avery lee, ms rennie ferguson, mhs susan henderson, md,...

Avery Lee, MS

Rennie Ferguson, MHS

Susan Henderson, MD, MPH

Outline

• Dengue• Virus

• Vector

• Clinical Manifestation

• Immunity

• Epidemiology

• Intervention

• Results• Dengue Incidence among PCVs

• Peace Corps vs. WHO data

• Explanation• Increased risk among travelers

• Underreporting

• Other explanations

• Dengue is caused by four serologically related but antigenically distinct

viruses, known as DENV-1, DENV-2, DENV-3, and DENV-4

• Dengue viruses are single-stranded, positive-sense, and composed of

RNA

• DENV-1 was first isolated in 1943 from the blood of a Japanese patient

The Virus

• The four dengue viruses originated in monkeys and independently

jumped to humans between 100 and 800 years ago (9)

• The record of a disease outbreak in Philadelphia in 1780 points to

dengue fever

• Dengue was geographically limited until the middle of the 20th Century

• The first known epidemic of severe dengue occurred in the Philippines in

1953

The Virus

• Aedes aegypti mosquitoes are the principal vector of dengue

• They can also transmit chikungunya, yellow fever, and zika virus

• Females preferentially feed indoors during the daytime and bite multiple

people in a single feeding period

The Vector

• Eggs are commonly deposited in man-

made water containers and can survive

drying for up to several months

• Female mosquitoes acquire the virus by biting an infected human

• The virus incubates for 8 to 12 days inside the mosquito before it

can be transmitted

• The virus is introduced into the blood stream of a human from the

mosquito salivary glands when the female takes a blood meal

• Symptoms generally last for 2 to 7 days, during which time the virus

can be taken up by mosquitos

Transmission

• Dengue infections are often asymptomatic in children younger than 15,

but symptomatic in adults

• Clinical disease can present as dengue or severe dengue

• Dengue is a milder, generally self-limiting infection

• Severe dengue is characterized by complications

such as plasma leakage or severe bleeding

Clinical Manifestations

• Chikungunya presents with

similar symptoms to dengue

fever

• Clinical distinction: severe joint

pain accompanies most

chikungunya infections but is

rare among dengue patients

• Laboratory distinction: elevated

hematocrit occurs in 40-69% of

dengue patients but does not

occur in patients with

chikungunya (23)

PAHO and CDC (2011) Preparedness and

Response for Chikungunya Virus Introduction in

the Americas

• Dengue infection provides long-term immunity to the infecting serotype

and 2 to 3 months immunity to the three non-infecting serotypes

• Secondary infection with a different serotype increases the risk of severe

disease

– Improved clinical management has resulted in a decline in case fatality

among hospitalized severe dengue cases from 20% to less than 0.5%

• Antibody-dependent enhancement

– Explains the increased risk for severe disease among dengue patients with a

secondary infection

Immunity

Antibody-Dependent Enhancement

• Dengue infections occur in more than 100 countries in the Asia-Pacific

region, the Americas, the Middle East and Africa

• Incidence, distribution, and clinical severity of dengue has increased

globally over the last 60 years

Epidemiology

• The WHO currently estimates that there are 390 million dengue

infections per year, of which 96 million manifest apparently (24)

• Roughly 2.5 billion people live in areas potentially at risk for dengue

transmission

• 5 vaccines are in the clinical

stages of development

• CYD-TDV vaccine

– The only vaccine to enter Phase

III clinical trials

– Tetravalent live-attenuated

vaccine developed by Sanofi

Pasteur Group

Clinical Interventions

• Asia CYD-TDV Vaccine Phase III Trial

– 10,275 subjects aged 2 to 14 years old

– 56.5% overall efficacy

– 88.5% efficacy against severe dengue

• Latin America CYD-TDV Vaccine Phase III Trial

– 20,869 subjects aged 9 to 16 years old

– 60.8% overall efficacy

– 91.7% efficacy against severe dengue

• December 2015: market approval in Mexico,

Brazil, and the Philippines

Clinical Interventions

• Environmental management and modification

• Chemical control interventions

• Biological interventions

• Integrated vector management involves

a combination of interventions as well as

community education and involvement (11)

