Dengue and Yellow Fever: The Anatomy of Decline and Emergence Duane J. Gubler, Professor and Director Signature Research Program in Emerging Infectious Diseases Duke-NUS Graduate Medical School, Singapore and Asia-Pacific Institute of Tropical Medicine and Infectious Diseases, John A Burns School of Medicine, University of Hawaii, Honolulu 1 Dengue and yellow fever: decline and emergence Background on epidemiology and clinical Yellow fever decline Re-emergence emergence of dengue Reasons for re-emergence of dengue Re-emergence of yellow fever? Possible explanations for the lack of yellow fever re-emergence 2 Yellow fever and dengue viruses Family: Flaviviridae Genus: Flavivirus Yellow fever virus; Prototype flavivirus Dengue viruses Serotypes: Denv-1 Denv-2 Denv-3 Denv-4 3 1
Flavivirus phylogeny Nonstructural gene JE MVE WN SLE ROC ILH BAG BSQ IGU KOK KED ZIKA DEN1 DEN2 DEN3 Mosquito-borne 0.1 DEN4 YF SEP ENT LI TBE LGT ALK DT POW RB MML MOD APOI KRV CFA Tick-borne No vector Insect TB 4 Yellow fever and dengue virus genome Kuhn, et al., 2006 5 Africa Transmission cycles of yellow fever Enzootic zone Ae. africanus Zone of emergence Ae. furcifer etc. Epidemic zone Ae. aegypti Monkey?Transovarial Monkey transmission Transovarial Human transmission Monkey Human Ae. africanus Tick Tick (Amblyomma) Ae. furcifer taylori luteocephalus opok Other africanus vertebrate? simps. ni monkey etc. Ae. aegypti Known part of cycle Speculative part of cycle 6 2
Yellow fever transmission cycle in the Americas Haemagogus Ae. aegypti Monkey Marmoset Transovarial Monkey Marmoset Human Transovarial Human Haemagogus Ae. aegypti Jungle cycle Urban cycle 7 Transmission and maintenance cycles of dengue viruses Aedes Mosquitos Aedes Mosquitos Aedes Mosquitos Vertical Vertical Vertical Primates transmission Primates Humans transmission Humans Humans transmission Humans Aedes Mosquitos Aedes Mosquitos Aedes aegypti 8 Aedes aegypti 9 3
Principal urban vector of DEN and YF Vector: Aedes aegypti Biology: Urban Day biting Breeds in domestic water Preferentially bites man Highly efficient epidemic vector 10 Aedes aegypti 11 12 4
Yellow fever Disease: the original viral hemorrhagic fever, a systemic illness with High viremia Hepatic, renal, myocardial injury Hemorrhage Shock syndrome Case fatality, 20% 13 Dengue hemorrhagic fever Fever, or recent history of acute fever Hemorrhagic manifestations Low platelet count (100,000/mm 3 or less) Objective evidence of vascular leakage Case fatality rate: average 5% Pan American Organization: Dengue and Dengue Hemorrhagic Fever: Guidelines for Prevention and Control; PAHO: Washington, DC, 1994: 13 14 Differential diagnosis of dengue and yellow fever Influenza Measles Rubella Malaria Typhoid fever Leptospirosis Rickettsial infections Bacterial sepsis Other viral hemorrhagic fevers 15 5
16 Yellow fever history 1600s - Virus, vector introduced from Africa 1648 - Yucatan epidemic, Mayan records 1750 - Term yellow fever first used in Barbados 18th-19th Centuries - major epidemics, Americas, Europe, West Africa 1900 - Reed demonstrates filterable virus transmitted by Ae. aegypti; vector control o begins 1904-1912 - Yellow fever controlled in Cuba and Panama 1905 - Last outbreak in U.S. (New Orleans) 1927 - Virus isolated in Africa 1932 - YF jungle transmission cycle (Brazil, then Africa) sylvatic mosquitoes and non-human primates 1936 - Yellow fever vaccine developed 1946 - Aedes aegypti eradication program in Americas 17 Importance of the 1890s Filterable agent (=virus) as cause of animal disease Malaria transmission by mosquito Discovery of extrinsic incubation period Yellow fever transmission by Ae. aegypti Spanish-American War 18 6
