] In severe dengue, physical findings reflect hypovolemic shock, significant bleeding, or organ dysfunction. Patients may exhibit hypotension, altered mental status, oliguria, respiratory distress, or overt hemorrhage.[2][3][21] Neurologic abnormalities, eg, confusion, seizures, or impaired consciousness, and cardiac findings are uncommon but recognized manifestations of severe disease.[2][5] During the recovery phase, fever resolves, hemodynamic status stabilizes, and reabsorption of extravascular fluid occurs. A characteristic convalescent rash—a confluent erythematous eruption with islands of spared skin—may appear and is often pruritic.[5] Persistent fatigue may last for several weeks, particularly in adults.[3][5] This clinical assessment framework, integrating history, epidemiologic risk, and phase-specific physical findings, is essential for early diagnosis, risk stratification, and timely supportive management, all of which remain cornerstones in reducing dengue-related morbidity and mortality.[3][21]

Evaluation of suspected dengue integrates clinical and epidemiologic likelihood, phase-specific risk stratification using warning signs and basic laboratory trends, and confirmatory virologic or serologic testing when available.[3][22][23] Because early manifestations overlap with those of other acute febrile illnesses (eg, malaria, chikungunya, Zika), the diagnostic approach should proceed in parallel with assessment for alternative or co-circulating pathogens, informed by geography, season, and exposure history.[4][24] Clinical Diagnosis and Severity Classification In endemic or outbreak settings, a presumptive diagnosis can be made for a patient with compatible exposure, fever, and supportive features, eg, nausea and vomiting, rash, headache or eye pain, myalgia or arthralgia, leukopenia, or a positive tourniquet test.[4][23] Disease severity should be classified using the WHO 2009 scheme (dengue without warning signs, dengue with warning signs, and severe dengue) to guide the intensity of monitoring and disposition.[23] Warning signs include abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation (ascites or pleural effusion), mucosal bleeding, lethargy or restlessness, hepatomegaly, and an increase in hematocrit concurrent with a rapid decrease in platelet count.[3][23] Severe dengue is defined by severe plasma leakage leading to shock or respiratory distress, severe bleeding, or severe organ involvement (eg, AST/ALT ≥1000 units/L, impaired consciousness, or organ failure).[7][23] Baseline Laboratory Evaluation

Warning signs include abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation (ascites or pleural effusion), mucosal bleeding, lethargy or restlessness, hepatomegaly, and an increase in hematocrit concurrent with a rapid decrease in platelet count.[3][23] Severe dengue is defined by severe plasma leakage leading to shock or respiratory distress, severe bleeding, or severe organ involvement (eg, AST/ALT ≥1000 units/L, impaired consciousness, or organ failure).[7][23] Baseline Laboratory Evaluation Initial evaluation should include a complete blood count with platelet count and hematocrit to support diagnosis (eg, leukopenia, thrombocytopenia) and to establish a baseline for trend-based detection of plasma leakage during the critical phase.[20][3] Serial hematocrit and platelet monitoring is central to risk stratification, since rising hematocrit with a falling platelet count is a key warning pattern that may precede shock.[3][23] A comprehensive metabolic panel, including hepatic aminotransferases, should be obtained, given the frequency of hepatic involvement and the role of markedly elevated AST/ALT in defining severe organ involvement.[7][23] Coagulation studies may be considered in patients with bleeding, severe disease, or planned procedures, recognizing that transient aPTT prolongation and reduced fibrinogen can occur during the critical phase.[5] Virologic and Serologic Confirmation Laboratory confirmation can be performed by direct detection of viral components in serum or by serology, and test performance depends strongly on the day of illness at presentation.[24][25] During the first week of illness, diagnosis may be established by RT-PCR (typically positive during the first 5 days) or by NS1 antigen testing (typically positive during the first 4 to 7 days).[25] NS1 sensitivity in primary infection may exceed 90%, and antigenemia can persist for several days after fever resolution, whereas NS1 sensitivity is lower in secondary infection (approximately 60% to 80%).[25]

Laboratory confirmation can be performed by direct detection of viral components in serum or by serology, and test performance depends strongly on the day of illness at presentation.[24][25] During the first week of illness, diagnosis may be established by RT-PCR (typically positive during the first 5 days) or by NS1 antigen testing (typically positive during the first 4 to 7 days).[25] NS1 sensitivity in primary infection may exceed 90%, and antigenemia can persist for several days after fever resolution, whereas NS1 sensitivity is lower in secondary infection (approximately 60% to 80%).[25] Dengue IgM can be detected as early as day 4 after symptom onset and is widely used to establish a presumptive diagnosis when obtained in the context of a compatible clinical syndrome.[25] Confirmation may be achieved by IgM seroconversion between paired acute and convalescent specimens (with the convalescent sample obtained about 10 to 14 days after the acute phase) or by a 4-fold or greater rise in antibody titer.[25] IgG kinetics differ by immune status: primary infection typically shows later, lower-titer IgG beginning around day 7, whereas secondary infection can produce a rapid rise beginning around days 3 to 4 with broader cross-reactivity.[25] Serologic interpretation is limited by cross-reactivity with other flaviviruses and may be unreliable after recent dengue vaccination or recent infection/vaccination with related flaviviruses (eg, yellow fever, Japanese encephalitis, or Zika), so results must be contextualized with exposure risk and clinical course.[24][25] Imaging for Plasma Leakage and Complications Imaging is not routinely required in uncomplicated dengue but is useful when warning signs are present or when plasma leakage is suspected.[3][23] Ultrasonography of the chest and abdomen, along with chest radiography, can detect pleural effusion and ascites, particularly around defervescence, and ultrasound may identify leakage as early as day 3 after fever onset.[5] Pleural effusions may be observed more commonly than ascites, and gallbladder wall thickening can also be evident and may support evolving plasma leakage in the appropriate clinical context.[5] Bedside Testing and Practical Considerations

Imaging is not routinely required in uncomplicated dengue but is useful when warning signs are present or when plasma leakage is suspected.[3][23] Ultrasonography of the chest and abdomen, along with chest radiography, can detect pleural effusion and ascites, particularly around defervescence, and ultrasound may identify leakage as early as day 3 after fever onset.[5] Pleural effusions may be observed more commonly than ascites, and gallbladder wall thickening can also be evident and may support evolving plasma leakage in the appropriate clinical context.[5] Bedside Testing and Practical Considerations The tourniquet test can support a presumptive diagnosis and reflects capillary fragility; a commonly used criterion for positivity is 10 petechiae or more per 2.5 cm (1 inch) square after maintaining cuff pressure midway between systolic and diastolic pressures for 5 minutes.[26] However, the tourniquet test may be negative or only mildly positive during profound shock and can become more positive after recovery, so this test should not be used as a stand-alone determinant of severity.[26] In many settings, confirmatory test results are not available soon enough to guide initial management, reinforcing the importance of clinical classification and trend-based monitoring during the critical phase.[3][25]

