A Dengue Epidemic in Puerto Rico, 2010
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Transcript of A Dengue Epidemic in Puerto Rico, 2010
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LT Tyler M. Sharp, Ph.D.
USPHS Scientific and Training SymposiumJune 21, 2011
A Dengue Epidemic in Puerto Rico, 2010
National Center for Emerging and Zoonotic Infectious DiseasesDivision of Vector-Borne Diseases — Dengue Branch
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Dengue Most important vector-borne
viral disease worldwide ~100 million infections/year ~500,000 hospitalizations/year ~25,000 deaths/year
Four dengue viruses (DENV1–4) cause an acute febrile illness Common symptoms: fever,
headache, myalgia, retro-orbital and joint pain, rash
Severe symptoms: hemorrhage, shock, death
Photos credits: “Train-the-Trainer” course material, CDC 2010
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Adapted from Vaccine 2002; 3043-3046
Dengue Virus Infections
Survive95-99.5%
Death0.5 - 5%
Infection Incidence ~ 5% / year
Asymptomatic 75%
Symptomatic 25%
Dengue Fever95-99%
Severe dengue1-5%
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The Vicious Cycle of DENV InfectionsMosquito acquires virus during
feeding, virus replicates in mosquito
Mosquito acquires virus during feeding, virus replicates in
mosquito
Mosquito bites
susceptible human,
transfers DENV
Mosquito bites
susceptible human,
transfers DENV
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Prevention and Control of Dengue Surveillance
Disease Vector
Primary prevention Vector control Vaccination
Secondary prevention Clinical care Anti-viral drugs
Image: http://www.lafayettela.gov/eos/dpt122mosquitocontrol.asp
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Puerto Rico and Dengue 3.7 million individuals
Endemic
Seasonal
7,000 – 24,000 cases/year
Passive surveillance Image: http://www.caribbeanplanning.com/caribbean-map.htm
PuertoRico
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Diagnostics
Positive: RT-PCR or IgM ELISA positive
Negative: RT-PCR and IgM ELISA negative
Indeterminate: negative RT-PCR, no convalescent specimen
0 5Day Post-Onset of Symptoms
IgG
IgM
Virus
10 90
RT-PCR IgM ELISAAcute Convalesce
nt
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Negative11.0%
Positive46.6%
Diagnostic Results, 2010
Indeterminate42.2%
Suspected Cases (n = 23,622)
IgM32.3%
RT-PCR67.7%
Positive Cases (n = 10,947)
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Viral Serotypes, 2010
DENV-169.0%DENV-2
7.4%
DENV-423.6%
RT-PCR Positive Cases(n = 7,416)
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Dengue incidence per 10,000 pop
1.16 - 16.33
16.34 - 27.41
27.42 - 42.97
42.98 - 161.33
Rates of Lab Positive Cases by Municipality, 2010
Dengue incidence per 10,000 pop
1.16 - 16.33
16.34 - 27.41
27.42 - 42.97
42.98 - 161.33
Lab positive cases per 1,000 persons
0.1-1.61.7-2.72.8-4.34.4-16.1
Overall incidence: 2.9 lab positive cases per 1,000 persons
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<1 1-4 5-9 10-14
15-19
20-29
30-39
40-49
50-59
60-69
70 +0
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1000
1500
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Age Group
Case
sAge Distribution of Lab Positive Cases,
201047% of cases were in
adults Cases per 1,000 Individuals
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<1 1-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60-69 70+0
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Age Group
Case
sAge distribution of serotypes, 2010
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<1 1-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60-69 70+0
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0%
10%
20%
30%
40%
50%
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100%DENV-1
Age Group
Case
sAge distribution of serotypes, 2010
Percent Serotype
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Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec0
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1000
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Month of Illness Onset
Case
sLab Positive Cases and Lab
Positive Deaths by Month, 2010D
eaths
Suspected deaths: 123Lab positive deaths: 38
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Age Distribution of Lab Positive Deaths, 2010
89% of deaths were in adults
<1 1-4 5-9 10-14
15-19
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Age Group
Dea
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<1 1-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60-69 70 +0
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7 DENV-1DENV-4DENV-2
Age Group
Dea
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Deaths by Serotype*, 2010(n = 17)
*32 of 38 deaths have a confirmed serotype.
