Guideline sources The following summarized guidelines for the evaluation and management of dengue are prepared by our editorial team based on guidelines from the World Health Organization (WHO 2023), the Pan American Health Organization (PAHO/WHO 2022), the Center for Disease Control (CDC 2021), the Philippine Pediatric Society (PPS/PIDSP 2017), the European Academy of Neurology (EAN 2017), and the Association of British Neurologists (ABN/BIANG 2012). 1 2 3 4 5 6 7 7 7 8 9 9 Definition Dengue fever is an acute arthropod-borne viral illness caused by an RNA virus of the Flaviviridae family. 7 Epidemiology Dengue fever is caused by the dengue virus of the family Flaviviridae that includes four different serotypes (DEN-1, DEN-2, DEN-3, and DEN-4) and is transmitted through Aedes aegypti mosquito. 7 Pathophysiology https://web.pathway.md/diseases/rec7ykc9vTLUsq4fr 1/8 6/29/23, 10:08 PM Dengue Pathway The average incidence of dengue in the Americas is 58.02 per 100,000 person-years. 8 Disease course The host-viral interaction, viral replication, and/or direct skin infection by the virus trigger humoral, cellular, and innate host immune response that leads to alterations in endothelial microvascular permeability and thromboregulatory mechanisms causing increased plasma and protein loss resulting in thrombocytopenia associated with platelet dysfunction, damage, or depletion causing significant hemorrhages, breakbone fever, multiorgan damage and DIC. 7 Prognosis and risk of recurrence The mortality associated with a lack of early appropriate intervention is around 10-20%. The recurrence rate associated with shock is approximately 30%. 9 9 Guidelines 1. Screening and diagnosis Differential diagnosis (arbovirus infections): Recognize clinical manifestations of different arbovirus infections to help differentiate them: Situation Guidance Findings that help in differentiation - thrombocytopenia, progressive increase in hematocrit, leukopenia Dengue Findings that probably help in differentiation - anorexia or hyporexia, vomiting, abdominal pain, chills, hemorrhages, including bleeding on the skin, mucous membranes, or both Findings that may help in differentiation - retro-ocular pain, hepatomegaly, headache, diarrhea, dysgeusia, cough, elevated transaminases, positive tourniquet test B Findings that help in differentiation - arthralgias Chikungunya Findings that probably help in differentiation - eruption, conjunctivitis, arthritis, myalgias, bone pain Findings that may help in differentiation - hemorrhages, including bleeding on the skin, mucous membranes, or both B Findings that help in differentiation - pruritus Zika https://web.pathway.md/diseases/rec7ykc9vTLUsq4fr 2/8 6/29/23, 10:08 PM Dengue Pathway Findings that probably help in differentiation - eruption, conjunctivitis Findings that may help in differentiation - lymphadenopathies, pharyngitis, odynophagia B Differential diagnosis (COVID-19 infection): Test for dengue fever as appropriate based on the local epidemiology and clinical symptoms in patients with suspected COVID-19. A Include arbovirus infections (including dengue and chikungunya) in the differential diagnosis of undifferentiated febrile illness in endemic areas, particularly in the presence of thrombocytopenia. Test for dengue in patients with a febrile illness in endemic areas, irrespective of the presence of respiratory signs and symptoms. Recognize that coinfection with COVID-19 may also occur, and a positive diagnostic test for dengue (such as dengue rapid diagnostic tests) does not exclude the testing for COVID-19 virus. 2. Classification and risk stratification Severity assessment: Consider assessing for the following warning signs to identify patients with an increased risk of progression to severe disease: Situation Guidance Progressive until it is continuous or sustained and intense, and at the end of the febrile stage Abdominal pain Irritability, drowsiness, and lethargy Sensory disorder Gingivorrhagia, epistaxis, vaginal bleeding not associated with menstruation or more menstrual bleeding than usual, and hematuria Mucosal bleeding Clinical, on imaging, or both, at the end of the febrile stage Fluid accumulation > 2 cm below the costal margin and abrupt onset Hepatomegaly Persistent ( 3 episodes in 1 hour or 4 episodes in 6 hours) Vomiting On at least 2 consecutive measurements during patient monitoring. C Progressive increase in hematocrit 3. Diagnostic investigations https://web.pathway.md/diseases/rec7ykc9vTLUsq4fr 