1. A Global Perspective on Emerging Mosquito-Borne Diseases
JV Irons / RR Parker Memorial Lecture
Laura D. Kramer
Wadsworth Center
New York State Dept Health
Ft. Worth, Texas June 3, 2009

2. Defined the concept of EID Identified factors contributing
to disease emergence
Pointed to challenges posed
by infectious diseases
This landmark report defined the concept of emerging and reemerging infections, identified factors contributing to disease emergence and reemergence, and emphasized current and future challenges posed by infectious diseases. The report also highlighted deficiencies in our nation's public health infrastructure and made recommendations on the need to strengthen surveillance systems, address new areas of research, provide multidisciplinary training for the next generation of scientists and public health workers, and establish new and enhance existing disease prevention and control programs
Emerging Infections: Microbial Threats to Health in the United States. Joshua Lederberg, Robert E. Shope, and Stanley C.Oaks, Jr., Editors; Committee on Emerging Microbial Threats to Health, Institute of Medicine (1992)

3. “…the United States has no comprehensive national system for detecting outbreaks of infectious disease. Outbreaks of any disease that is not on CDC's current list of notifiable illnesses may go undetected or may be detected only after an outbreak is well under way.”
“Although many local and regional vector-control programs can effectively combat small and even medium-size outbreaks of vector-borne disease, they are not equipped to deal with outbreaks that are national in scope.”
This landmark report defined the concept of emerging and reemerging infections, identified factors contributing to disease emergence and reemergence, and emphasized current and future challenges posed by infectious diseases. The report also highlighted deficiencies in our nation's public health infrastructure and made recommendations on the need to strengthen surveillance systems, address new areas of research, provide multidisciplinary training for the next generation of scientists and public health workers, and establish new and enhance existing disease prevention and control programs
“The significance of zoonoses in the emergence of human infections cannot be overstated.”
Emerging Infections: Microbial Threats to Health in the United States. Joshua Lederberg, Robert E. Shope, and Stanley C.Oaks, Jr., Editors; Committee on Emerging Microbial Threats to Health, Institute of Medicine (1992)

4. Outline Drivers of emerging / re-emerging diseases
Re/emerging flavivirus
West Nile
Re/emerging alphavirus
Chikungunya
Atlantic Monthly, 1997

5. Re/emerging infectious diseases
Define the concept. EIDs are infections that have newly appeared in a population, or have existed but are rapidly increasing in incidence or geographic range (Morse 1995)
Process
Introduction of agent
Establishment and dissemination
Introduction of the agent into a new host population (whether the pathogen originated in the environment, possibly in another species, or as a
variant of an existing human infection),
2. establishment and further dissemination within the new host population (“adoption”)
The majority (60.3%) of EID events are caused by zoonotic pathogens (ie, those which have a non-human animal source). Furthermore, 71.8% of these zoonotic EID events were caused by pathogens with a wildlife origin—for example, the emergence of Nipah virus in Perak, Malaysia and SARS in Guangdong Province, China.

6. Introduction: The ‘Zoonotic Pool’
Assuming 50,000 vertebrates, each with 20 endemic viruses. There are likely 1,000,000 vertebrate viruses.
99.8% of vertebrate viruses remain to be discovered
Large potential for future zoonotic emergence!
If we 1st consider the introduction step, the numerous examples of infections originating as zoonoses suggest that the “zoonotic pool”—introductions of infections from other species—is an important and potentially rich source of emerging diseases.
The number of EID events caused by pathogens originating in wildlife has increased significantly with time.
S Morse 1993

7. What leads to selection
Question
What leads to selection or
emergence
a new agent?

8. Vectors Modified from Jones et al 2008 Nature 451:990. Genetic and
biological factors
Physical and
environmental
factors
Vectors
So what leads to selection or emergence of a new agent which has pathogenic consequences ?
I’m showing here the convergence model of disease emergence and consequent epidemics. It depicts emergence as being a product of the interaction of diverse factors that fit w/in 4 major groupings that together foster the transfer of infectious agents from animals to humans or dissemination from geographically isolated groups into new populations. This has been referred to as “microbial traffic” (Morse 3,4). Most emerging infections appear to be caused by pathogens already present in the environment, brought out of obscurity or given a selective advantage by changing conditions that afford them an opportunity to infect new host populations.
Ecological
factors
Socal, political and
economic factors
Modified from Jones et al 2008 Nature 451:990.

9. Underlying factors in emergence:
Genetic and biologic factors
Microbial genetics and adaptation
Host susceptibility to infection
Physical environmental factor
Climate and weather
Economic development and land use
Ecological factors
Changing ecosystems
Human demographics and behavior
Social, political, and economic factors
International travel and commerce
Poverty and society inequity
War and famine
Intent to harm
Modified from King L CDC 2008

10. Population in millions
World population growth. Population of the world and its regions (in millions). Data from .
Solid line: medium variant. Shaded region: low to high variant. Dashed line: constant-fertility variant. In the 20th century, the world saw the biggest increase in its population in human history due to lessening of the mortality rate in many countries due to medical advances and massive increase in agricultural productivity attributed to the Green Revolution.[24][25][26]. Globally, the population growth rate has been steadily declining from its peak of 2.19% in 1963, but growth remains high in Latin America, the Middle East and Sub-Saharan Africa.[29]
In some countries there is negative population growth (i.e. net decrease in population over time), especially in Central and Eastern Europe (mainly due to low fertility rates) and Southern Africa (due to the high number of HIV-related deaths). Within the next decade, Japan and some countries in Western Europe are also expected to encounter negative population growth due to sub-replacement fertility rates.
The United Nations states that population growth is rapidly declining due to the demographic transition. The world population is expected to peak at 9.2 billion in 2050.[2]