(n = 10)(n = 5)
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History of Dengue in the United States
First documented outbreak in Philadelphia in 1780
Dengue disappeared in the US following vector elimination due to concerns of yellow fever
Travel-associated dengue has re-introduced the virus into the US
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Re-emergence of Dengue in the United States
Dengue more common than malaria in some travelers
Mosquito vector exists in US
Imported outbreaks in TX, FL, HI
In 2010, 702 cases reported from 38 states
18X under-reporting
Distribution of Aedes mosquitoes
Mosquito surveillance data courtesy of Chester G. Moore, Colorado State University
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Travel-associated Dengue in US, 2010
Source: ArboNET
Lead StatesNY 178FL 133CA 36NJ 29IL 23PA 22TX 19WA 19IN 19OH 16
702 cases reported from 38 states
>3011-303-101-20
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Travel-associated Dengue in US, 2010
Source: ArboNET
1 5 9 13 17 21 25 29 33 37 41 45 490
102030405060 US Travel Cases
Puerto Rico, Dominican Republic, Haiti and other Caribbean Islands made up nearly half of all cases
Travel Destination Cases Percent
PUERTO RICO 93 16
DOMINICAN REPUBLIC 82 14
OTHER CARIBBEAN ISLANDS
50 8
INDIA 50 8HAITI 38 6NICARAGUA 26 4
PHILIPPINES 22 4
VENEZUELA 22 4
COLOMBIA 21 4
HONDURAS 21 4
Cas
es
Week of Report
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Travel-associated Dengue in US, 2010
Source: ArboNET
Puerto Rico, Dominican Republic, Haiti and other Caribbean Islands made up nearly half of all cases
Travel Destination Cases Percent
PUERTO RICO 93 16
DOMINICAN REPUBLIC 82 14
OTHER CARIBBEAN ISLANDS
50 8
INDIA 50 8HAITI 38 6NICARAGUA 26 4
PHILIPPINES 22 4
VENEZUELA 22 4
COLOMBIA 21 4
HONDURAS 21 41 5 9 13 17 21 25 29 33 37 41 45 49
0100200300400500600
0102030405060US Travel
CasesPuerto Rico
Puer
to R
ico
Cas
es
Week of Report
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Conclusions Dengue is re-emerging Large epidemic in PR in 2010
2.9 lab positive cases/1,000 individuals Most lab positive deaths ever (n = 38)
3.5 lab positive deaths/1,000 lab positive cases 10–19 year olds most affected
6.5 lab positive cases per 1,000 persons Most deaths in adults
Median age: 44 years Epidemics in PR overflow into the
continental U.S.