Management of dengue is guided by the WHO 2009 severity classification (dengue without warning signs, dengue with warning signs, and severe dengue) and by recognition of the triphasic clinical course (febrile, critical/plasma-leakage, and recovery phases).[2][27] Because no direct antiviral therapy is currently available, treatment is fundamentally supportive and centers on early risk stratification, close monitoring, and maintenance of adequate intravascular volume, especially during the critical phase around defervescence, when rapid clinical deterioration can occur.[2][10][28][29] Initial Triage and Site-of-Care Decisions Disposition should be individualized based on severity classification, presence of warning signs, comorbidities or high-risk host factors, and the reliability of follow-up and social supports.[2][27][29][30] Inpatient and outpatient care recommendations include the following: Outpatient management is appropriate for patients without warning signs and without high-risk coexisting conditions who can maintain oral intake, have preserved urine output, and can return for daily reassessment during the high-risk interval (typically from approximately illness day 3 through the end of the critical phase).[5][29] Inpatient management is indicated for patients with warning signs, severe dengue, or relevant coexisting conditions (eg, pregnancy, infancy, older age, diabetes, renal failure, obesity, underlying hemolytic disorders, or poor social situation), given the potential for sudden onset of clinically significant plasma leakage and shock.[2][27][29][30] Outpatient Management of Dengue Without Warning Signs Most patients with uncomplicated dengue can be managed with supportive care at home, emphasizing adequate oral hydration, antipyresis, and clear return precautions.[10][29] Fever and myalgias should be treated with acetaminophen, while aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided because of effects on platelet function and increased bleeding risk (and the potential risk of Reye syndrome in children).[31]

Most patients with uncomplicated dengue can be managed with supportive care at home, emphasizing adequate oral hydration, antipyresis, and clear return precautions.[10][29] Fever and myalgias should be treated with acetaminophen, while aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided because of effects on platelet function and increased bleeding risk (and the potential risk of Reye syndrome in children).[31] Patients should be counseled that clinical worsening often occurs near defervescence and instructed to seek urgent care for warning signs, as well as for signs of dehydration or evolving shock.[2][10][29][30] Daily clinical reassessment and serial basic laboratory monitoring (particularly hematocrit and platelet trends) are recommended during the period of greatest risk, since a rising hematocrit with a rapid decline in platelets may signal plasma leakage and impending deterioration, even when fever is improving.[5][10][28][29] Patients in endemic settings should also receive counseling to reduce onward transmission.[29] Inpatient Management Monitoring and supportive care Hospitalized patients require frequent reassessment of hemodynamics and perfusion, strict intake and output documentation, and serial laboratory monitoring, with particular attention to urine output and dynamic hematocrit trends to guide fluid therapy and detect occult bleeding.[2][5][10][29] Management should be titrated to the illness phase; intravenous fluids should be reduced and discontinued once the plasma-leakage period resolves and the patient enters the reabsorption phase, because ongoing fluid administration after capillary permeability normalizes can precipitate hypervolemia and pulmonary edema.[5][10][29] Fluid therapy for plasma leakage and prevention of shock

Hospitalized patients require frequent reassessment of hemodynamics and perfusion, strict intake and output documentation, and serial laboratory monitoring, with particular attention to urine output and dynamic hematocrit trends to guide fluid therapy and detect occult bleeding.[2][5][10][29] Management should be titrated to the illness phase; intravenous fluids should be reduced and discontinued once the plasma-leakage period resolves and the patient enters the reabsorption phase, because ongoing fluid administration after capillary permeability normalizes can precipitate hypervolemia and pulmonary edema.[5][10][29] Fluid therapy for plasma leakage and prevention of shock The cornerstone of dengue management is judicious fluid therapy to maintain effective circulating volume without causing iatrogenic fluid overload.[10][28][29] In mild leakage identified early, oral rehydration may be sufficient; intravenous isotonic crystalloid is warranted when there is established intravascular volume depletion or inability to maintain oral intake.[10][29] Isotonic crystalloids, eg, normal saline or Ringer’s lactate, are preferred, and hypotonic fluids should be avoided due to risks, eg, hyponatremia and potentially worsening plasma leakage physiology.[10] Hematocrit must be interpreted in a clinical context, recognizing the confounding effects of dehydration (which may elevate hematocrit) and hemorrhage (which may lower hematocrit).[29] Management of dengue shock Shock and impending shock require rapid recognition and protocolized resuscitation with frequent bedside reassessment to balance underresuscitation (persistent hypoperfusion) against overresuscitation (fluid overload).[10][29] Initial resuscitation with crystalloid is appropriate, and randomized data do not demonstrate a clinical advantage of colloids over crystalloids for routine initial management.[29] Colloid solutions may be considered only in refractory shock that does not respond to adequate crystalloid resuscitation.[29] Patients with persistent hypoperfusion and a falling hematocrit should be evaluated for significant bleeding and managed with transfusion rather than further crystalloid escalation alone.[29] Metabolic complications associated with severe shock (eg, acidosis, hypoglycemia, hypocalcemia) should be assessed and corrected when present.[29] Management of bleeding and transfusion strategies

