Dengue Stephen J. Thomas, MD Director, Viral Diseases Branch Walter Reed Army Institute of Research (WRAIR) 14 AUG 2012

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1 Dengue Stephen J. Thomas, MD Director, Viral Diseases Branch Walter Reed Army Institute of Research (WRAIR) 14 AUG 2012

2 Dengue Lecture Outline Dengue Virus Dengue Epidemiology Military Significance Clinical Presentation and Management Diagnosis Pathophysiology Slide 2

Vector Mosquito (Aedes aegypti/albopictus)

3 Dengue Virus (DENV) Virus Positive-polarity, single-stranded RNA genome Flavivirus (YF, JE, WNV, DENV) 4 serotypes: DENV-1-4 Multiple genotypes Vector Mosquito (Aedes aegypti/albopictus) Transmission Feeding mosquito vector Laboratory Slide 3 Aedes aegypti

4 Dengue Virus Slide 4

5 Dengue Epidemiology Dengue Ward: QSNICH, Bangkok, Thailand (Photo: Christopher Brown, IHT) Slide 5

6 Facts Leading arboviral infection of humans >120 countries reporting indigenous transmission >3.5 billion people living at risk for infection >50 million infections annually >500,000 severe cases annually >30,000 deaths annually No licensed vaccine / therapeutic Effective vector control very difficult Dengue Ward: QSNICH, Bangkok, Thailand (Photo: Christopher Brown, IHT) Slide 6

7 Areas supporting dengue virus transmission. Slide 7

8 Factors Driving Transmission Population increases Migration Urbanization Poverty Vector expansion International travel Changing global ecology Vector evolution Viral evolution Slide 8

9 Dengue Aedes Slide 9

10 DENV Type Distribution D. Gubler Slide 10

11 Global Air Travel Flight Patterns Slide 11

12 DENV Type Distribution D. Gubler Slide 12

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14 14 AUG 2012 Slide 14

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16 Average dengue incidence per 100,000 by country, Region of the Americas, Slide 16

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18 Pakistan Slide 18

19 Brown dengue reported Light Brown dengue not reported but vector exists White data not available Slide 19

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With respect to specific diagnoses, malaria was one of the three most frequent causes of systemic febrile illness among travelers from every region,

23 With respect to specific diagnoses, malaria was one of the three most frequent causes of systemic febrile illness among travelers from every region, although travelers from every region except subsaharan Africa and Central America had confirmed or probable dengue more frequently than malaria. Slide 23

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25 Dengue s Military Significance Philippines World War II Vietnam Philippines Haiti Somalia Slide 25

26 Disease Malaria Dengue Diarrhea, bacterial MDR wound pathogens Leishmaniasis Q fever (Coxiella burnetti) Norovirus and other viral diarrhea Influenza Leptospirosis Diarrhea, protozoal TB CCHF HIV HFRS Chikungunya Meningococcal meningitis Plague Ricketsioses Viral encephalitides 2010 COCOM panel rank Slide 26 ID-IDEAL Rank NA NA NA 7 11 NA NA

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28 Dengue During Viet Nam War Slide 28

29 Hospitalized troops with fever / Unit survey of / 289 hospitalized w/ fever = no diagnosis 41 / 96 had DENV isolated (39 = DENV-2, 2 = DENV-3) 18 / 37 culture negative had IgM antibodies vs. dengue Survey of 494 = 77% prevalence of dengue antibodies Slide 29

30 OBJECTIVE: Describe outbreak of dengue fever (DF) during Operation Uphold Democracy, Haiti, PATIENTS: 101 US military personnel with acute febrile illnesses. RESULTS: Febrile illnesses accounted for 103 (25%) of the 406 combat support hospital admissions during the first 6 weeks of deployment. A total of 30 patients had DF. Dengue virus serotypes 1, 2, and 4 were isolated from 22 patients, and 8 patients developed IgM antibody to dengue virus. Patients with DF could not be distinguished from other febrile patients on clinical grounds alone. CONCLUSIONS: DF accounted for at least 30% of the febrile illnesses among hospitalized US troops. Slide 30

31 59th Annual Meeting ASTMH USASOC DODSR 500 samples Dengue ELISA 11% seroprevalence Slide 31

32 WRAIR USASOC DODSR Study Seroprevalence Based on 1,000 Post-Deployment Samples in First Time Deployers Percent Central America* South America Asia Africa* Total Overall seroprevalence = 7.6% Highest prevalence among those serving in the Army Positive association with older age No effect of deployment length Increased self-report of fever among those w/ antibodies Slide 32