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Future Steps Examine dengue deaths for:
Risk factors Under-reporting and -recognition
Emphasize personal protection Avoid mosquito bites
Educate physicians in clinical case management 8,300 physicians and 2,500 nurses trained
Evaluation of clinical case management
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For more information please contact Centers for Disease Control and Prevention1600 Clifton Road NE, Atlanta, GA 30333Telephone, 1-800-CDC-INFO (232-4636)/TTY: 1-888-232-6348E-mail: [email protected] Web: www.cdc.govThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
AcknowledgementsAidsa Rivera, M.S. –Fatal case findings and PDSS oversight
Rosa Rodriguez, Ph.D. – EDSS oversightJorge L. Muñoz-Jordan, Ph.D. – Lab Chief, Molecular diagnostics and research
Elizabeth Hunsperger, Ph.D. – Lab Chief, Serology diagnostics and researchLuis Santiago, MPH – Statistical analysis and data processing
LCDR Fermín Argüello, M.D., MPH – Study design and analysisHal Margolis, M.D. – Dengue Branch Chief
CAPT Kay Tomashek, M.D., MPH – Epidemiology Chief
National Center for Emerging and Zoonotic Infectious DiseasesDivision of Vector-Borne Diseases — Dengue Branch
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Deaths per Population, 2010
<1 1-4 5-9 10-14
15-19
20-29
30-39
40-49
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9
10
0.00
0.50
1.00
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2.00
2.50
Age Group
Dea
ths
Deaths per 100,000 Individuals
Overall : 0.9 lab positive deaths per 100,000 individuals
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Consecutive Infections, 2010
Age SexFirst Onset
Date Dx-1Second
Onset Date Dx-2
Interval between
events (days)
11 Male 12/10/2010 DENV-1 12/10/2010 DENV-4 0
12 Male 12/8/2010 DENV-1 12/8/2010 DENV-4 0
5 Male 8/9/2010 DENV-1 9/15/2010 IgM(+) 3766 Male 7/28/2010 DENV-2 9/22/2010 IgM(+) 56
22 Male 4/27/2010 IgM(+) 6/28/2010DENV-1, IgM(+) 62
34 Male 9/3/2010 DENV-2 12/6/2010 IgM(+) 9473 Male 8/16/2010 DENV-4 11/27/2010 IgM(+) 103
0.83 Male 7/10/2010 DENV-1 11/7/2010 DENV-4 120
16 Male 3/6/2010 DENV-1 8/14/2010 DENV-4 161
41 Male 12/30/2009 DENV-1 10/27/2010 DENV-4 301
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Distribution of Aedes aegypti, 2007
Source: Chester G. Moore, Dept. of Microbiology, Immunology & Pathology, Colorado State
University
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Distribution of Aedes albopictus, 2007
Source: Chester G. Moore, Dept. of Microbiology, Immunology & Pathology, Colorado State
University
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Dengue incidence per 10,000 pop
1.16 - 16.33
16.34 - 27.41
27.42 - 42.97
42.98 - 161.33
Rates of Lab Positive Cases by Municipality, 2010
Dengue Incidence 10,000 pop
39.74 - 153.83
24.55 - 39.73
15.24 - 24.54
1.13 - 15.23123
Fatalities
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Under-reporting of Dengue in Puerto Rico
Lack of reporting 10-27 symptomatic cases for every reported case in
1990’s• Failure of patients to present• Lack of clinical supicion• Failure of clinicians to report
Alternative methods of reporting Category-1 form Specimens sent off island for diagnostics (3 major
companies)• Company A: ~2,000 from June-December, 2010
Asymptomatic cases ≤ 90% of all infections
In total, we estimate that 5-10% of Puerto Ricans were infected in 2010 ~350,000 individuals
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Accuracy of Enhanced Fatal Dengue Surveillance, 2010
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec0
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1500
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Month, 2010
Dea
ths Cases
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DENV-1DENV-4DENV-2
Age Group
DHFC
ases
DHF Cases by Serotype, 2010
(n = 57)(n = 70)(n = 17)
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DHF Cases by Serotype, 2010
DENV-1 DENV-2 DENV-40%
10%
20%
30%
40%
50%
60%Kids
Adults
Serotype
DH
F Ca
ses
(%)
(n = 92)
(n = 52)
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DHF Cases per PopulationD