19 Urban yellow fever epidemics in the United States 1793-1905 1. Philadelphia, 1793; 5,000 dead 2. New York City, 1795; 730 dead 3. Boston, New York City and Philadelphia; 1798; more than 5,000 dead 4. Baltimore, 1800; 1,200 dead 5. New Orleans, 1853; 8000 or more dead 6. Norfolk, 1855; 2,000 dead 7. Mississippi Valley, 1878; 20,000 dead 8. Cuba, 1898; hundreds dead 9. New Orleans, 1905; more than 900 dead Currently: Rare imported cases with travel history No local transmission 20 21 7
Reported cases of yellow fever 1948-98 WHO Report, 2000 22 Aedes aegypti distribution in the Americas 1930's 1970 2010 Adapted from Gubler, 1998 23 Dengue: a historical perspective More important epidemics of dengue-like illness China - 992 Caribbean - 1635 Panama - 1699 Spain/Africa - 1700s Batavia, Indonesia - 1779 Cairo, Egypt - 1779 Philadelphia, PA, USA - 1780 Spain - 1801 Cuba - 1828 Americas and Asia-Pacific - 1800s & early 1900s World War II - 1941-45 Aedes aegypti eradication program in Americas, 1946 Post war era - 20 th Century re-emergence 24 8
Epidemic dengue hemorrhagic fever / dengue shock syndrome emerged as newly recognized disease in Southeast Asia in the 1950s At the end of WWII all four serotypes of dengue were widespread in Asia 25 Expanding geographic distribution of epidemic dengue/dengue hemorrhagic fever in Asia 1950-1969 1970-1979 1980-2010 Adapted from Gubler, 1998 26 Aedes aegypti distribution in the Americas 1930's 1970 2010 Adapted from Gubler, 1998 27 9
The emergence of dengue hemorrhagic fever in the Americas Prior to 1981 1981-2010 Adapted from Gubler, 1998 28 Re-emergence emergence of dengue in the US 1980 29 Autochthonous dengue in the United States Year 1980 1986 1995 1997 1998 Location Texas Texas Texas Texas Texas No. Cases 27 9 7 3 1 1999 Texas 17 2001 Hawaii 122 2005 Texas 25 2007 Texas? 2009 Florida 27 2010 Florida 16 30 10
Dengue fever in Africa Prior to 1980 1981-2010 Adapted from Gubler, 1998 Epidemic transmission Areas at risk 31 Expanding geographic distribution Increased epidemic activity Hyperendemicity Emergence of DHF The 20th century re-emergence of epidemic dengue ses Number of cas 1400000 1200000 1000000 800000 600000 Average annual number of DF/DHF cases reported to WHO, 1955-2008 400000 295,554 Number of cases 200000 122,174 479,848 1,151,300 70 60 50 40 30 20 10 Number of countr ries Source: DengueNet 2008 data provisional 0 908 15,497 1955-1959 1960-1969 1970-1979 1980-1989 1990-1999 2000-2008 0 32 Approximate global distribution of dengue and Aedes aegypti, by state/province, 2010 Adapted from Gubler, 1998 Areas with recent dengue transmission Areas infested with Aedes aegypti 33 11
Public health impact of dengue 2.5-3 billion people live in areas of risk 50-100 million cases/infections/year Millions hospitalized 500,000 cases of dengue hemorrhagic fever 20,000 plus deaths Incidence and geographic range are increasing Economic impact No vaccine or antiviral drugs Mosquito control has been largely ineffective 34 Why have we seen such a dramatic increase in epidemic dengue/dengue hemorrhagic fever? Complacency, Lack of political will Policy changes Changes in public health Changing life styles/behavior Microbial adaptation Technology Climate change? 35 Why have we seen such a dramatic increase in epidemic dengue/dengue hemorrhagic fever? Major drivers Demographic changes (Pop. growth and distribution) Environmental change Uncontrolled urbanization Modern transportation (Globalization) Increased movement of people, animals, commodities Lack of effective mosquito control 36 12
Estimated number of people living in urban areas of people Billions o 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 1950 1985 2000 2030 Source: UN 37 The urban and rural population of the world 1950-2030 38 Urbanization The case of Dhaka, Bangladesh Number of people e (Millions) 16,000,000 14,000,000 12,000,000 10,000,000000 000 8,000,000 6,000,000 4,000,000 2,000,000 0 1,500,000 14,000,000 1970 2008 Source: UN 39 13