Shock and impending shock require rapid recognition and protocolized resuscitation with frequent bedside reassessment to balance underresuscitation (persistent hypoperfusion) against overresuscitation (fluid overload).[10][29] Initial resuscitation with crystalloid is appropriate, and randomized data do not demonstrate a clinical advantage of colloids over crystalloids for routine initial management.[29] Colloid solutions may be considered only in refractory shock that does not respond to adequate crystalloid resuscitation.[29] Patients with persistent hypoperfusion and a falling hematocrit should be evaluated for significant bleeding and managed with transfusion rather than further crystalloid escalation alone.[29] Metabolic complications associated with severe shock (eg, acidosis, hypoglycemia, hypocalcemia) should be assessed and corrected when present.[29] Management of bleeding and transfusion strategies Clinically significant bleeding (eg, gastrointestinal bleeding, severe epistaxis, or heavy menstrual bleeding) may require blood transfusion, particularly when intravascular hypovolemia is present without an appropriately elevated hematocrit or when clinical response to fluid resuscitation is inadequate.[10][29] Blood products (packed red cells, plasma, platelets) should be reserved for clinically meaningful bleeding or coagulopathy rather than used prophylactically.[2][10] Prophylactic platelet transfusion is not recommended and may increase the risk of fluid overload; platelet transfusion has not reliably prevented or controlled hemorrhage in dengue and is generally reserved for severe thrombocytopenia with active bleeding in selected cases.[2][5][10][29] In patients with severe liver dysfunction and/or prolonged prothrombin time, vitamin K may be considered as part of supportive management while addressing the underlying critical illness physiology.[29] Organ dysfunction, expanded dengue syndrome, and critical care

Clinically significant bleeding (eg, gastrointestinal bleeding, severe epistaxis, or heavy menstrual bleeding) may require blood transfusion, particularly when intravascular hypovolemia is present without an appropriately elevated hematocrit or when clinical response to fluid resuscitation is inadequate.[10][29] Blood products (packed red cells, plasma, platelets) should be reserved for clinically meaningful bleeding or coagulopathy rather than used prophylactically.[2][10] Prophylactic platelet transfusion is not recommended and may increase the risk of fluid overload; platelet transfusion has not reliably prevented or controlled hemorrhage in dengue and is generally reserved for severe thrombocytopenia with active bleeding in selected cases.[2][5][10][29] In patients with severe liver dysfunction and/or prolonged prothrombin time, vitamin K may be considered as part of supportive management while addressing the underlying critical illness physiology.[29] Organ dysfunction, expanded dengue syndrome, and critical care Severe dengue may involve shock, severe bleeding, or severe organ involvement and can require intensive care support, including vasopressors, ventilatory support, renal replacement therapy, and other organ-directed management, alongside dengue-specific supportive principles (meticulous fluid titration and frequent reassessment).[3][5][10][27] Neurologic involvement and other atypical/expanded dengue manifestations are managed supportively (airway protection when indicated, correction of metabolic derangements, and targeted organ support), typically requiring interprofessional input.[2][10][27] Therapies not routinely recommended and investigational approaches Corticosteroids are not routinely recommended for dengue management, and evidence supporting the routine use of immunomodulators, eg, intravenous immunoglobulin, is lacking.[10][32] Several antiviral and host-targeted therapies have been investigated, but randomized trials have not demonstrated consistent clinical benefit, and no agent is currently recommended for standard clinical use.[10][32] Discharge considerations and follow-up

Corticosteroids are not routinely recommended for dengue management, and evidence supporting the routine use of immunomodulators, eg, intravenous immunoglobulin, is lacking.[10][32] Several antiviral and host-targeted therapies have been investigated, but randomized trials have not demonstrated consistent clinical benefit, and no agent is currently recommended for standard clinical use.[10][32] Discharge considerations and follow-up Patients may be considered for discharge when they are clinically well and beyond the critical period, with stable hemodynamics, adequate oral intake, normalizing urine output, and reassuring laboratory trends; guidance commonly includes being afebrile for at least 24 hours and having a stable hematocrit without ongoing intravenous fluid requirements.[29] Postdischarge counseling should reinforce hydration, avoidance of NSAIDs and aspirin until recovery is complete, and return precautions for delayed bleeding or recurrent symptoms.[31]

The differential diagnosis of dengue is broad and varies with the phase of illness, exposure history, and local epidemiology, particularly in areas where multiple acute febrile illnesses and arboviruses circulate concurrently.[2][33] Due to substantial overlap in early clinical features, confirmatory microbiologic testing (molecular, antigen-based, and/or serologic, depending on day of illness and regional availability) is often required to establish a definitive diagnosis and to identify clinically important alternative pathogens.[33][34] Arboviral Infections (often clinically indistinguishable early) Dengue disease risk commonly overlaps with other arboviral infections, which are often clinically indistinguishable early in the clinical course, particularly chikungunya and Zika. Other flaviviruses, eg, West Nile virus, may also present with fever, rash, and arthralgia and may circulate in the same geographic regions and seasons.[2][5][24][33][35] In comparative studies, arthralgia is reported more frequently with chikungunya, while abdominal pain and leukopenia are more common with dengue; joint swelling is highly specific for chikungunya, whereas bleeding manifestations and thrombocytopenia are relatively more specific for dengue.[36][37][38] Zika virus infection can present similarly to dengue but is more commonly associated with conjunctivitis, and coinfection with dengue, chikungunya, and Zika has been described in endemic regions.[33][39][40][41] In the Americas, Oropouche virus infection is an additional arboviral consideration because it can cause an abrupt onset of fever with severe headache, chills, myalgias, and arthralgias, and the distinction from dengue relies on microbiologic testing.[33] Other Viral Infections Several viral illnesses may mimic dengue, particularly those presenting with undifferentiated febrile illness and rash, including measles, rubella, influenza, adenovirus, enterovirus, Epstein–Barr virus infection, and acute HIV seroconversion.[2][5][10] Acute HIV infection may present with fever, rash, lymphadenopathy, sore throat, myalgias/arthralgias, and headache, and is distinguished by appropriate HIV immunoassay (preferably combination antigen/antibody testing) with confirmatory virologic testing when indicated.

Several viral illnesses may mimic dengue, particularly those presenting with undifferentiated febrile illness and rash, including measles, rubella, influenza, adenovirus, enterovirus, Epstein–Barr virus infection, and acute HIV seroconversion.[2][5][10] Acute HIV infection may present with fever, rash, lymphadenopathy, sore throat, myalgias/arthralgias, and headache, and is distinguished by appropriate HIV immunoassay (preferably combination antigen/antibody testing) with confirmatory virologic testing when indicated. Viral hepatitis (A through E) can enter the differential when prominent hepatic manifestations accompany systemic symptoms, and diagnosis is established using pathogen-specific serology and PCR-based testing as appropriate. In contemporary practice, COVID-19 and seasonal influenza should be considered based on circulating community transmission and respiratory features, with confirmation by molecular testing. Bacterial Infections Leptospirosis, typhoid (enteric) fever, rickettsial infections, and bacterial sepsis can mimic dengue, presenting with fever and systemic symptoms that may include myalgias, gastrointestinal complaints, and (less commonly) rash or hemorrhagic manifestations.[2][5][10][33][42][43] Leptospirosis classically features fever, rigors, myalgia, conjunctival suffusion, and headache, and is typically diagnosed by serology (and other regionally available microbiologic methods).[33] Typhoid fever may include fever, abdominal pain, rash, and, in some cases, characteristic relative bradycardia, and is diagnosed by blood or stool cultures.[33] Rickettsial infections may present with fever, headache, myalgia, rash, and—in some syndromes—eschar and regional lymphadenopathy, and are distinguished via appropriate epidemiologic exposure assessment and targeted testing (often serology and PCR, depending on syndrome and availability). Sepsis due to bacteremia may present with fever, tachycardia, and altered mental status and requires prompt evaluation, including blood cultures and early supportive management. Parasitic Infections