HF Cases per 1,000 Individuals<1 1-4 5-9 10-
1415-19
20-29
30-39
40-49
50-59
60-69
70 +0
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20
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50
60
0.00
0.05
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Age Group
Coun
t DH
F Ca
ses
Overall : 6.7 lab positive DHF casesper 100,000 individuals
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DHF Cases per DF CasesD
HF Cases per 1,000 D
F Cases<1 1-4 5-9 10-14
15-19
20-29
30-39
40-49
50-59
60-69
70 +0
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30
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50
60
010
20304050
6070
8090100
Age Group
Coun
t DH
F Ca
ses
Overall : 21.4 lab positive DHF cases per 1,000 lab positive cases
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Sus
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ed C
ases
Suspected and Confirmed Cases by Week, 2010
Outbreak declaredFeb. 27, 2010
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-2 0 2 4 6 8 10 12 Day of Illness
Critical Phase
Clinical Course of Dengue Infection
Mosquitobite
Acute Febrile Phase
Viremia
Convalescent Phase
Usually 3 to 5 days
1 to 3 days; usually <48 hrs
Range: 2 to 7 days; usually 3 to 5 days
* Typically uncomplicated DHF/DSS lasts for 10 to 12 days
Range: 3 to 14 d; usually 4 to 7 days
Incubation
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WHO Dengue Case Definitions (1997)• Dengue fever (DF)
– Fever plus 2 of: headache, retro-orbital pain, myalgia, joint pain, bone pain, rash, bleeding, low WBC count
• Dengue hemorrhagic fever (DHF): – Fever, hemorrhagic manifestation(s),
thrombocytopenia (≤100,000 cells per mm³), plasma leakage
• Dengue shock syndrome (DSS):– DHF plus rapid, weak pulse and narrow pulse
pressure, OR DHF plus hypotension and cold, clammy skin and restlessness
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Characteristics of the 2010 EpidemicSuspected
casesn = 23,622
Laboratory positive cases
n = 10,956
Laboratory negative cases
n = 2,588
Indeterminate cases
n = 9,999
Median age, years 18 18 18 18
Age range 5 days – 102 years
1 month – 102 years
17 days – 90 years
5 days – 100 years
Male, # (%) 12,720 (53.8) 6,061 (55.3) 1,313 (50.7) 5,298 (53.0)
Dengue fever, # (%) 17,035 (72.1) 8,844 (80.7) 1,756 (67.9) 6,401 (61.0)
Hospitalized*, # (%) 8,004 (58.7) 4,173 (66.0) 887 (57.4) 2,911 (54.5)
Hemorrhage, # (%) 6,989 (29.6) 3,773 (34.4) 753 (29.1) 2,394 (23.9)
DHF/DSS, # (%) 408 (1.7) 254 (2.3) 57 (2.2) 93 (0.9)
Deaths, # (%) 118 (0.5) 38 (0.3) 36 (1.4) 44 (0.4)
* denominator varies due to data availability
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<1 1-4 5-9 10-14
15-19
20-29
30-39
40-49
50-59
60-69
70+0
100
200
300
400
500
600
700
800
900
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%DENV-1
Age Group
Hos
pita
lized
Cas
esAge Distribution of Hospitalized Cases,
2010Percent Serotype
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<1 1-4 5-9 10-14
15-19
20-29
30-39
40-49
50-59
60-69
70+0
10
20
30
40
50
60
70
80
90
100Rates of Hospitalization by
Serotype, 2010 DENV-1DENV-4
Age Group
Hos
pita
lizat
ions
per
100
Infe
ctio
ns
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Infecting Serotypes in Non-Hospitalized and Hospitalized Individuals, 2010
<1 1-4 5-9 10-14
15-19
20-29
30-39
40-49
50-59
60-69
70+0.0%5.0%
10.0%15.0%20.0%25.0%
Hospitalized
DENV-1DENV-4
Age GroupTota
l Inf
ectio
ns p
er
Sero
type
<1 1-4 5-9 10-14
15-19
20-29
30-39
40-49
50-59
60-69
70+0.0%5.0%
10.0%15.0%20.0%25.0%
Non-Hospitalized
DENV-1DENV-4
Tota
l Inf
ectio
ns
per
Sero
type
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Hospitalization something or other, 2010
<1 1-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60-69 70+0.0%10.0%20.0%30.0%40.0%50.0%60.0%70.0%80.0%90.0%
100.0%
Non-Hospitalized Cumulative
DENV-1DENV-2DENV-4
Age Group
Cum
ulat
ive
% H
ospi
taliz
ed
<1 1-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60-69 70+0.0%10.0%20.0%30.0%40.0%50.0%60.0%70.0%80.0%90.0%
100.0%
Hospitalized Cumulative
DENV-1DENV-2DENV-4
Age Group
Cum
ulat
ive
% H
ospi
taliz
ed
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DENV-1 74.1%