Environmental Interventions

• Personal protection can be an important barrier to Aedes aegypti

mosquitoes and other disease-carrying vectors

• Insecticides

– The CDC recommends using products with 20% to 50% DEET

concentration

• Clothing

– Permethrin-treated clothing repels mosquitoes and kills insects that come in

contact with the cloth (28)

Individual-Level Interventions

• Created by President JFK in 1961

• To help the people of interested countries in meeting their need for

trained men and women

• To help promote a better understanding of Americans on the part of

the peoples served

• To help promote a better understanding

of other peoples on the part of Americans

United States Peace Corps

• Americans who have served: nearly 220,000

• Host countries served to date: 141

• Gender: 63% female, 37% male

• Minorities: 28% of Volunteers

• Average age: 28

• Volunteers over 50: 7% of Volunteers

Peace Corps Demographics

Carolyn Hessler-Radelet,

Peace Corps Director

• Percentage of total Volunteers serving, by geographic region, in 2015

– Africa: 45%

– Latin America: 22%

– Eastern Europe/

Central Asia: 10%

– Asia 13%

– The Caribbean: 4%

– North Africa/ Middle East: 3%

– Pacific Islands: 3%

Peace Corps Location of Service

• Peace Corps Volunteers (PCVs) commit to a 27-month assignment

abroad

• Work at the grass-roots level around the world, primarily in low- and

middle-income countries

• Generally young and healthy individuals

• PCVs have a unique risk of dengue due

to long-term travel to endemic countries as

as well as in-country living conditions

Peace Corps Volunteers

• Monthly Epidemiological Surveillance System (ESS) reports submitted

to the PC Epidemiology Unit by Peace Corps Medical Officers (PCMOs)

• ESS reports include the number of laboratory confirmed dengue cases

• Peace Corps countries divided into the following regions: Europe and

Central Asia, East and South Asia, Africa, Caribbean, Central America,

South America, and Pacific Islands

Methods

• Dengue incidence rates calculated using the yearly total of dengue

cases and Volunteer/Trainee years (VT years)

– All rates reported in cases per 1,000 VT Months

• Data analyzed using SAS 9.3 (Cary, NC), OpenEpi 3 (Atlanta, GA), and

ArcGIS 10.3.1 (Redlands, CA)

Methods

Results

1.2

0.9

0.6

1.2

1.0

1.2 1.2

1.7

0.7

1.2

1.5

0.7

1.4

1.6

0.8

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Case

s p

er

1,000 V

T M

on

ths

Overall Incidence Rates of Dengue among PCVs, 2000-2014

Results

0.03 0.12

1.16

2.302.55

3.34

5.51

0.0

1.0

2.0

3.0

4.0

5.0

6.0

Europe andCentral Asia

Africa South America Pacific Islands Central America East and SouthAsia

Caribbean

Case

s p

er

1,000 V

T M

on

ths

Cumulative Incidence Rates of Dengue Among PCVs by Region, 2000-2014

Results

Europe and Central Asia0.5%

East and South Asia19.8%

Africa4.3%

Central America31.6%

Caribbean25.8%

South America9.8%

Pacific Islands8.2%

Percentage of Dengue Cases by Region, 2000-2014

Results

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Case

s p

er

1,000 V

T M

on

ths

Incidence Rates of Dengue Among PCVs, 2000-2014

Results

0

100

200

300

400

500

600

700

800

900

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Rati

o

Ratio of Dengue Incidence Among PCVs Compared to WHO Reported Dengue Incidence

Domincan Republic

Nicaragua

Philippines

Risk Among Travelers

• A cohort study of Dutch travelers to Asia in 2002 reported an dengue

incidence rate of 30.0 cases per 1,000 person-months (7)