Typhoid fever may include fever, abdominal pain, rash, and, in some cases, characteristic relative bradycardia, and is diagnosed by blood or stool cultures.[33] Rickettsial infections may present with fever, headache, myalgia, rash, and—in some syndromes—eschar and regional lymphadenopathy, and are distinguished via appropriate epidemiologic exposure assessment and targeted testing (often serology and PCR, depending on syndrome and availability). Sepsis due to bacteremia may present with fever, tachycardia, and altered mental status and requires prompt evaluation, including blood cultures and early supportive management. Parasitic Infections Malaria is a critical alternative diagnosis in endemic areas and in travelers with compatible exposure, as it can present with fever, malaise, gastrointestinal symptoms, myalgias, and systemic illness that overlaps clinically with dengue.[2][5][10][33][44] Diagnosis is established by rapid antigen testing or identification of parasites on peripheral blood smear.[33] Viral Hemorrhagic Fevers and Other High-Consequence Infections In patients with hemorrhagic manifestations and severe systemic illness, especially with relevant exposure risks, other viral hemorrhagic fevers must be considered (eg, Ebola, Marburg, Lassa, yellow fever, Crimean-Congo hemorrhagic fever, hantavirus hemorrhagic fever with renal syndrome, and severe fever with thrombocytopenia syndrome virus).[5][10][33][43] These entities may require specific infection-prevention and control measures and are distinguished by exposure history and by confirmatory PCR or serologic testing.[33] Neurologic Presentations When neurologic manifestations occur, alternative diagnoses include Japanese encephalitis, West Nile virus infection, herpes simplex virus infection, malaria, tuberculosis, and rickettsial infections, with evaluation guided by epidemiology and targeted neurodiagnostic testing.[13] Practical Distinguishing Clues Certain clinical and laboratory patterns can support a diagnosis of dengue over alternative febrile illnesses, eg,  leukopenia, thrombocytopenia, elevated transaminases, and relatively low C-reactive protein, but overlap remains substantial, and laboratory confirmation is recommended whenever feasible.[34][45][46]

Despite a substantial global disease burden, no specific therapeutic agent has demonstrated definitive clinical benefit for dengue, and management remains primarily supportive while investigational strategies continue to evolve.[2] Current clinical research includes randomized controlled trials and early-phase studies investigating antivirals, immunomodulatory strategies, and monoclonal antibodies aimed at reducing viral replication or attenuating downstream inflammatory and endothelial dysfunction.[2] A multicenter randomized controlled trial evaluated montelukast for the prevention of progression to dengue with warning signs and found that oral montelukast did not reduce the incidence of warning signs among patients with dengue. However, a reduction in transaminase elevations was observed, warranting further investigation to clarify the potential hepatoprotective effects of montelukast.[2][47] Among antiviral candidates, JNJ-1802 (mosnodenvir) is an orally administered small molecule designed to inhibit dengue replication by blocking the NS3–NS4B protein interaction, with reported pan-serotype activity in vitro and in animal models and a high barrier to resistance.[48] In a phase 1 study of healthy volunteers, JNJ-1802 was safe and well-tolerated.[48] A controlled human infection model further supported prophylactic efficacy, demonstrating a reduction in viremia and clinical symptoms after dengue challenge.[49] Based on these early data, JNJ-1802 was progressing in clinical studies for both prevention and treatment of dengue.[48] In 2024, a reprioritization within the sponsor led to the discontinuation of further trials and development.[Johnson & Johnson. Johnson & Johnson to Discontinue Phase 2 Field Study Evaluating Investigational Antiviral for the Prevention of Dengue. 2024]

Among antiviral candidates, JNJ-1802 (mosnodenvir) is an orally administered small molecule designed to inhibit dengue replication by blocking the NS3–NS4B protein interaction, with reported pan-serotype activity in vitro and in animal models and a high barrier to resistance.[48] In a phase 1 study of healthy volunteers, JNJ-1802 was safe and well-tolerated.[48] A controlled human infection model further supported prophylactic efficacy, demonstrating a reduction in viremia and clinical symptoms after dengue challenge.[49] Based on these early data, JNJ-1802 was progressing in clinical studies for both prevention and treatment of dengue.[48] In 2024, a reprioritization within the sponsor led to the discontinuation of further trials and development.[Johnson & Johnson. Johnson & Johnson to Discontinue Phase 2 Field Study Evaluating Investigational Antiviral for the Prevention of Dengue. 2024] Passive immunotherapy is also an area of active development.[2] VIS513 is a recombinant humanized monoclonal antibody targeting a conserved epitope on domain III of the dengue envelope protein and is reported to neutralize all 4 dengue serotypes.[50] In a phase 1 trial in healthy adults, VIS513 was safe and well-tolerated, with no serious adverse events or anti-drug antibody responses, and demonstrated dose-proportional pharmacokinetics and a long half-life, which may support both prophylactic and therapeutic use.[50] Preclinical and early clinical assessments described to date have not demonstrated evidence of antibody-dependent enhancement with VIS513, and phase 2 studies in dengue patients are planned.[50] Additional agents remain in earlier stages of development with promising preclinical signals but limited human efficacy data.[51][2] Preclinical and early-phase clinical studies have also investigated small molecules, eg, JNJ-A07, that inhibit dengue replication.[50][51] Other candidates, including DV-B-120, are likewise at relatively early stages of development.[51]