DENV-2
5.4%
DENV-420.5%
Infecting Serotype in Hos-pitalized Individuals, 2010
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Acute specimens Are Representative of Hospitalization Rates of the Entire
Population
<1 1-4 5-9 10-14
15-19
20-29
30-39
40-49
50-59
60-69
70+0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
RT-PCRIgMTotal
Age Group
Hos
pita
lized
*
*
* *
*
*^
*
* = sig diff of IgM from RT-PCR^ = sig diff of Total from RT-PCR
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Dengue in Puerto Rico
• First major epidemics reported in 1915 and 1945
• In 1963, DENV first isolated in Puerto Rico
• There were six large, island-wide outbreaks between 1969 – 1986
• Two large outbreaks in 1990s (1994, 1998)
• In 2000s, one large outbreak in 2007 (all 4 serotypes) with 10,508 suspected cases or 3 cases per 1,000 − Over 50% hospitalized; 1/3 reported hemorrhage,
2% had DHF, and 44 died
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Dengue in Puerto Rico
• Dengue is endemic in PR with seasonal pattern − Low transmission: March—June− Peak transmission: August—November
• Dengue is reportable by law in Puerto Rico• Suspected dengue cases are reported every
week to the Puerto Rico Department of Health; free diagnostic testing is done at CDC Dengue Branch in San Juan – Passive surveillance since 1969– Purpose of surveillance is to use data to guide vector
control and prevention efforts
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1987
1989
1991
1993
1995
1997
1999
2001
2003
2005
2007
2009
0
1000
1500
2000
5000
6000
Denv-1Denv-2Denv-3Denv-4Marker
Number of dengue viral isolates by year in Puerto Rico, 1986-2006
RT-P
CR P
osit
ive
Case
s
Year
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Sex Distribution of Lab Positive Cases and Deaths, 2010
Male55.3%
Female44.7%
Sex of Positive Cases(n = 10,936)
Male39%
Female61%
Sex of Positive Fatal Cases(n = 33)
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Dengue Virus (DENV)• Single stranded RNA virus• Member of Flavivirus family
Selected Flaviruses
Tick-borne encephalitis virus
West Nile VirusMurray Valley Encephalitis VirusJapanese Encephalitis Virus
St. Louis Encephalitis Virus
DENV 1DENV 3
DENV 2DENV 4
Yellow Fever Virus
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0 5 90yearsTime Post-Onset of Symptoms
IgGIgM
Virus
5Time Post-Onset of Symptoms
IgG
IgM
0 90years
Virus
Primary Dengue Infection Secondary Dengue Infection
Current Diagnostic Methods
IgM is not detectable ~20% of acute 2° cases
days days
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Atypical Routes of Dengue Transmission
• Evidence of transmission of dengue through receipt of donor organs or tissue1
− Bone marrow, renal transplant• Transmission of dengue documented via receipt
of blood products (RBC transfusion)2,3
– Screening of PR blood bank donors found virus in 1 per 1,000 donors during a non-outbreak year4
• Seven reports of transmission after occupational exposure in a healthcare setting1
1 Wilder-Smith A, et al. ,Threat of Dengue to Blood Safety in Dengue-Endemic Countries. EID 2009; 15(1):8-11. 2 Chuang et al., Review of dengue fever cases in Hong Kong during 1998 to 2005. Hong Kong Med J 2008;14:170-177.3 Tambyah et al., Dengue hemorrhagic fever transmitted by blood transfusion. N Engl J Med 2008;359:1526-1527.4 Mohammed, H. et al. , Dengue Virus in Blood Donations, Puerto Rico, 2005. Transfusion 2008; 48:1348-1354.
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Vertical Transmission of Dengue4
• Infrequent, but can occur in utero or during parturition – Rates may depend on severity of maternal infection
• Symptomatic congenital DENV infections had symptomatic mother with infection late in pregnancy or at delivery
• Average time between mom and newborn onset is 7 days
• Most congenital cases described had fever, thrombocytopenia and hepatomegaly– Hemorrhagic manifestation in half– Pleural effusion and/or rash in one quarter– Clinical presentation not associated with maternal immune
status or mode of delivery4Pouliot S.H., et al., Maternal dengue and pregnancy outcomes: a systematic review. Obstetr Gynecol Survey 2010.