• A study conducted in 2013 among long-term aid workers from New

Zealand reported a dengue incidence

rate of 3.4 cases per 1,000

person-months (31)


• Bhatt et al. compiled data from 27 cohort studies and determined a

mean dengue incidence rate of 129.7 cases per 1,000 person-years

(10.8 per 1,000 person-months) (2)

• Multiple cohort studies involving short-term American missionary trips to

the Caribbean have reported dengue infection in 25% or more of

travelers (20, 21, 26)


• The increased risk among PCVs could potentially be explained by their

lack of previous exposure

• A study conducted in 2006 in Nicaragua found that the overall

seroprevalence of dengue antibodies among school-aged children was

91% (1)

• A similar study in the Dominican Republic reported that 98% of adults

and 56% of children under 10 were positive for dengue IgG anitbodies

(35)

Underreporting

• Underreporting is a major issue in

dengue surveillance

• In 2010, there were an estimated

96 million clinically apparent

dengue cases globally; only 2.2

million cases were reported to the

WHO

Underreporting

• Most dengue surveillance is passive and many countries do not require

reporting of dengue cases in adults

• The Nicaraguan Pediatric Dengue Cohort Study identified an average of

21.3 times more dengue cases per 100,000 persons per year than the

Nicaraguan Ministry of Health (27)

• Vong et al. estimated that there was as high as a 30-fold degree of

under-recognition and underreporting of dengue in Cambodia between

2006 and 2008 (32)

Other Explanations

• Differences in treatment seeking behavior

• Demographic and genetic differences between PCVs and host country

nationals

• Differences in use of personal protection to avoid mosquito bites

• Dengue testing may be more readily available to PCVs

• PCMOs may be more inclined to test for dengue than other physicians

Conclusions

• The incidence rate of dengue among PCVs globally appears to follow a

3-year cyclical pattern

• Each region demonstrated a unique pattern in dengue incidence rates

over the 15-year study period

• Peace Corps Volunteers serving in the Caribbean appear to be at the

highest risk for contracting dengue

• Countries with the highest cumulative incidence rates appear to be

geographically clustered within each region

Conclusions

• The rate of dengue infection among PCVs appears to be higher than

the rate reported among host country nationals in high-incidence

countries. Explanations:

– Lack of previous exposure to dengue

– Underreporting

• The distribution of dengue is ever-changing

• Continued surveillance is critical for understanding transitions in

disease patterns and informing public health decision making

• Continued monitoring of dengue incidence among PCVs in order to

inform decision making when a vaccine becomes available

• PCMEDICS

– Information about demographics, comorbidities, and hospitalization of

dengue patients

• Education for PCVs

– Adherence to mosquito control is currently the only way to reduce dengue

incidence

– This data may eventually be available for prospective Peace Corps

Volunteers

Next Steps

Questions?

1. Balmaseda A, Hammond SN, Tellez Y, et al. (2006) High seroprevalence of antibodies against dengue virus in a prospective study of

schoolchildren in Managua, Nicaragua. Tropical Medicine and International Health;11(6): 935-942

2. Bhatt S, Gething W, Brady OJ, et al. (2013) The global distribution and burden of dengue. Nature;496: 504-507.

doi:10.1038/nature12060

3. Blamont M and Mennella N (2015) Sanofi wins first dengue vaccine market approval in Mexico. Reuters.

http://www.reuters.com/article/us-sanofi-dengue-idUSKBN0TS1ZK20151209

4. Brady OJ, Gething PW, Bhatt S, et al. (2012) Refining the Global Spatial Limits of Dengue Virus Transmission by Evidence-Based

Consensus. PLoS Neglected Tropical Diseases;6(8): e1760. doi:10.1371/journal.pntd.0001760

5. Brown MG, Vickers IE, Salas RA, Smikle MF (2009) Seroprevalence of dengue virus antibodies in healthy Jamaicans. Human