33 Dengue Clinical Presentation / Management Dengue Ward: QSNICH, Bangkok, Thailand (Photo: Christopher Brown, IHT) Slide 33

34 Dengue Infection Clinical Phenotypes Slide 34

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37 Dengue Hemorrhagic Fever Slide 37

38 Dengue Fever in US Military Personnel in Haiti JAMA 1997; 277:19: Symptoms in Febrile Patients Admitted to the 28th Combat Support Hospital, Port-auPrince, Haiti, SEP 27, 1994 NOV 4, 1994 Slide 38

39 Physical Findings in Febrile Patients Febrile Patients Admitted to the 28th Combat Support Hospital, Port-au-Prince, Haiti, September 27, 1994 to November 4, 1994* Slide 39

40 Dengue Fever Slide 40

41 WHO Treatment Guidelines DF/DHF (1999) Slide 41

42 WHO Treatment Guidelines DF/DHF (1999) Slide 42

43 Dengue Hemorrhagic Fever Slide 43

44 Pleural Effusion Index R LAT decubitus X-ray showing a large pleural effusion, DHF the day after defervescence. Degree of plasma leakage may be quantified by means of the pleural effusion index. The pleural effusion index is calculated as 100 times the maximum width of the R pleural effusion, divided by the maximal width of the R hemithorax. Slide 44

45 Hemoconcentration Slide 45

46 DHF: I / II Slide 46

47 Petechiae on chest wall in child with DHF. Subcutaneous hemorrhage in child with DHF. Slide 47

48 DHF I / II Volume Replacement Slide 48

49 DHF: III / IV Slide 49

50 DHF: III / IV Petechiae Slide 50

51 Gastric Bleeding Melena Slide 51

52 DHF III / IV Volume Replacement Slide 52

53 Diagnosing Dengue Infant w/ dengue: Thai Cambodia border Slide 53

54 Diagnosing Dengue - Basics Maintain high degree of suspicion Geographic location Clustering of cases History and physical Clinical presentation consistent with dengue Vital signs (T, BP, pulse pressure, HR) Dengue tourniquet test Clinical lab assessment CBC (WBC, HCT, PLT), AST/ALT, Bilirubin Endemic area, +Clinical, +Tourniquet test, WBC<5k = High PPV Slide 54

55 Dengue Tourniquet Test SBP+DBP / 2 x 5 mins Inspect area for new petechiae Positive = 10 or cm2 Slide 55

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57 Disease Course Windows of Diagnostic Opportunity Slide 57

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60 Dengue Pathophysiology Slide 60

61 Infection / Disease Determinant Questions What places a person at risk for acquiring a dengue virus infection? Why do some Aedes feeding episodes result in infection and others do not? Why do some people experience disease following infection and others do not? Why is the dengue clinical phenotype spectrum so broad? Slide 61

62 Exposure and Infection Outcome Determinants Virus Vector Ecology Host Slide 62

63 Exposure Determinants Risk of Infection Tropism for Aedes Tropism for man Replicative kinetics Man / Aedes Immune avoidance Man / Aedes Evolutionary capacity Virus Response to ecology Temperature Rain Infection resistance Co-infection Evolutionary capacity Vector Host Immune profile (dengue, other flavivirus) Vector exposure dynamics (duration, concentration) Neighbors infection status Activities of daily living (who, what, where, when) Slide 63

64 Infection Outcome Determinants Risk of Disease DENV type DENV genoptype Replicative kinetics Immune evasion Virus Vector Salivary proteins Target cell tropism Evolutionary capacity Sequence of infection Host Immune profile (first infection, humoral, cellular) Demographic (age, race, genetic background [HLA]) Co-morbidities Medical system sophistication treating dengue Slide 64

65 Dengue Ward: QSNICH, Bangkok, Thailand (Photo: Christopher Brown, IHT) Slide 65

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68 Immunologic Response Clinical Phenotype (Rothman) Slide 68

69 Questions? Slide 69

Dengue. Stephen J. Thomas, MD Deputy Commander for Operations Walter Reed Army Institute of Research. Infectious Diseases Consultant to TSG JUL 2014

Dengue. Stephen J. Thomas, MD Deputy Commander for Operations Walter Reed Army Institute of Research. Infectious Diseases Consultant to TSG JUL 2014 Dengue Stephen J. Thomas, MD Deputy Commander for Operations Walter Reed Army Institute of Research Infectious Diseases Consultant to TSG JUL 2014 UNCLASSIFIED Case Presentation 18 year old native from