Dengue Virus Adenovirus Non Polio Enteroviruses Coxsackie virus Echovirus Enterovirus

1. Dengue Virus Adenovirus Non Polio Enteroviruses Coxsackie virus Echovirus Enterovirus

2. Dengue Clinical Manifestations and Epidemiology

3. I. Virus, Vector and Transmission

4. Dengue Virus • Causes dengue and dengue hemorrhagic fever • Is an arbovirus • Transmitted by mosquitoes • Composed of single-stranded RNA • Has 4 serotypes (DEN-1, 2, 3, 4)

5. Dengue Viruses • 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

6. Extrinsic incubation period Illness Illness Transmission of Dengue Virusby Aedesaegypti Mosquito refeeds / Mosquito feeds / transmits virus acquires virus Intrinsic incubation period Viremia Viremia 0 5 8 12 16 20 24 28 DAYS Human #1 Human #2

7. 1 2 4 3 Replication and Transmissionof Dengue Virus (Part 1) 1. Virus 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

8. 6 7 5 Replication and Transmissionof Dengue Virus (Part 2) 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

9. Aedes aegypti Mosquito

10. Aedes aegypti • Dengue transmitted by infected female mosquito • Primarily a daytime feeder • Lives around human habitation • Lays eggs and produces larvae preferentially in artificial containers

11. II. Epidemiology

12. Areas infested with Aedes aegypti Areas with Aedes aegypti and dengue epidemic activity World Distribution of Dengue - 2005

13. Mean Annual Number of DHF CasesThailand, Indonesia and Vietnam, by Decade * Provisional data through 1998

14. III. Disease Pathogenesis

15. Risk Factors Reported for DHF • Virus strain • Pre-existing anti-dengue antibody • previous infection • maternal antibodies in infants • Host genetics • Age

16. Risk Factors for DHF (continued) • Higher risk in secondary infections • Higher risk in locations with two or more serotypes circulating simultaneously at high levels (hyperendemic transmission)

17. Increased Probability of DHF Hyperendemicity Increased circulation of viruses Increased probability of secondary infection Increased probability of occurrence of virulent strains Increased probability of immune enhancement Increased probability of DHF Gubler & Trent, 1994

18. Hypothesis on Pathogenesisof DHF (Part 1) • Persons who have experienced a dengue infection develop serum antibodies that can neutralize the dengue virus of that same (homologous) serotype

19. 1 1 1 1 1 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

20. Hypothesis on Pathogenesisof DHF (Part 2) • In a subsequent infection, the pre-existing heterologous antibodies form complexes with the new infecting virus serotype, but do not neutralize the new virus

21. 2 2 2 2 2 2 Heterologous Antibodies Form Infectious Complexes Dengue 2 virus Non-neutralizing antibody to Dengue 1 virus Complex formed by non-neutralizing antibody and virus

22. Hypothesis on Pathogenesisof DHF (Part 3) • Antibody-dependent enhancement is the process in which certain strains of dengue virus, complexed with non-neutralizing antibodies, can enter a greater proportion of cells of the mononuclear lineage, thus increasing virus production

23. 2 2 2 2 2 2 2 2 2 2 2 2 Heterologous Complexes Enter More Monocytes, Where Virus Replicates Dengue 2 virus Non-neutralizing antibody Complex formed by non-neutralizing antibody and Dengue 2 virus

24. Hypothesis on Pathogenesisof DHF (Part 4) • Infected monocytes release vasoactive mediators, resulting in increased vascular permeability and hemorrhagic manifestations that characterize DHF and DSS

25. Viral Risk Factorsfor DHF Pathogenesis • Virus strain (genotype) • Epidemic potential: viremia level, infectivity • Virus serotype • DHF risk is greatest for DEN-2, followed by DEN-3, DEN-4 and DEN-1

26. IV. Clinical Manifestations of Dengue and Dengue Hemorrhagic Fever

27. Dengue Clinical Syndromes • Undifferentiated fever • Classic dengue fever • Dengue hemorrhagic fever • Dengue shock syndrome