Additional agents remain in earlier stages of development with promising preclinical signals but limited human efficacy data.[51][2] Preclinical and early-phase clinical studies have also investigated small molecules, eg, JNJ-A07, that inhibit dengue replication.[50][51] Other candidates, including DV-B-120, are likewise at relatively early stages of development.[51] Adjunctive and immunomodulatory approaches have been assessed across heterogeneous, generally small clinical studies.[52] Systematic reviews have summarized trials of agents, eg, doxycycline, Carica papaya extract, and platelet-enhancing strategies (eg, recombinant human IL-11, anti-rhD immunoglobulin, eltrombopag), but small sample sizes and study heterogeneity limit the available evidence.[52] Immunomodulatory agents, eg, rupatadine, have shown signals of increased platelet counts in some studies, although robust efficacy data remain insufficient to support routine use.[52] Preventive research continues in parallel, including licensed vaccines and next-generation platforms.[50][53][54][55] Vaccine development includes licensed vaccines (Dengvaxia and Qdenga) as well as additional candidates, including mRNA-based approaches, with efficacy reported to vary by serotype and be influenced by prior exposure.[50][53][54][55] Overall, the therapeutic pipeline reflects sustained effort across antivirals, immunotherapies, and vaccines, but current evidence does not yet support a definitive disease-modifying pharmacologic therapy for routine clinical care.[2][48][50]

The prognosis of dengue is generally favorable because most infections are asymptomatic or self-limited and resolve without sequelae.[2] Approximately 60% to 80% of DENV infections are asymptomatic or subclinical, and among symptomatic cases, more than 90% follow a mild course with full recovery with supportive management.[2][28] The clinical course typically progresses through febrile, critical, and recovery phases, with most patients improving after the febrile phase and entering convalescence without complications.[2] A minority of symptomatic patients progress to severe dengue, estimated at approximately 2% to 5%.[2][28] Risk of progression is influenced by host and viral factors, including age, comorbidities, secondary infection, and serotype, with DENV serotype 2 associated with a higher risk in some populations (particularly children).[2][28][56][57] Extremes of age (children and older adults) are associated with a higher risk of severe disease and adverse outcomes.[58][59] Comorbidities, including diabetes, hypertension, renal disease, cardiovascular disease, and related chronic conditions, are consistently associated with increased odds of severe dengue and warrant closer monitoring.[28][56][57] Mortality is uncommon in uncomplicated disease but increases substantially in severe dengue, where the principal causes of death include shock, severe hemorrhage, and organ failure.[2][59] The median case fatality rate for dengue has been estimated at approximately 5%, but with timely recognition and appropriate supportive management—particularly careful fluid resuscitation during the critical phase—mortality can be reduced to below 1% in well-resourced settings.[2][20][28]

Mortality is uncommon in uncomplicated disease but increases substantially in severe dengue, where the principal causes of death include shock, severe hemorrhage, and organ failure.[2][59] The median case fatality rate for dengue has been estimated at approximately 5%, but with timely recognition and appropriate supportive management—particularly careful fluid resuscitation during the critical phase—mortality can be reduced to below 1% in well-resourced settings.[2][20][28] Early identification of patients at risk for progression is central to improving outcomes.[2][28][59] Laboratory abnormalities associated with increased risk include thrombocytopenia, low serum albumin, and elevated aminotransferases.[2][30] In children, serum albumin less than 35 g/L, mucosal bleeding, and a hematocrit change of 10% or greater within the first 5 days have been identified as strong predictors of severe dengue and warrant heightened surveillance.[60] Emerging biomarkers reflecting inflammation and endothelial activation (eg, elevated C-reactive protein, syndecan-1, and vascular cell adhesion protein 1) have shown predictive value in some studies, although routine application varies by setting.[61] Long-term sequelae are uncommon; however, adults may experience prolonged postviral fatigue and depressive symptoms for weeks to months after apparent clinical recovery.[2]

Complications of dengue occur most commonly during the critical phase and reflect the pathophysiologic consequences of increased capillary permeability, hemostatic derangements, and end-organ dysfunction.[2][5] The most clinically important complications are severe plasma leakage leading to hypovolemic shock (dengue shock syndrome), clinically significant bleeding (eg, gastrointestinal, mucosal, or vaginal hemorrhage), and severe organ impairment.[2][5] Severe organ involvement may include acute liver failure, myocarditis, encephalitis, and acute kidney injury.[2][5] Consistent with international severity frameworks, the World Health Organization (WHO) classifies severe dengue by the presence of severe plasma leakage (with shock or respiratory distress), severe bleeding, or severe organ involvement, and Advisory Committee on Immunization Practices (ACIP) guidance likewise emphasizes these as major complications that require intensive monitoring and supportive care.[3][5] Respiratory distress can complicate dengue due to clinically significant fluid accumulation, including pleural effusions and ascites, particularly when plasma leakage is substantial.[2][3] Coagulopathy may occur and can contribute to bleeding risk, especially in severe disease.[2][3] Bone marrow suppression has also been described and may exacerbate cytopenias during the acute illness.[2][3] Less commonly, dengue can be complicated by sight-threatening ophthalmic inflammation.[2][3] Neurologic complications are increasingly recognized, particularly in severe dengue, and may include encephalitis and meningitis as well as immune-mediated syndromes, eg, Guillain-Barré syndrome and acute disseminated encephalomyelitis.[13][27] Cardiac involvement has also been reported and may manifest as myocarditis, arrhythmias, or pericardial effusion, with associations to greater overall disease severity.[5][15] Special populations warrant heightened vigilance. In pregnancy, dengue has been associated with increased risk of maternal complications, fetal loss, and neonatal death.[2] Overall, many severe outcomes are potentially preventable with early recognition of clinical deterioration and timely, appropriate supportive management.[2][5]

Optimal management of dengue fever relies on the timely involvement of appropriate medical specialties, particularly in patients with severe disease, atypical presentations, or evolving complications. Infectious disease consultation is recommended to assist with diagnostic confirmation, clinical risk stratification, interpretation of laboratory testing, including virologic and serologic assays, and guidance on evidence-based supportive management, especially in severe, complicated, or diagnostically uncertain cases.[2][5][28] Hematology consultation should be considered in patients with severe thrombocytopenia, clinically significant bleeding, or complex transfusion decisions. This is particularly important given that prophylactic platelet transfusions are not routinely indicated in dengue and should generally be reserved for patients with active bleeding or specific high-risk scenarios. Hematology input can support individualized transfusion strategies and evaluation of coagulopathy in severe disease.[2][5][28] Critical care consultation is essential for patients with severe dengue, including those with shock, significant plasma leakage, respiratory distress, severe bleeding, or organ failure. Intensive care specialists play a key role in advanced hemodynamic monitoring, protocolized fluid resuscitation, vasoactive support, and management of multisystem complications during the critical phase of illness.[3][5] Organ-specific specialist consultation may be required in cases of severe or atypical organ involvement. Neurology consultation is appropriate for patients with neurologic manifestations, eg, encephalopathy, encephalitis, seizures, or other central or peripheral nervous system complications. Cardiology or hepatology consultation may be indicated for patients with suspected myocarditis, significant arrhythmias, or severe hepatic injury, respectively.[3][13]

