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Dengue Fever 1. ABOUT DENGUE Dengue, the most common arboviral illness transmitted worldwide, is caused by infection with 1 of the 4 serotypes of dengue virus. Dengue is transmitted by the bite of an infected female mosquito (more commonly Aedes aegypti), which are widely distributed in subtropical and tropical areas of the world. Dengue virus infections may be asymptomatic, or may lead to undifferentiated fever, dengue fever (DF) or dengue hemorrhagic fever (DHF) with plasma leakage that may lead to hypovolemic shock (dengue shock syndrome, or DSS). Dengue Fever: Clinical features vary depending on the age of the patient. Infants and young children may have an undifferentiated febrile disease, often with a maculopapular rash. Older children and adults may have either a mild febrile syndrome or the classic incapacitating disease: high fever of abrupt onset, sometimes with 2 peaks (saddle-backed or biphasic pattern), severe headache, retro-orbital pain, muscle and bone or joint pains, nausea and vomiting, and rash. A small percentage of persons who have previously been infected by one dengue serotype develop bleeding and endothelial leak upon infection with another dengue serotype. This syndrome, termed dengue hemorrhagic fever (DHF), is a potentially deadly complication. Dengue Hemorrhagic Fever (DHF) criteria: WHO criteria for DHF (1997) History of recent fever of 2-7 days duration, usually biphasic Hemorrhagic tendencies o (+) tourniquet test o petechiae, ecchymoses, purpura o bleeding from the GIT, injection sites o hematemesis or melena Low platelet count (≤100,000/mm3) Plasma leakage (“leaky capillaries”) as evidenced by: o Rise in hematocrit ≥ 20% With a drop in hematocrit following volume replacement o Decrease in serum albumin, or hypoproteinemia o Pleural or other effusions Philippine Pediatric Society (PPS) criteria for DHF (1998) History of recent fever, 2-7 days duration, regardless of characteristic Hemorrhagic manifestations o (+) tourniquet test, except in shock o mucocutaneous bleeding o G.I. bleeding Evidence of consumptive coagulopathy o Fall in Platelet count o Prolonged bleeding time o Prolonged apt o Prolonged PT Increasing hematocrit in spite of proper hydration Serosal effusions Edema due to hypoprotenemia Grading Severity of DHF: DHF is classified into 4 grades of severity, where grades III and IV are considered to be DSS. The presence of thrombocytopenia with concurrent hemoconcentration differentiates grades I and II DHF from DF. Grade I: Fever accompanied by nonspecific constitutional symptoms; the only hemorrhagic manifestation is a positive tourniquet test and/or easy bruising Grade II: Spontaneous bleeding, in addition to the manifestations of Grade 1 patients, usually in the forms of skin or other hemorrhages Grade III: Circulatory failure manifested by a rapid, weak pulse, and narrowing of pulse pressure or hypotension, with the presence of cold clammy skin and restlessness. Grade IV: Profound shock with undetectable blood pressure or pulse. Dengue Shock Syndrome (DSS): all of the 4 criteria (WHO 1997), plus signs of circulatory failure: 1) narrow pulse pressure ≤ 20 mmHg 2) cold, clammy skin 3) rapid, weak pulse 4) hypotension 2. PATHOPHYSIOLOGY Dengue infection is caused by 1 of 4 related, antigenically distinct, viral serotypes: dengue virus 1 (DENV-1), dengue virus 2 (DENV-2), dengue virus 3 (DENV-3), and dengue virus 4 (DENV-4), which can be distinguished by serological methods. Albert Sabin speciated these in 1944 Dengue viruses are small, spherical, single-stranded enveloped RNA viruses of the family Flaviviridae, genus Flavivirus. Once inoculated into a human host, dengue has an incubation period of 3-14 days (average 2 to 7 days). During this time, viral replication takes place in target dendritic cells, primarily those of the reticuloendothelial system (dendritic cells, hepatocytes, endothelial cells) which results in the production of immune mediators that determine the quantity, type and duration of cellular and humoral immune response to both the initial and subsequent virus infections. The first infection produces life-long immunity to the infecting serotype, but only temporary and partial protection against the 3 other serotypes, and secondary or sequential infections are possible after a short time. Viremia levels directly predict disease severity. Incubation is followed by an acute phase of infection (acute febrile illness) lasting 5-7 days. Recovery is usually complete by 7-10 days. Dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) usually develops around the 3rd to 7th day of illness, approximately at the time of defervescence. DSS occurs with higher frequency in two immunologically defined groups: 1) children who have experienced a previous dengue infection, and 2) infants with waning levels of maternal dengue antibody. Two main pathophysiological changes occur in DHF/DSS: 1) increased vascular permeability that gives rise to loss of plasma from the vascular compartment: This results in hemoconcentration, low pulse pressure, and other signs of shock, if plasma loss becomes critical. 2) The second change is a disorder in hemostasis involving vascular changes, thrombocytopenia and coagulopathy. A constant finding in DHF/DSS is activation of the complement system, with profound depression of C3 and C5 levels. The mediators that increase vascular permeability and the precise mechanism(s) of the bleeding phenomena in dengue infections have not yet been identified; immune complexes have been described in DHF but their role is not yet clear. 