DENGUE FEVER CLINICAL MANAGEMENT PROTOCOL Introduction Dengue is the most prevalent mosquito-borne viral disease, with an estimated 50 million infections occurring annually throughout the world. Dengue affects all age groups with a spectrum of clinical presentations from an asymptomatic, mild viral syndrome to severe disease characterized by hemorrhage and shock. Case fatality rates vary from 1% to 5% but can less than 1% if appropriate treatment is instituted. There are four different dengue viruses, DENV-1, DENV-2, DENV-3, and DENV-4, of the genus Flavivirus. There is only transient and weak cross-protection among the four serotypes, so an exposed individual may acquire dengue virus infection up to four times during their lifetime. The risk of severe disease increases with subsequent infection from a different dengue serotype rather than primary dengue infection. Clinical Presentation Classic Dengue Fever Symptoms typically develop between 4 to 10 days after being bitten by an infected mosquito; the incubation period may range between 3 to 14 days. Classic dengue fever is febrile illness accompanied by headache, retro-orbital pain, myalgia (sometimes severe) and athralgia. Fever typically lasts for 5 to 7 days. Affected individuals may display a biphasic/saddleback fever curve, with the second febrile phase lasting 1 to 2 days. Other symptoms include skin rash, gastrointestinal symptoms such as nausea or vomiting and diarrhea, respiratory tract symptoms including cough, sore throat and nasal congestion. Hemorrhagic manifestations due occur and may be life-threatening. The physical examination is generally nonspecific. Conjunctival injection, pharyngeal erythema, lymphadenopathy, hepatomegaly and a macular or maculopapular skin rash may be seen. Laboratory findings typical of dengue fever include the following: Leukopenia Thrombocytopenia Elevated serum aspartate transaminase (AST) levels Dengue hemorrhagic fever Dengue hemorrhagic fever (DHF) is a serious manifestation of dengue virus infection and can be associated with circulatory failure, shock and multi-organ dysfunction. The 4 features of DHF, as defined by the World Health Organization (WHO), include: Increased vascular permeability as evidenced by hemoconcentration, ≥ 20% rise in hematocrit above baseline value, pleural effusion and/ or ascites. Typically described as plasma leakage syndrome. Marked thrombocytopenia (<100,000 cells/mm3). Fever lasting 2 to 7 days. A hemorrhagic tendency as demonstrated by a positive tourniquet test or spontaneous bleeding. Dengue Shock Syndrome (DSS) occurs when shock is present along with these four criteria. Hemorrhagic manifestations — Spontaneous petechiae or ecchymoses are typically seen. Other manifestations include hematemesis, metrorrhagia, melena and epistaxis. Microvascular fragility may be demonstrated by a positive tourniquet test. The test is performed by inflating a blood pressure cuff on the arm, midway between systolic and diastolic blood pressures for 5 minutes. The skin below the cuff is examined for petechiae, and a finding of ≥20 petechiae in a one square inch area is considered positive. Other uncommon syndromes may occur and include: Liver failure Encephalopathy, encephalitis, seizures, acute motor weakness, Reye syndrome, mononeuropathies, polyneuropathies, Guillain-Barré syndrome, and transverse myelitis Myocarditis Classification The World Health Organization (WHO) previously classified symptomatic dengue virus infections into three categories: undifferentiated fever, classic dengue fever, and dengue hemorrhagic fever (DHF). These categories have caused controversy in the past, so the WHO has adopted a revised classification of Dengue and Severe dengue, where Severe dengue is designated to those who demonstrate severe plasma leakage, severe hemorrhage or severe organ impairment (defined as AST or ALT ≥1000, impaired consciousness, or severe involvement of the heart or other organs). The revised classification also further divides Non-severe dengue into Dengue with or without warning signs (abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy or restlessness, liver enlargement >2 cm, or increase in hematocrit concurrent with rapid decrease in platelet count). Suggested Dengue Case Classification and Levels of Severity Adpated from WHO, 2009 Treatment Supportive treatment is available for the specific disease manifestations of dengue virus infection. Decreasing dengue morbidity and mortality requires an organized process of early recognition, management and referral. The majority of patients will recover without hospital admission. It is however important to identify those with risk factors for severe disease and institute