Critical care consultation is essential for patients with severe dengue, including those with shock, significant plasma leakage, respiratory distress, severe bleeding, or organ failure. Intensive care specialists play a key role in advanced hemodynamic monitoring, protocolized fluid resuscitation, vasoactive support, and management of multisystem complications during the critical phase of illness.[3][5] Organ-specific specialist consultation may be required in cases of severe or atypical organ involvement. Neurology consultation is appropriate for patients with neurologic manifestations, eg, encephalopathy, encephalitis, seizures, or other central or peripheral nervous system complications. Cardiology or hepatology consultation may be indicated for patients with suspected myocarditis, significant arrhythmias, or severe hepatic injury, respectively.[3][13] In complex cases involving multiorgan dysfunction, postoperative status, or renal impairment, additional specialty input (eg, surgery, nephrology) may be warranted on a case-by-case basis. Although formal guidance on the routine involvement of these specialties in dengue management is limited, interprofessional collaboration is often necessary to address complications arising from concurrent conditions or invasive procedures.[3][13] Overall, coordinated interprofessional consultation supports accurate diagnosis, appropriate escalation of care, judicious use of blood products and fluids, and timely management of complications, all of which are central to reducing morbidity and mortality associated with DENV infection.[2][5][28]

Effective deterrence and patient education are central components of dengue prevention and control, addressing both individual risk reduction and broader public health impact. Because no specific prophylactic medication is available for routine use, prevention depends on minimizing exposure to infected Aedes mosquitoes and, when feasible, avoiding travel to areas with active transmission.[2][23][2][66][67] Vector Control Strategies Vector control remains the cornerstone of dengue prevention. Recommended measures focus on eliminating mosquito breeding sites by removing standing water from containers, tires, flower pots, and other domestic or peri-domestic reservoirs, combined with community-based environmental management programs.[2][67][68][69] Household and environmental measures include identifying and eliminating breeding areas, covering stored water in buckets, pots, and other vessels, and maintaining rooftops and sunshades to reduce water accumulation and potential larval habitats.[2][67][68][69] Chemical interventions, including larvicides for large breeding containers and adulticiding (eg, space sprays delivered as thermal fogs or cold aerosols), may be used as adjunctive measures.[2][23][70] However, chemical control is increasingly constrained by widespread insecticide resistance and concerns regarding environmental and ecological harm, necessitating greater emphasis on sustainable, eco-friendly approaches.[2][70] Biological control strategies may include introducing larvivorous fish (eg, Poecilia reticulata and other native larvicidal fish) into confined water bodies, eg, large water tanks or open freshwater wells, and using predatory copepods in specific container habitats to reduce immature mosquito populations.[2][23][2][70] Innovative biotechnological interventions have demonstrated promising results in reducing dengue transmission. Field trials involving the release of Aedes mosquitoes infected with Wolbachia or genetically modified mosquitoes have shown significant reductions in dengue incidence and related hospitalizations in affected communities.[2][69][70][71] These approaches represent important adjuncts to traditional vector control strategies, particularly in hyperendemic urban settings. Personal Protective Measures

Innovative biotechnological interventions have demonstrated promising results in reducing dengue transmission. Field trials involving the release of Aedes mosquitoes infected with Wolbachia or genetically modified mosquitoes have shown significant reductions in dengue incidence and related hospitalizations in affected communities.[2][69][70][71] These approaches represent important adjuncts to traditional vector control strategies, particularly in hyperendemic urban settings. Personal Protective Measures Personal protection against mosquito bites is essential for both the general population and individuals with suspected or confirmed dengue infection. Recommended measures include using Environmental Protection Agency (EPA)-approved insect repellents (eg, DEET), wearing long-sleeved clothing and long pants, and ensuring that windows and doors are screened.[2][10][28][72] Additional bite-prevention strategies include the use of bed nets from daytime onward in settings where indoor biting is likely, insecticide-treated materials (eg, window curtains), and mosquito-repellent coils as supplemental household measures.[28][23][2][72] Use of air conditioning further reduces indoor mosquito exposure.[2] Because Aedes mosquitoes primarily bite during daytime hours, particularly in the early morning and late afternoon, preventive measures should be emphasized during these periods.[10][72] Patients should be counseled that repellents provide time-limited protection; for example, formulations containing approximately 13% DEET may confer only about 1 hour of protection, necessitating frequent reapplication to maintain efficacy.[72] Febrile patients with dengue should be advised to minimize mosquito exposure to reduce onward transmission during the viremic phase, including consistent use of repellents and physical barriers to mosquito contact.[72] Vaccination

Patients should be counseled that repellents provide time-limited protection; for example, formulations containing approximately 13% DEET may confer only about 1 hour of protection, necessitating frequent reapplication to maintain efficacy.[72] Febrile patients with dengue should be advised to minimize mosquito exposure to reduce onward transmission during the viremic phase, including consistent use of repellents and physical barriers to mosquito contact.[72] Vaccination Vaccination represents an important preventive strategy in carefully selected populations. The live-attenuated tetravalent vaccine Dengvaxia (CYD-TDV) is recommended for children aged 9 to 16 years living in endemic areas who have laboratory-confirmed prior dengue infection.[28][53][66][69] This restriction reflects evidence of increased risk of severe dengue associated with antibody-dependent enhancement in seronegative vaccine recipients. Limitations of current vaccination strategies include the need for reliable serostatus confirmation and variable protection across DENV serotypes.[53] Although CYD-TDV has been approved for use in endemic settings in multiple countries, eligibility and programmatic implementation should follow local guidance and serostatus-based criteria to mitigate vaccine-associated risk.[28][53][28][66][69] A second vaccine, Qdenga, is a live-attenuated dengue 2 strain combined with recombinant dengue serotypes 1, 3, and 4 surface envelope proteins. This vaccine has received WHO prequalification and is approved in over 40 countries, not including the United States. Studies have shown 61% effectiveness against symptomatic disease and 84% against hospitalization, with the highest efficacy against dengue serotype 2 and lower for other serotypes; efficacy was demonstrated regardless of prior flavivirus exposure. [73] Additional vaccines and monoclonal antibody–based preventive approaches remain under investigation but are not yet broadly recommended for routine use.[53][74] Patient and Community Education

