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DENGUE Dr. Halesh .L.H. Professor and Head of the department , Microbiology SIMS,Shimoga *Virus, Vector and Transmission *Causative agent of dengue fever, belongs to family flaviviridae, genus flavivirus. *It is a spherical enveloped virus *Genomic material – single stranded RNA *There are presently 5 serotypes identified * *Fifth serotype, identified in 2013, october follows sylvatic cycle,and is found only in Sarawak forest, Malaysia *Each serotype provides specific lifetime immunity, and short-term cross-immunity *All serotypes can cause severe and fatal disease * *Genetic variation within serotypes *Some genetic variants within each serotype appear to be more virulent or have greater epidemic potential * oThe first record of dengue fever is in chinese medical encyclopedia referred as water poison caused by flying insects oReports of epidemics – 1779-80 oThen until 1940 , epidemics were infrequent oThen there was marked spread of dengue during and after second world war *HISTORY *The incidence is dramatically increasing *390 million dengue cases per year *Infections are acquired in urban environment *Rate of dengue has increased 10folds between 1960-2010 *HISTORY *Replication and Transmission of Dengue Virus 1. Virus is transmitted to human in mosquito saliva 2. Virus replicates in target organs 3. Virus infects white blood cells and lymphatic tissues 4. Virus released and circulates in blood * 5. Second mosquito ingests virus with blood 6. Virus replicates in mosquito midgut and other organs, infects salivary glands 7. Virus replicates in salivary glands *Aedes aegypti Mosquito *Dengue transmitted by infected female mosquito *Primarily a daytime feeder *Lives around human habitation *Lays eggs and produces larvae preferentially in artificial containers *Aedes aegypti * Clinical Manifestations of Dengue and DHF *Undifferentiated fever *Classic dengue fever *Dengue hemorrhagic fever *Dengue shock syndrome *Dengue Clinical Syndromes *Clinical Characteristics of Dengue Fever 4 Necessary Criteria: 1.Fever, or recent history of acute fever 2.Hemorrhagic manifestations 3.Low platelet count (100,000/mm3 or less) 4.Objective evidence of “leaky capillaries:” *elevated hematocrit (20% or more over baseline) *low albumin *pleural or other effusions *Clinical Case Definition for Dengue Hemorrhagic Fever *Clinical Case Definition for Dengue Shock Syndrome criteria for DHF 1.Evidence of circulatory failure manifested indirectly by all of the following: *Rapid and weak pulse *Narrow pulse pressure ( 20 mm Hg) OR hypotension for age *Cold, clammy skin and altered mental status 2.Frank shock is direct evidence of circulatory failure 4 Grades of DHF Grade 1 *Fever and nonspecific constitutional symptoms *Positive tourniquet test is only hemorrhagic Manifestation Grade 2 *Grade 1 manifestations + spontaneous bleeding Grade 3 *Signs of circulatory failure (rapid/weak pulse, narrow pulse pressure, hypotension, cold/clammy skin) Grade 4 *Profound shock (undetectable pulse and BP) * Abdominal pain - intense and sustained * Persistent vomiting * Abrupt change from fever to hypothermia, with sweating and prostration * Restlessness or somnolence DANGER SIGNS OF DHS Four Criteria for DHF: • Fever • Hemorrhagic manifestations • Excessive capillary permeability • 100,000/mm3 platelets Initial Warning Signals: • Disappearance of fever • Drop in platelets • Increase in hematocrit * Alarm Signals: • Severe abdominal pain • Prolonged vomiting • Abrupt change from fever to hypothermia • Change in level of consciousness (irritability or somnolence) When Patients Develop DSS • 3 to 6 days after onset of symptoms *Encephalopathy *Hepatic damage *Cardiomyopathy *Severe gastrointestinal hemorrhage *Unusual Presentations of Severe Dengue Fever Disease Pathogenesis *Higher risk in secondary infections *Higher risk in locations with two or more serotypes circulating simultaneously at high levels (hyperendemic transmission) *Risk Factors for DHF *Persons who have experienced a dengue infection develop serum antibodies that can neutralize