Antibodies;18(4): 123-126. doi: 10.3233/HAB-2009-0207

6. Capeding MR, Tran NH, Hadinegoro SR, et al (2014) Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy

children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. The Lancet;384(9951): 1358-1365. doi:

10.1016/S0140-6736(14)61060-6

7. Chan M, Johansson MA (2012) The Incubation Periods of Dengue Viruses. PLoS ONE 7(11): e50972.

doi:10.1371/journal.pone.0050972

8. Cobelens F, Groen J, Osterhaus A, Leentvaar-Kuipers A, Dillen P, Kager P (2002) Incidence and risk factors of probable dengue virus

infection among Dutch travelers to Asia. Tropical Medicine and International Health;7(4): 331-338.

9. Cologna R, Armstrong P, Rico-Hesse R (2005) Selection for Virulent Dengue Viruses Occurs in Humans and Mosquitos. Journal of

Virology;79(2): 853-859. doi:10.1128/JVI.79.2.853-859.2005

10. Dechant EJ, Rigau-Perez JG (1999) Hospitalizations for suspected dengue in Puerto Rico, 1991 – 1995: estimation by capture-

recapture methods. The Puerto Rico Association of Epidemiologists. American Journal of Tropical Medicine and Hygiene;61(4): 574-

578.

11. Dick OB, San Martin JL, Montoya RH, Diego J, Zambrano B, and Dayan GH (2012) Review: The History of Dengue Outbreaks in the

Americas. American Journal of Tropical Medicine and Hygiene;87(4): 584-593. doi:10.4269/ajtmh.2012.11-0770.

12. Erlanger TE, Keiser J, Utzinger J (2008) Effect of dengue vector control interventions on entomological parameters in developing

countries: a systematic review and meta-analysis. Medical and Veterinary Entomology;22(3): 203-221. doi: 10.1111/j.1365-

2915.2008.00740.x

References

13. Gibbons RV, Vaughn DW (2002) Dengue: an escalating problem. British Medical Journal;324: 1563-1564. Internet ISSN: 1756-1833

14. Gubler DJ. (1998) Dengue and dengue hemorrhagic fever. Clinical Microbiology Reviews;11(3): 480-496. PMCID: PMC88892

15. Guha-Sapir D, Schimmer B. (2005) Dengue fever: new paradigms for a changing epidemiology. Emerging Themes in

Epidemiology;2(1). doi:10.1186/1742-7622-2-1

16. Guzman MG, Kouri G (2003) Dengue and dengue hemorrhagic fever in the Americas: lessons and challenges. Journal of Clinical

Virology; 27(1): 1-13. doi:10.1016/S1386-6532(03)00010-6

17. Hoffman AA, Montgomery BL, Popovici J, et al. (2011) Successful establishment of Wolbachia in Aedes populations to suppress

dengue transmission. Nature;476(7361): 454-457. doi:10.1038/nature10356

18. Mahmood S, Nabeel H, Hafeez S, Zahra U, Nazeer H (2013) Seroprevalence of Dengue IgG Antibodies among Healthy Adult

Population in Lahore, Pakistan. ISRN Tropical Medicine. Article ID 521396, 6 pages. http://dx.doi.org/10.1155/2013/521396

19. Martin JLS, Brathwaite O, Zambrano B, Solorzano JO, et al. (2010) The Epidemiology of Dengue in the Americas Over the Last

Three Decades: A Worrisome Reality. The American Journal of Tropical Medicine and Hygiene; 82(1): 128-135.

doi:10.4269/ajtmh.2010.09-0346

20. Messina JP, Brady OJ, Scott TW, et al. (2014) Global spread of dengue virus types: mapping the 70 year history. Trends in

Microbiology;22(3): 138-146. doi:10.1016/j.tim.2013.12.011

21. Moncayo AC, Baumblatt J, Thomas D, et al. (2015) Short Report: Dengue among American Missionaries Returning from Jamaica,

2012. The American Journal of Tropical Medicine and Hygiene;92(1): 69-71. doi:10.4269/ajtmh.l4-0341

22. MMWR (2010)Dengue Fever Among U.S. Travelers Returning from the Dominican Republic – Minnesota and Iowa, 2008;59(21):

654-656.