Vaccination represents an important preventive strategy in carefully selected populations. The live-attenuated tetravalent vaccine Dengvaxia (CYD-TDV) is recommended for children aged 9 to 16 years living in endemic areas who have laboratory-confirmed prior dengue infection.[28][53][66][69] This restriction reflects evidence of increased risk of severe dengue associated with antibody-dependent enhancement in seronegative vaccine recipients. Limitations of current vaccination strategies include the need for reliable serostatus confirmation and variable protection across DENV serotypes.[53] Although CYD-TDV has been approved for use in endemic settings in multiple countries, eligibility and programmatic implementation should follow local guidance and serostatus-based criteria to mitigate vaccine-associated risk.[28][53][28][66][69] A second vaccine, Qdenga, is a live-attenuated dengue 2 strain combined with recombinant dengue serotypes 1, 3, and 4 surface envelope proteins. This vaccine has received WHO prequalification and is approved in over 40 countries, not including the United States. Studies have shown 61% effectiveness against symptomatic disease and 84% against hospitalization, with the highest efficacy against dengue serotype 2 and lower for other serotypes; efficacy was demonstrated regardless of prior flavivirus exposure. [73] Additional vaccines and monoclonal antibody–based preventive approaches remain under investigation but are not yet broadly recommended for routine use.[53][74] Patient and Community Education Patient education is critical to both clinical management and prevention of dengue. Clinicians should counsel patients and families regarding modes of transmission, the importance of preventing mosquito bites, and early recognition of warning signs that may indicate progression to severe disease.[72] Education should emphasize household-level interventions, including source reduction, consistent repellent use, and protection of ill individuals, as these measures reduce both individual risk and community transmission.[67][69][72] Public health messaging may be strengthened through audiovisual and mass awareness campaigns implemented at both individual and population levels to improve knowledge, adherence to source reduction, and sustained engagement in prevention behaviors.[23][67][69]

Patient education is critical to both clinical management and prevention of dengue. Clinicians should counsel patients and families regarding modes of transmission, the importance of preventing mosquito bites, and early recognition of warning signs that may indicate progression to severe disease.[72] Education should emphasize household-level interventions, including source reduction, consistent repellent use, and protection of ill individuals, as these measures reduce both individual risk and community transmission.[67][69][72] Public health messaging may be strengthened through audiovisual and mass awareness campaigns implemented at both individual and population levels to improve knowledge, adherence to source reduction, and sustained engagement in prevention behaviors.[23][67][69] Sustainable dengue prevention requires community engagement and intersectoral collaboration involving healthcare systems, public health authorities, urban planning, education, and environmental sectors.[67][69] Current gaps include suboptimal risk communication, limited vaccine uptake, and insufficient integration of eco-friendly vector control strategies.[53][70][72] Ongoing research into improved vaccines and novel vector control methods continues, but durable reductions in dengue burden will depend on coordinated clinical, public health, and community-based efforts adapted to local epidemiology and resource availability.

Clinical Pearls in Context: Applying Evidence-Based Principles Through Real-World Clinical Scenarios Clinical improvement may precede deterioration Patients with dengue may appear to improve clinically at the time of defervescence; however, this period often coincides with transition into the critical phase, characterized by increased vascular permeability and plasma leakage. Rising hematocrit, tachycardia, and falling platelet counts during or shortly after fever resolution signal a high-risk window for clinical deterioration, even in the absence of overt symptoms. Classify disease severity before determining disposition Early application of the WHO 2009 dengue severity classification (dengue without warning signs, dengue with warning signs, and severe dengue) allows clinicians to determine the appropriate level of monitoring and disposition without awaiting confirmatory testing. Severity classification combined with serial reassessment is essential for timely escalation of care. Maintain diagnostic breadth in endemic and outbreak settings Early dengue infection shares clinical features with other acute febrile illnesses, including malaria, chikungunya, and Zika virus infection. Diagnostic evaluation should proceed in parallel for co-circulating pathogens based on epidemiologic context, geographic exposure, and seasonality to avoid anchoring bias and delayed treatment of alternative diagnoses. Interpret diagnostic tests in relation to the illness day The diagnostic performance of dengue tests is highly time-dependent. During the early febrile phase (days 1–5), RT-PCR and NS1 antigen assays provide the highest sensitivity. In later stages (≥ day 6), serologic testing (IgM and IgG) becomes more informative but requires cautious interpretation due to flavivirus cross-reactivity and potential vaccine-related confounding. Fluid therapy is phase-dependent and requires frequent reassessment Intravenous fluid resuscitation is lifesaving during the plasma leakage phase but may be harmful if continued beyond physiologic need. Fluids should be initiated promptly in patients with signs of hypovolemia or shock and titrated based on frequent clinical and laboratory reassessment. As capillary permeability normalizes during recovery, intravenous fluids should be reduced or discontinued to prevent fluid overload and pulmonary edema. Hematocrit trends must be interpreted in a clinical context

Intravenous fluid resuscitation is lifesaving during the plasma leakage phase but may be harmful if continued beyond physiologic need. Fluids should be initiated promptly in patients with signs of hypovolemia or shock and titrated based on frequent clinical and laboratory reassessment. As capillary permeability normalizes during recovery, intravenous fluids should be reduced or discontinued to prevent fluid overload and pulmonary edema. Hematocrit trends must be interpreted in a clinical context Rising hematocrit suggests hemoconcentration from plasma leakage, whereas a falling hematocrit in the setting of shock may indicate occult hemorrhage rather than adequate volume resuscitation. Hematocrit trends should always be interpreted alongside hemodynamic status, fluid balance, and bleeding assessment. Avoid nonsteroidal anti-inflammatory drugs Acetaminophen is the preferred antipyretic in suspected or confirmed dengue. Aspirin and nonsteroidal anti-inflammatory drugs should be avoided due to increased bleeding risk, platelet dysfunction, and the risk of Reye's syndrome in pediatric patients. Outpatient management requires both low severity and reliable follow-up Patients without warning signs who are hemodynamically stable, tolerating oral intake, maintaining urine output, and able to return reliably for daily reassessment during days 3 to 6 of illness may be managed as outpatients. Safe outpatient care depends on strict return precautions and planned clinical and laboratory monitoring. Admission is indicated for warning signs or high-risk conditions Patients with dengue who develop warning signs, have significant comorbidities, or belong to high-risk groups (including pregnancy) should be admitted for close monitoring, strict fluid balance, and serial laboratory evaluation to detect plasma leakage, bleeding, or organ dysfunction. Discharge criteria extend beyond symptomatic improvement Hospital discharge should occur only after patients have passed the critical phase, remained afebrile for at least 24 hours, achieved hemodynamic stability without intravenous fluids, demonstrated stable or improving hematocrit, maintained adequate urine output, and tolerated oral intake. Discharge counseling must emphasize delayed bleeding risk, return precautions, and avoidance of NSAIDs until full recovery. Severe thrombocytopenia alone is not an indication for transfusion