the dengue virus of that same (homologous) serotype *Hypothesis on Pathogenesis of DHF Homologous Antibodies Form Non-infectious Complexes Dengue 1 virus Neutralizing antibody to Dengue 1 virus Non-neutralizing antibody Complex formed by neutralizing antibody and virus *In a subsequent infection, the pre-existing heterologous antibodies form complexes with the new infecting virus serotype, but do not neutralize the new virus Hypothesis on Pathogenesis of DHF Heterologous Antibodies Form Infectious Complexes Dengue 2 virus Non-neutralizing antibody to Dengue 1 virus Complex formed by non-neutralizing antibody and virus *Antibody-dependent enhancement is the process in which certain strains of dengue virus, complexed with nonneutralizing antibodies, can enter a greater proportion of cells of the mononuclear lineage, thus increasing virus production Hypothesis on Pathogenesis of DHF * Dengue 2 virus Non-neutralizing antibody Complex formed by nonneutralizing antibody and Dengue 2 virus *Infected monocytes release vasoactive mediators, resulting in increased vascular permeability & hemorrhagic manifestations that characterize DHF and DSS *Hypothesis on Pathogenesis of DHF Virus serotype *DHF risk is greatest for DEN-2, followed by DEN-3, DEN-4 & DEN-1 *Viral Risk Factors for DHF Pathogenesis * Diagnosis Clinical Evaluation in Dengue Fever *Blood pressure *Evidence of bleeding in skin or other sites *Hydration status *Evidence of increased vascular permeabilitypleural effusions, ascites * Laboratory Tests in Dengue Fever *Clinical laboratory tests *CBC--WBC, platelets, hematocrit *Albumin *Liver function tests *Urine--check for microscopic hematuria VIRUS SPECIFIC TEST *Virus isolation *Serology *Laboratory Tests in Dengue Fever *Virus Isolation: Cell Culture Virus Isolation: Mosquito Inoculation *Virus Isolation: Fluorescent Antibody Test * Treatment *No hemorrhagic manifestations and patient is well-hydrated: home treatment *Hemorrhagic manifestations or hydration borderline: outpatient observation center or hospitalization *Warning signs (even without profound shock) or DSS: hospitalize *Outpatient Triage *Patients treated at home *Instruction regarding danger signs *Consider repeat clinical evaluation *Patients with bleeding manifestations *Serial hematocrits and platelets at least daily until temperature normal for 1 to 2 days *Patient Follow-Up *All patients *If blood sample taken in first 5 days after onset, need convalescent sample between days 6 - 30 *All hospitalized patients need samples on admission and at discharge or death *Patient Follow-Up (cont’d.) *Treatment of Dengue Fever *Fluids *Rest *Antipyretics (avoid aspirin & NSAIDs) *Monitor blood pressure, hematocrit, platelet count, level of consciousness *Only needed until fever subsides, to prevent Aedes aegypti mosquitoes from biting patients and acquiring virus *Keep patient in screened sick room or under a mosquito net *Mosquito Barriers * Indications for Hospital Discharge *Absence of fever for 24 hours (without anti-fever therapy) and return of appetite *Visible improvement in clinical picture *Stable hematocrit *3 days after recovery from shock *Platelets 50,000 / mm3 *No respiratory distress from pleural effusions / ascites * DHF is a pediatric disease All age groups are involved DHF is a problem of low income families All socioeconomic groups are affected *No licensed vaccine at present *Effective vaccine must be tetravalent *Field testing of an attenuated tetravalent vaccine currently underway *Effective, safe and affordable vaccine is awaited *Dengue Vaccine? *Disease Prevention and Control *Larvicides may be used to kill immature aquatic stages *Ultra-low volume fumigation ineffective against adult mosquitoes *Mosquitoes may have resistance to commercial aerosol sprays *Vector Control Methods: Chemical Control Biological control *Largely experimental *Option: place fish in containers to eat larvae Environmental control *Elimination of larval habitats *Most likely method to be effective in the long term *Vector Control Methods: Biological & Environmental Control THANK YOU