treatment measures promptly. Stepwise approach to management of Dengue Step 1 History This should include: Date of onset of fever Quantity of oral intake Nausea, vomiting or diarrhea Assessment for warning signs Change in mental status/seizures Urine output (frequency, volume, time of last voiding) Family or community dengue, travel to dengue endemic areas Co-existing conditions – pregnancy, diabetes mellitus, cardiovascular disease Physical Examination This should include: Assessment of mental status Assessment of hydration status Hemodynamic status Assessing for pleural effusion Assessing for abdominal pain, ascites, hepatomegaly Assessing for rash, bleeding manifestations Tourniquet test Investigations Complete blood count (CBC) Serum electrolytes, urea and creatinine Glucose Liver function test Dengue serology Other test that may be considered include cardiac enzymes, ECG Step 2 Diagnosis, assessment of disease phase and severity The history, physical examination and CBC with hematocrit should assist the clinician in determining the phase of dengue (febrile, critical or recovery), whether there are warning signs and the need for hospital admission. The Course of Dengue Illness Adapted from WHO, 2009 Depending on the clinical manifestations, patients may be sent home, referred for hospital management or referred for emergency management. All cases of suspected, probable and confirmed cases should be notified promptly to the Public Health Department. Ambulatory patients Patients who are sent home should be able to tolerate oral fluids, urinate at least once every six hours, and not have warning signs. Ambulatory patients should be reviewed daily for disease progression (CBC, warning signs and defervescence). Health care providers should document temperature pattern, volume of oral fluid intake, urine output, signs of plasma leakage and bleeding, the hematocrit, WBC and platelet counts. Those with stable signs and CBC may continue to be managed as outpatients. Paracetamol may be used for fever and myalgias. Aspirin, ibuprofen and other nonsteroidal anti-inflammatory agents (NSAIDS) should not be used due to the risk of bleeding complications and aspirin in children has been associated with Reye’s syndrome. Care givers should be instructed to take patient to hospital immediately, if there is deterioration around time of defervescence, persistent vomiting, severe abdominal pain, cold and clammy extremities, lethargy or restlessness, bleeding and oliguria. In-Patient management Patients with warning signs, those with co-existing conditions that may make the management of dengue complicated such as infancy, elderly, pregnancy, diabetes mellitus, hemolytic diseases, and cardiovascular disease should be admitted to hospital. Obtain hematocrit prior to commencing fluid therapy. Give isotonic fluids such as 0.9% normal saline or Ringer’s lactate. Start with 5-7 ml/kg/hour for 1-2 hours, then reduce to 3-5 ml/kg/hour for 2-4 hours and then reduce to 2-3ml/kg/hour. Reassess the clinical status and repeat the hematocrit. If the hematocrit remains the same or minimally increased, continue with the infusion rate at 2-3 ml/kg/hour for 2-4 hours. If vital signs worsen and hematocrit rises, increase rate to 5-10 ml/kg/hr for 1-2 hours. Reassess clinical status along with hematocrit and review intravenous fluid rate accordingly. Maintain urine output ≥ 0.5 ml/kg/hour. Intravenous fluids may be required for 24-48 hours. Emergency treatment Patients require emergency treatment and referral to a critical care centre when they are in the critical phase of disease, that is: Severe plasma leakage leading to shock and/or fluid accumulation with respiratory distress. Severe hemorrhage. Severe organ impairment (liver failure, renal failure, cardiomyopathy, encephalopathy or encephalitis. Treatment of Shock Treatment of hemorrhagic complications Blood transfusion should be given to patients with significant bleeding (gastrointestinal bleeding, metrorrhagia or menorrhagia). Hematocrit measurements should be interpreted cautiously, since it also assesses the adequacy of fluid repletion. Platelet transfusions should be given to patients with severe thrombocytopenia (<10,000/mm3) and active bleeding. Other potential diagnoses It is important to exclude other treatable diseases mimicking Dengue virus infection such as Malaria, Typhoid fever, Influenza and Leptospirosis. References WHO. Dengue: Guidelines for diagnosis, treatment, prevention and control- new edition. World Health Organization, Geneva 2009. Kroeger, A, Nathan, M, Hombach, J. Dengue. Nat Rev Microbiol 2004; 2:360. Teixeira, MG, Barreto, ML. Diagnosis and management of dengue. BMJ 2009; 339:b4338. – MOH, December 2010.