23. OhAinle M, Balmaseda A, Macalalad A, et al.(2011) Dynamics of Dengue Disease Severity Determined by the Interplay Between

Viral Genetics and Serotype-Specific Immunity. Science Translational Medicine;3(114): 114-128. doi:10.1126/scitranslmed.3003084.

24. Pan American Health Organization. Chikungunya.

http://www.paho.org/hq/index.php?option=com_topics&view=article&id=343&Itemid=40931&lang=en

References

25. Pan American Health Organization. Dengue.

http://www.paho.org/hq/index.php?option=com_content&view=article&id=264:dengue&Itemid=40170&lang=en

26. Rigau-Perez J, Clark G, Gubler D, Reiter P, Sanders E, Vorndam A (1998) Dengue and dengue haemorrhagic fever.

Lancet;352(9132): 971-977. doi:10.1016/S0140-6736(97)12483-7

27. Sharp TM, Pillai P, Husperger E, et al.(2012) A cluster of dengue cases among American missionaries returning from Haiti, 2010.

The American Journal of Tropical Medicine and Hygiene; 86(1): 16-22. doi:10.4269/ajtmh.2012.11-0427.

28. Standish K, Kuan G, Avile´s W, Balmaseda A, Harris E (2010) High Dengue Case Capture Rate in Four Years of a Cohort Study in

Nicaragua Compared to National Surveillance Data. PLoS Neglected Tropical Diseases;4(3): e633.

doi:10.1371/journal.pntd.0000633

29. Sukumaran D, Sharma A, Wasu Y, Pandey P, Tyagi V (2014) Knockdown and repellent effect of permethrin-impregnated army

uniform cloth against Aedes aegypti after different cycles of washings. Parasitology Research;113(5):1739-1747.

doi:10.1007/s00436-014-3819-7

30. Van Roey K, Sokny M, Durnez L, et al. (2014) Field Evaluation of Picaridin Repellents Reveals Differences in Repellent Sensitivity

between Southeast Asian Vectors of Malaria and Arboviruses. Plos Neglected Tropical Diseases;8(12):1-10.

doi:10.1371/journal.pntd.0003326

31. Villar L, Dayan GH, Arredondo-Garcia JL, et al. (2015) Efficacy of a Tetravalent Dengue Vaccine in Children in Latin America. The

New England Journal of Medicine;372(2): 113-123. doi:10.1056/NEJMoa1411037

32. Visser JT, Edwards CA (2013) Dengue Fever, Tuberculosis, Human Immunodeficiency Virus, and Hepatitis C Virus Conversion in a

Group of Long-Term Development Aid Workers. Journal of Travel Medicine;20(6): 361-367. doi:10.1111/jtm.12072

33. Vong S, Goyet S, Ly S, et al. (2012) Under-recognition and reporting of dengue in Cambodia: a capture-recapture analysis of the

National Dengue Surveillance System. Epidemiology and Infection;140(3): 491-499. doi: 10.1017/S0950268811001191

34. World Health Organization. Annual Dengue Data in the Western Pacific Region.

http://www.wpro.who.int/emerging_diseases/annual.dengue.data.wpr/en/

35. World Health Organization. Dengue and severe dengue. http://www.who.int/mediacentre/factsheets/fs117/en/

36. Yamashiro T, Dilsa M, Petit A, et al. (2004) Seroprevalence of IgG Specific for Dengue Virus Among Adults and Children in Santo

Domingo, Dominican Republic. American Journal of Tropical Medicine and Hygiene;71(2): 138-143.

References

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