3/8 6/29/23, 10:08 PM Dengue Pathway Evaluation for encephalitis (flavivirus): Obtain acute and convalescent blood samples in patients with suspected arbovirus encephalitis. B Test CSF for IgM antibodies in patients with suspected flavivirus encephalitis. B Evaluation for encephalitis (tick-borne encephalitis virus): obtain virus neutralization test in areas with possible exposure to other pathogenic flaviviruses (including dengue) to assess the specific immunity against tick-borne encephalitis virus. A 4. Medical management Setting of care: Consider using the following criteria for the hospitalization of patients with dengue: presence of warning signs (abdominal pain, sensory disorder, mucosal bleeding, fluid accumulation, hepatomegaly, persistent vomiting, progressive increase in hematocrit) meeting criteria for severe disease, according to the WHO 2009 definition oral intolerance difficulty breathing narrowing pulse pressure arterial hypotension acute renal failure prolonged capillary refill time pregnancy coagulopathy. C Fluid resuscitation: initiate intense oral hydration in patients with dengue to decrease the progression to severe forms and the appearance of disease complications. B Show 2 more Antipyretics: consider offering acetaminophen or metamizole over NSAIDs, antihistamines, or corticosteroids for the initial symptomatic management of patients with arboviral infection. C Corticosteroids: avoid administering systemic corticosteroids in patients with dengue shock. D Intravenous immunoglobulin: avoid administering immunoglobulins in patients with severe dengue. D 5. Therapeutic procedures Blood transfusion: do not administer blood components (platelet concentrate, FFP) in patients with thrombocytopenia, regardless of platelet count. Consider administering blood component transfusion in patients with bleeding or additional conditions predisposing to bleeding (such as pregnancy). D 6. Specific circumstances https://web.pathway.md/diseases/rec7ykc9vTLUsq4fr 4/8 6/29/23, 10:08 PM Dengue Pathway Pediatric patients (indications for hospital admission): Admit patients with a confirmed or presumptive diagnosis of dengue in an outpatient setting to a healthcare facility for closer monitoring and observation in the presence of the following signs and symptoms: shortness of breath irritability or drowsiness pleural effusion abdominal pain melena elevated hematocrit decreased or decreasing platelet count. B Show 2 more Pediatric patients (risk of bleeding): Recognize that hospitalized patients with dengue having 1 of the following clinical or laboratory findings may increase the risk of bleeding: hypotension narrow pulse pressure platelet count < 50, 000/mm WBC count < 5, 000/mm hepatomegaly elevated ALT (> 3 times the ULN). B Show 2 more Pediatric patients (risk of mortality): Recognize that patients with dengue presenting with any of the following clinical findings may be at increased risk for mortality: hypotension on admission narrow pulse pressure on admission dengue hemorrhagic fever stage 3 and 4 (severe dengue) history of previous dengue prolonged shock respiratory failure liver failure (AST > 200 U/L and INR > 1.3) renal failure (BUN > 20 mg/dL and serum creatinine > 1.0 mg/dL) significant bleeding, including gastrointestinal bleeding severe plasma leakage in multiple sites (pleural effusion, pericardial effusion, and ascites). B Show 2 more Pediatric patients (fluid resuscitation): Insufficient evidence regarding the tonicity of IV fluid influencing mortality in patients with dengue without shock. Consider administering isotonic fluids as maintenance for patients with dengue without shock, recognizing that hypotonic IV fluids are associated with hyponatremia in hospitalized pediatric patients. I Consider administering either crystalloids or colloids for fluid resuscitation in patients with dengue with shock. Insufficient evidence to recommend colloids over crystalloids to improve https://web.pathway.md/diseases/rec7ykc9vTLUsq4fr 5/8 6/29/23, 10:08 PM Dengue Pathway mortality, recognizing that colloids may be associated with more adverse reactions (such as bleeding and allergic reactions) compared to crystalloids. B Pediatric patients (blood transfusion): insufficient evidence to recommend administering prophylactic platelet transfusion to prevent bleeding and reduce mortality in patients with minimal or no active bleeding. Do not administer prophylactic platelet transfusion in pediatric patients with