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Risk factors for Severe Dengue• Host factors
• Obesity1
• Chronic disease (diabetes, asthma)2
• Previous dengue infection1 • Age (infant)1
• Co-circulation of multiple serotypes in the same geographic region
• Level of neutralizing antibody• Timing of infection key as protective immunity wanes2
1 Scott Halstead (2008). Dengue. Tropical Medicine: Science and Practice. London: Imperial College Press.2Figueiredo MAA, et al. (2010) Allergies and Diabetes as Risk Factors for DHF. PLoS Negl Trop Dis 4(6): e699.
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0100200300400500600700800900
1000
Rep
orte
d C
ases
(Tho
usan
ds)
Reported Cases of Dengue in the Americas, 1980 – 2008*
*Note: Reported cases as of January 27,2009 from Pan American Health Organization (PAHO)
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Evaluation
Developer Producer Vaccine Type Phase 1Phase
2Phase
2b
Sanofi Pateur Sanofi PateurTetravalent
live-attenuatedchimera (YF17d)
2010(underway)
WRAIR GlaxoSmithKline
Tetravalentlive Attenuated ? 2010
NIH Buntantan
DENV-DENV (1,2,3)
Chimera + DENV-4
with gene deletion
2009(completed
in USA)2010
(Brazil)
CDC InViragen/SingVax
DENV-DENV (1,3,4)
Chimera + DENV-2 live attenuated
2010?
HawaiiBiotech
HawaiiBiotech
MonovalentRecombinant
Envelope subunit2009
(underway)
Current dengue vaccine candidates
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Differential Diagnosis of Dengue
• Leptospirosis• Influenza• Malaria• Typhoid fever• Measles• Rubella• Rickettsial
infections (typhus, scrub typhus)
• Enterovirus• Meningococcemia• Bacterial sepsis• Chikungunya• West Nile Virus• Other viral
hemorrhagic fevers
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Dengue Case Investigation Report
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Life Cycle of Aedes aegypti
Eggs
Larva
Pupa
Adult
Female lays on average 100-120 eggs on inside of containers (above water) five times in her lifetime.
Eggs survive for up to 6 months and hatch when submerged in water (takes ~24 hours).
Approximately 6 days
2 days
Note: Fecundability dependent on environmental conditions such as rain, humidity and temperature. The total time for development is dependent upon water temperature and food supply, and typically ranges from 4 to 10 days. Larvae die at temperatures below 10 degrees and above 44 degrees Celsius.
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Recent US Dengue Outbreaks 1980 – Texas 63 cases (23 no travel) 1986 – Texas-Mexico border 17 cases from
passive surveillance (9 no travel) 1995 – Texas 29 cases from active
surveillance (7 no travel) 1999 – Laredo, Texas 11 cases from active
surveillance (2 no travel) 2001 – Hawaii 165 cases via active
surveillance 122 no travel, 7 cases in visitors to Hawaii
2005 – Cameron County, Texas Active surveillance (24 cases, 2 no travel) Retrospective medical review (16 cases)
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Leptospirosis Potentially fatal acute
febrile illnesses Clinical presentation similar to
dengue
Infection via exposure to animal urine Rats, dogs most common
Caused by Leptospira bacteria >200 serovars
Endemic in Puerto Rico Passive surveillance
Images: khmersong.info (top); (bottom).
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Lepto Deaths and Dengue Cases by Month, 2010
Lepto Deaths
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec0
500
1000
1500
2000
2500
0
2
4
6
8
10Suspected lepto deaths*
Week of Illness Onset
Confi
mre
d De
ngue
Cas
es
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Geographic Distribution of Leptospirosis Deaths, 2010
= 1 confirmed fatal case= 2 confirmed fatal cases
= 1 suspected fatal case
= 2 suspected fatal cases