28. Undifferentiated Fever • May be the most common manifestation of dengue • Prospective study found that 87% of students infected were either asymptomatic or only mildly symptomatic • Other prospective studies including all age- groups also demonstrate silent transmission

29. Clinical Characteristicsof Dengue Fever • Fever • Headache • Muscle and joint pain • Nausea/vomiting • Rash • Hemorrhagic manifestations

30. Signs and Symptoms ofEncephalitis/EncephalopathyAssociated with Acute Dengue Infection • Decreased level of consciousness: lethargy, confusion, coma • Seizures • Nuchal rigidity • Paresis

31. Hemorrhagic Manifestationsof Dengue • Skin hemorrhages: petechiae, purpura, ecchymoses • Gingival bleeding • Nasal bleeding • Gastro-intestinal bleeding: hematemesis, melena, hematochezia • Hematuria • Increased menstrual flow

32. Clinical Case Definition forDengue Hemorrhagic Fever 4 Necessary Criteria: • Fever, or recent history of acute fever • Hemorrhagic manifestations • Low platelet count (100,000/mm3 or less) • Objective evidence of “leaky capillaries:” • elevated hematocrit (20% or more over baseline) • low albumin • pleural or other effusions

33. Clinical Case Definition for Dengue Shock Syndrome • 4 criteria for DHF • 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 • Frank shock is direct evidence of circulatory failure

34. Four 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)

35. Danger Signs inDengue Hemorrhagic Fever • Abdominal pain - intense and sustained • Persistent vomiting • Abrupt change from fever to hypothermia, with sweating and prostration • Restlessness or somnolence Martínez Torres E. Salud Pública Mex 37 (supl):29-44, 1995.

36. Warning Signs for Dengue Shock • Alarm Signals: • Severe abdominal pain • Prolonged vomiting • Abrupt change from fever to hypothermia • Change in level of • consciousness (irritability somnolence) • 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 • When Patients Develop DSS: • 3 to 6 days after onset of symptoms

37. Unusual Presentationsof Severe Dengue Fever • Encephalopathy • Hepatic damage • Cardiomyopathy • Severe gastrointestinal hemorrhage

38. V. Diagnosis

39. General Recommendationsfor Medical Care • Epidemiologic considerations • Season of year • Travel history • Diagnosis • Treatment • Follow-up

40. Travel History • Important for assessment of symptomatic patients in non-endemic areas • Determine whether the patient travelled to a dengue-endemic area • Determine when the travel occurred • If the patient developed fever more than 2 weeks after travel, eliminate dengue from the differential diagnosis

41. Differential Diagnosis of Dengue • Influenza • Measles • Rubella • Malaria • Typhoid fever • Leptospirosis • Meningococcemia • Rickettsial infections • Bacterial sepsis • Other viral hemorrhagic fevers

42. Clinical Evaluation in Dengue Fever • Blood pressure • Evidence of bleeding in skin or other sites • Hydration status • Evidence of increased vascular permeability-- pleural effusions, ascites • Tourniquet test

43. Petechiae

44. PEI = A/B x 100 B A Pleural Effusion Index Vaughn DW, Green S, Kalayanarooj S, et al. Dengue in the early febrile phase: viremia and antibody responses. J Infect Dis 1997; 176:322-30.

45. Tourniquet Test • Inflate blood pressure cuff to a point midway between systolic and diastolic pressure for 5 minutes • Positive test: 20 or more petechiae per 1 inch2 (6.25 cm2)

46. Positive Tourniquet Test

47. Laboratory Testsin Dengue Fever • Clinical laboratory tests • CBC--WBC, platelets, hematocrit • Albumin • Liver function tests • Urine--check for microscopic hematuria • Dengue-specific tests • Virus isolation • Serology

48. Laboratory Methods for Dengue Diagnosis, CDC Dengue Branch • Virus isolation to determine serotype of the infecting virus • IgM ELISA test for serologic diagnosis

49. Virus Isolation:Cell Culture

50. Virus Isolation:Cell Culture