platelet count < 50, 000/mm with minimal or no active bleeding. I Show 2 more Pediatric patients (mosquito repellents): insufficient evidence to recommend using citronella-based repellents over DEET-based repellents to reduce dengue transmission. I 7. Preventative measures Vaccination: offer vaccination against dengue (3-dose vaccination series, administered 6 months apart at 0, 6, and 12 months) in 9-16 years old pediatric patients with evidence of previous dengue infection (such as confirmation with previous laboratory-confirmed infection or a highly specific serodiagnostic test) and living in dengue-endemic areas. E Clinical findings Symptoms Social history Abdominal pain Exposure to aedes mosquitoes Arthralgia Living in or travel to subtropical regions Bone pain Living in or travel to tropical regions Change in taste Chills Confusion Vascular exam Drowsiness Cold extremities Fever Narrow pulse pressure Gingival bleeding Headache Ocular exam Hematemesis Hematuria Conjunctival injection Irritability Cotton wool spots Malaise Macular edema Melena Retinal hemorrhage Myalgia Abdominal exam Nausea Nosebleed Abdominal tenderness Restlessness Ascites Retro-orbital pain Hepatomegaly Seizure Skin flushing Integument exam Skin rash Dehydration Throat pain https://web.pathway.md/diseases/rec7ykc9vTLUsq4fr 6/8 6/29/23, 10:08 PM Dengue Pathway Vaginal bleeding Ecchymosis Vomiting Jaundice Maculopapular rash Vital signs Morbilliform rash Mucosal bleeding Hypotension Petechiae Signs of shock Purpura Neurological exam Skin erythema Altered mental status Hematological findings Respiratory exam hematocrit WBC count Respiratory distress blood platelet count Diagnostic maneuvers Imaging findings tourniquet test Pericardial effusion Pleural effusion Lab findings gallbladder wall thickness serum creatinine serum transaminases dengue virus NS1 antigen dengue virus RNA Serological findings dengue virus IgA d i I M Likelihood Ratios Pertinent positives The following findings increase the probability of dengue in adults. 9 10 Finding LR+ Value Positive dengue virus NS1 antigen and IgM 27.5 Positive dengue virus IgA 22 Positive dengue virus NS1 antigen 14.4 Positive dengue virus IgM 8.24 Pertinent negatives The following findings decrease the probability of dengue in adults. 9 10 Finding LR- Value Negative dengue virus NS1 antigen 0.19 Negative dengue virus NS1 antigen or IgM 0.22 Negative dengue virus IgA 0.5 Negative dengue virus IgM 0.79 https://web.pathway.md/diseases/rec7ykc9vTLUsq4fr 7/8 6/29/23, 10:08 PM Dengue Pathway References 1. Jaime Santos, Ma. Liza Antoinette Gonzales, Mary Antonette Madrid et al. Clinical Practice Guidelines on Dengue in Children. PIDSP. 2017. Open 2. Gabriela Paz-Bailey, Laura Adams, Joshua M Wong et al. Dengue Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2021. MMWR Recomm Rep. 2021 Dec 17;70 6 1 16. Open 3. No authors listed. Guidelines for the Clinical Diagnosis and Treatment of Dengue, Chikungunya, and Zika. PAHO. 2022. Open 4. T Solomon, B D Michael, P E Smith et al. Management of suspected viral encephalitis in adults Association of British Neurologists and British Infection Association National Guidelines. J Infect. 2012 Apr;64 4 347 73. Open 5. Taba P, Schmutzhard E, Forsberg P et al. EAN consensus review on prevention, diagnosis and management of tick-borne encephalitis. Eur J Neurol. 2017 Oct;24 10 1214-e61. Open 6. No authors listed. Living guidance for clinical management of COVID 19. WHO living guidance. 2023 Jan 13. Open 7. Hasan S, Jamdar SF, Alalowi M et al. Dengue virus: A global human threat: Review of literature. J Int Soc Prev Community Dent. 2016 Jan-Feb;6 1 1 6. Open 8. Salles TS, da Encarnacao Sa-Guimaraes T, de Alvarenga ESL et al. History, epidemiology and diagnostics of dengue in the American and Brazilian contexts: a review. Parasit Vectors. 2018 Apr 24;11 1 264. Open 9. Huy NT, Thao NT, Ha TT et al. Development of clinical decision rules to predict recurrent shock in dengue. Crit Care. 2013 Dec 2;17 6 R280. Open 10. Viravarn Luvira, Charin Thawornkuno, Saranath Lawpoolsri et al. Diagnostic Performance of Dengue NS1 and Antibodies by Serum Concentration Technique. Trop Med Infect Dis. 2023 Feb 14;8 2 117. Open 11. K Alagarasu, A M Walimbe, S M Jadhav et al. A meta-analysis of the diagnostic accuracy of dengue virus-specific IgA antibody-based tests for detection of dengue infection. Epidemiol Infect. 2016 Mar;144 4 876 86. Open https://web.pathway.md/diseases/rec7ykc9vTLUsq4fr 8/8