Emergence of dengue/dengue hemorrhagic fever Uncontrolled urbanization Crowding Living conditions Lack of basic services: inadequate housing, piped water, sewage and waste management From: PAHO, 1997; Gubler, 1998 40 Urban agglomerations, 1950, 2000, 2015 5 million & over since 1950 5 million & over since 2000 5 million & over in 2015 (projected) Source: UN, World Urbanization Prospects, The 1999 Revision 120 100 80 60 40 20 0 1950 2000 2015 Asia S. America Sub-Sahara Africa 41 Urban Popu ulation (Millions) 3000 2500 2000 1500 1000 500 Urban population growth and reported dengue cases 0 1950s 1960s 1970s 1980s 1990s 2000s Estimated Number of People Living in Urban Areas - World Population data, UN; Dengue data, WHO, to April, 2008 1200000 1000000 800000 600000 400000 200000 Dengue C ases Dengue/DHF - Average Annual Number of Cases Reported to WHO - World 0 42 14
Dengue viruses & mosquitoes: hitching a ride on modern transportation 43 The global airline network PNAS, 2004 44 Mean annual number of airline passengers by decade, United States, 1954-2007 700 sengers Millions of pas 600 500 400 300 200 100 0 1950s 1960s 1970s 1980s 1990s 2000s Source: RITA, DOT 45 15
46 Global movement of dengue (1971-1980) 1979 1980 DENV 1; DENV 2; DENV 3; DENV 4 47 Global movement of dengue (1981-1990) 1985 DENV 1; DENV 2; DENV 3; DENV 4 48 16
Global movement of dengue (1991-2000) 1994 1994 DENV 1; DENV 2; DENV 3; DENV 4 49 Global distribution of dengue virus serotypes, 1970 DEN-3 DEN-4 Gubler, 1998 50 Global distribution of dengue virus serotypes, 2010 DEN-3 DEN-4 DEN-3 DEN-4 DEN-3 DEN-4 DEN-3 DEN-4 DEN-3 DEN-3 DEN-4 DEN-3 DEN-4 DEN-3 DEN-4 DEN-3 DEN-4 Adapted from Gubler,1998 51 17
Yellow fever: re-emergence? Low YF vaccine coverage rates Increased global travel Encroachment of humans into sylvatic cycle Human migration and urbanization Reinfestation by Aedes aegypti of urban areas threatens major population centers 52 Number of yellow fever cases and deaths reported to WHO, by decade, 1950-1999 18000 16000 14000 12000 10000 8000 6000 4000 2000 0 1950-59 1960-69 1970-79 1980-89 1990-99 Cases Deaths 53 Aedes aegypti distribution in the Americas 1930's 1970 2010 Adapted from Gubler, 1998 54 18
Potential for urban yellow fever epidemics in the Americas 55 Imported yellow fever Texas 2002 Belgium 2000 California 1999 Germany 1999 Switzerland 1996 Tennessee 1996 56 Urban yellow fever, Santa Cruz, Bolivia Dec 1997 - June 1998 Two clusters of transmission Six acute cases confirmed Five died (Three cases likely contracted infection in the city) Serosurvey - 281 16 (6%) had YF antibody 5 - no previous immunization 57 19
Epidemiologic distribution of yellow fever, Brazil RR AP AM PA RO AC TO MT Enzootic Area Epizootic Area YF Free Area MS RS GO DF SP PR SC MA MG PI BA RJ CE Dados Gerais: RN PB Endemic areas: PE AL States: 12 SE Population: 27,014,229 Epizootic area : States parts of 3 Population 10,443,215 ES YF free area : States: 15 Fonte: SUCAM/MS Vasconcelos, P.F. (1997) 58 Distribution of confirmed cases of yellow fever by date of onset of symptoms, Laurelty, Paraguay, 2008 Feb 1 Feb 15 Feb 6 Feb 2 Jan 11 Feb 8 Feb 4 Feb 17 Feb 1 Feb 28 59 Hypothesis to explain the absence of urban yellow fever epidemics in the Americas Cross-protective flavivirus immunity Evidence through monkey experiments Virus Adaptation ti Humans Aedes aegypti Evolutionary exclusion 60 20
Hypothesis to explain the absence of yellow fever in Asia A matter of logistics Cross-protective flavivirus immunity Low vector competence of Asian Aedes aegypti Geographic and demographic obstacles to spread yellow fever virus Evolutionary exclusion 61 Potential global spread of urban yellow fever 62 Dengue and yellow fever viruses Summary Both old diseases Both effectively controlled Dengue re-emerged; yellow fever did not Dengue viruses evolved with urbanization Yellow fever remained in the jungle Current global threat 63 21
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