Hospital discharge should occur only after patients have passed the critical phase, remained afebrile for at least 24 hours, achieved hemodynamic stability without intravenous fluids, demonstrated stable or improving hematocrit, maintained adequate urine output, and tolerated oral intake. Discharge counseling must emphasize delayed bleeding risk, return precautions, and avoidance of NSAIDs until full recovery. Severe thrombocytopenia alone is not an indication for transfusion Prophylactic platelet transfusion is not recommended in dengue patients without active bleeding or significant coagulopathy, as it does not reliably prevent hemorrhage and may increase the risk of volume overload. Blood products should be reserved for clinically significant bleeding or documented coagulation abnormalities. Warning signs require immediate reassessment and escalation The development of warning signs, eg, worsening abdominal pain, persistent vomiting, clinical fluid accumulation, mucosal bleeding, or lethargy, signals increased risk of progression to severe dengue and mandates reclassification of disease severity and intensified monitoring. Prevention and transmission control are components of clinical care Patients should be counseled on minimizing mosquito exposure during the viremic phase through the use of repellents, bed nets where feasible, and environmental measures to reduce standing water. Education on warning signs and the timing of potential deterioration is essential to prevent severe outcomes. Postoperative dengue carries an increased risk Dengue occurring in the postoperative setting poses heightened risks of bleeding and hemodynamic instability due to thrombocytopenia and capillary leak. These patients require interprofessional coordination, close monitoring throughout the critical phase, and individualized supportive management. Early ICU involvement improves outcomes in severe dengue Patients meeting criteria for severe dengue, eg, shock, respiratory distress due to plasma leakage, severe bleeding, or major organ involvement, benefit from early intensive care unit admission. Timely critical care support facilitates protocolized resuscitation, organ support, and targeted subspecialty consultation.

Dengue fever is a mosquito-borne viral illness caused by the dengue virus, a flavivirus transmitted primarily by Aedes aegypti and Aedes albopictus. The disease follows a phase-evolving clinical course consisting of febrile, critical, and recovery stages. Most infections are mild, but a subset progresses to severe dengue, characterized by plasma leakage, shock, hemorrhage, or organ dysfunction. Pathophysiology involves viral replication within immune cells, immune-mediated endothelial dysfunction, and increased capillary permeability, often intensified during secondary infections through antibody-dependent enhancement. Patients typically present with abrupt high fever, headache, myalgia, arthralgia, gastrointestinal symptoms, rash, leukopenia, and thrombocytopenia.[2][5] Diagnosis relies on epidemiologic risk assessment, clinical criteria, serial laboratory monitoring, and confirmatory testing such as RT-PCR or NS1 antigen detection. Management remains supportive and emphasizes early risk stratification, vigilant monitoring during the critical phase near defervescence, and careful fluid management to prevent shock or fluid overload. Because confirmatory diagnostics are often delayed or variably available, care quality hinges on shared clinical frameworks (eg, WHO 2009 severity classification), standardized monitoring, and team-based execution of phase-appropriate management to prevent shock, bleeding complications, and iatrogenic harm.[5][75] Interprofessional collaboration is essential for optimal dengue care. Physicians and advanced practice providers integrate clinical findings, epidemiologic context, and WHO severity classification to guide diagnosis, disposition, and escalation of care while considering alternative infectious etiologies. Primary care clinicians facilitate early recognition, triage, and follow-up monitoring in outpatient settings. Nurses perform continuous bedside assessment, track vital signs and urine output, and promptly communicate clinical deterioration.[2][75] Pharmacists ensure safe pharmacologic management, reinforce the use of acetaminophen for fever, and prevent harmful exposure to aspirin or NSAIDs. Laboratory professionals support timely diagnostic confirmation and trend analysis of hematologic parameters.

Interprofessional collaboration is essential for optimal dengue care. Physicians and advanced practice providers integrate clinical findings, epidemiologic context, and WHO severity classification to guide diagnosis, disposition, and escalation of care while considering alternative infectious etiologies. Primary care clinicians facilitate early recognition, triage, and follow-up monitoring in outpatient settings. Nurses perform continuous bedside assessment, track vital signs and urine output, and promptly communicate clinical deterioration.[2][75] Pharmacists ensure safe pharmacologic management, reinforce the use of acetaminophen for fever, and prevent harmful exposure to aspirin or NSAIDs. Laboratory professionals support timely diagnostic confirmation and trend analysis of hematologic parameters. High team performance depends on interprofessional communication and structured processes. Interprofessional rounds, standardized handoffs, and clear escalation pathways ensure that subtle changes (eg, narrowing pulse pressure, rising hematocrit with rapid platelet decline, new mucosal bleeding, persistent vomiting, abdominal pain, lethargy/restlessness, or fluid accumulation) prompt timely reassessment and reclassification of severity, rather than delayed recognition.[5] Coordination with radiology can support the detection of plasma leakage (eg, pleural effusion, ascites) when clinically suspected, while early involvement of critical care is essential for severe dengue, defined by shock/respiratory distress from plasma leakage, severe bleeding, or severe organ involvement.[75] Finally, dengue outcomes are improved when clinical care integrates public health collaboration. Public health professionals and vector control specialists reinforce prevention and transmission-reduction counseling—especially during the viremic period—through education on repellents, minimizing mosquito exposure, and environmental measures such as eliminating standing water containers and indoor mosquito breeding sites. Aligning clinic- and community-level messaging with clear education about warning signs and the timing of potential deterioration is a practical prevention strategy to reduce severe outcomes by promoting timely reassessment and early supportive intervention.[2]