1 Platelet defects may be both qualitative and quantitative, i.e. some circulating platelets during the acute phase of DHF may be exhausted or incapable of normal function. Therefore, even a patient with platelet count greater than 100,000 per mm3 may still have prolonged bleeding time. 3. myalgias, headache UTI or Pyelonephritis DIFFERENTIALS Early in the febrile phase, the differential diagnosis for DHF/DSS includes a wide spectrum of viral, bacterial and parasitic infections. By the 3rd or 4th day, laboratory findings may establish a diagnosis before shock occurs. Marked thrombocytopenia with concurrent hemoconcentration differentiates DHF/DSS from diseases such as endotoxin shock from bacterial infection, or meningococcemia. Common differential diagnoses Respiratory infections (e.g. influenza) Is a differential dx because: - acute, nonspecific clinical picture: fever, headache, body malaise, myalgia Measles - appearance of rash - severe prostration or exhaustion Leptospirosis - appearance of maculopapular eruption - presents with myalgia Typhoid fever - appearance of maculopapular rash, usually on trunk - presents with: variable abdominal pain, headache, myalgia, hepatosplenomegaly Meningococcemia - appearance of maculopapular or petechial eruptions - presents with: fever, arthritis, More likely rule out dengue with: - (+) presence of respiratory symptoms (cough, sore throat, nasal discharge) - bacterial pneumonia usually presents with productive cough and chest pain - CBC shows elevated total WBC with neutrophila; diagnosis can be made with CXR - pre-exanthematic phase (cough, nasal discharge, conjunctivitis) does not occur in dengue - rash usually begins in the face, with cephalocaudal progression - Koplik’s spots in the mucous membrane of mouth/ tongue are pathognomonic of measles - (+) jaundice plus epidemiologic data supporting a diagnosis of leptospirosis - labs show: increased ESR, elevated WBC with neutrophilia, slightly elevated transaminase levels, increased BUN and creatinine - (+) history of ingestion of contaminated food or water - transient, blanchable erythematous macules and papules usually appear on the trunk (rose spots) - diarrhea is not a symptom of dengue - neurologic manifestations tend to be absent in dengue fever - evaluation of CSF is 4. DIAGNOSTICS Test CBC with platelet count and differential count - presents with nonspecific signs and symptoms: high grade fever, body malaise the basis for diagnosis; in DF, the CSF is usually normal - WBC may show leukocytosis and neutrophilia - diagnosis is based on urine GS/CS Laboratory findings in Dengue WBC count will reveal leukopenia (presence of leukocytosis excludes possibility of dengue; bacterial infections like leptospirosis, meningococcemia, sepsis, pyelonephritis etc. must be considered) Platelet count reveals thrombocytopenia (≤100,000/mm3) Hematocrit elevated by >20% (hemoconcentration) PT/PTT May be prolonged in severe cases Laboratory criteria for the confirmation of the diagnosis (WHO, 1997) - at least one must be present Isolation of the dengue virus from the serum or autopsy samples Demonstration of a 4-fold or greater change in the reciprocal IgG or IgM antibody titers to one or more dengue virus antigens in paired serum samples Demonstration of dengue virus antigen in autopsy tissue, serum, or cerebrospinal fluid samples by immunochemistry, immunofluorescence or ELISA Detection of viral genomic sequences in the autopsy tissue, serum, or cerebrospinal fluid samples by PCR 5. PLAN Admitting Orders Admit to: W___ B ___ Diet: Avoid dark- colored foods (for monitoring of melena) and acidic foods VS: Monitor vital signs q1-4 hours and WOF any signs of bleeding; Monitor temperature q4h, and in between if febrile or with chills Nursing: I & O qshift IVF: D5NM x 8 hours; D5NSS or D5LR for shock Diagnostics: CBC with PC and DC PT, PTT Tourniquet test SGOT, SGPT Dengue serology if illness longer than 4 days U/A Chest X-ray (check for pneumonia, pleural effusion) Monitor: Platelet count ± hematocrit levels q12-24 hours Therapeutics: Medical treatment 1) Supportive: hydration 2) Optional medications: H2-blockers if with abdominal pain or GI bleeding 3) WOF complications: If there is frank, uncontrollable bleeding, transfuse fresh whole blood if indicated If PT, PTT are prolonged, and with thrombocytopenia, FFP transfusion is indicated If there is DIC, platelet transfusion is indicated Note: in the absence of bleeding, there is no need to administer platelet transfusion even if 2 platelet count is low Prevention 1) Environmental: Get rid of mosquito breeding places (ex. areas with stagnant water) 2) Vaccine: may be available in the near future… REFERENCES: Dengue Hemorrhagic Fever, pp.114-115. Expanded Medicine Blue Book 2nd edition by Willie Ong, et al. (2007) Harrison’s Principles of Internal Medicine 16th and 17th edition Dengue Fever article by Price and Wilson, Emedicine (2008) http://emedicine.medscape.com/article/781961-overview Dengue Fever article by Shepherd et al, Emedicine (2007) http://emedicine.medscape.com/article/215840-overview Dengue Hemorrhagic Fever: Diagnosis, treatment, prevention and control. 2nd edition. Geneva: WHO (1997) 3