11. There is nowhere that is too remote to reach
Global Aviation Network
Least frequent no. passengers / day
Most frequent
Hufnagel et al, 2004 PNAS

12. Speed of Global Travel in Relation to World Population Growth( ) D y C c m v g e h G
Year
1850
400
350
300
250
200
150
100 50
2000
1900
1950 1 2 3 4 5 6
Murphy and Nathanson Sems Virol 5, 87, 1994

13. Percentage of Population Without Reasonable Access
to Safe Drinking Water
Reasonable access to safe drinking water is defined as the availability of at least 20 litres per person per day from an improved source within 1 kilometer of the user's dwelling. More than five million people, most of them children, die every year from illnesses caused by drinking poor quality water
“Earth Dispatch”
Earth Dispatch

15. What is an Arbovirus? Arthropod-borne
Group of viruses spread by arthropods
Many are zoonotic
Infection spread to incidental hosts that are not essential to the life cycle.

16. Outline Drivers in emerging diseases Re/emerging flaviviruses
West Nile
Dengue
Japanese encephalitis
Yellow fever
Kyassanur Forest
Re/emerging alphavirus
Chikungunya

17. Flavivirus: Flaviviridae (~70 members)
11 kb
WNV modified from Kuhn RJ in Kramer LD et al. Lancet Neurology 2007

18. Flavivirus: Flaviviridae (~70 members)
Human pathogens
Hemorrhagic fevers (flavi=yellow)
Encephalitis
Febrile illness
3 phylogenetic clusters
No known vector
Tick-borne
Mosquito borne
Japanese encephalitis serocomplex
Includes JEV, SLEV, WNV
Primarily bird viruses
Humans not “amplifying” host
Other serocomplexes include YFV, DENV

19. Japanese encephalitis serogroup
WNV
SLEV
KUNV
JEV
MVEV

20. Smithburn JS, Hughes TP, Burke AW, Paul JH
Smithburn JS, Hughes TP, Burke AW, Paul JH. A neurotropic virus isolated from the blood of a native of Uganda. Am J Trop Med Hyg. 1940;20:471–92.
Medical Department of the Uganda Protectorate
International Health Division of The Rockefeller Foundation.

21. 1999 1996 2000 West Nile 1994-2003 France Israel Bucarest 2000 2003
Morocco
Bucarest
1996
2003
2000
1994
Italy
1998
1996
First recorded epidemic in Israel in 1950’s
Frequent outbreaks leading to 1990’s
Israel – , 1957
France – 1962
South Africa – 1974
Romania – 1996
Italy – 1998
1998
2000
Tunisia
2003
Israel
2003
2002
Modified from the French National Reference Center for Arboviruses, Pasteur Institute,Lyon, France
Horses
Humans
Birds

22. WNV geographic distribution
AFRICA, MIDDLE EAST, EUROPE, RUSSIA, INDIA, AUSTRALIA
In 1998, a virulent WN strain from lineage I was identified in dying migrating storks and domestic geese showing clinical symptoms of encephalitis and paralysis in Israel.
Pre-1999 distribution
Post-1999 distribution

23. West Nile Virus in North America: Background
Discovered in 1999 in New York City during an outbreak of meningitis and encephalitis in humans and an accompanying epizootic in birds
Emergence during heat wave

24. West Nile Virus In New York - 1999
NYC
Yellow Fever Outbreak
730 Deaths

25. Empezamos entonces con una discusion de la importancia de vigilancia
Empezamos entonces con una discusion de la importancia de vigilancia. En 1999 los Estados Unidos se encontro amenezado por la presencia de un virus que jamas se habia visto antes en el hemisfero occidental. El virus del oriente del nilo se detecto por primera vez en Nueva York a traves de la notificacion por unos medicos atentos de un congomerado de casos de encefalitis, y por una veterinaria que detecto muertes en aves. Despues de enfrentar directamente al brote en Nueva York, CDC monto un sistema de vigilance en colaboracion con todos los estados para detetectar diseminacion del virus en el resto del pais.

27. “I love the smell of malathion in the morning”

28. Buzz City by
Barry Blitt
The New Yorker
Sept. 27, 2000

29. The Bite of Spring by
Peter de Seve
The New Yorker
April 17, 2000

30. Possible pathways of introduction of WNV into the USA
Infected Human
Human-transported vertebrate host
Legal
Illegal
Human-transported mosquito vector
Storm-transported vertebrate host (bird)
Intentional introduction (terrorist event)
The expansion of global air travel and seaborne trade removes geographic barriers to insect disease vectors, enabling the insects to move great distances in short periods.
If they can adapt to the local environment, they establish themselves in new areas.

31. Lanciotti et al Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern U.S. [Science 286: ]

32. West Nile Virus Transmission Cycle
Mosquito vectors
Culex species
Epidemic
Secondary Hosts
Epizootic
Amplification hosts

33. WNV Surveillance, United States,1999-2008
WNV Surveillance, United States, *: Summary of Mosquito and Dead Bird Data
64 WNV-positive mosquito species reported
Culex species account for >98% of the total reported
317 WNV-positive dead bird spp.
reported
2006: American crows and blue jays
accounted for 62% of the dead birds
A Hitchcock, The Birds
* Reported as of 3/2009

34. Spatio-temporal Declines, American Crow
North American Breeding Bird Survey
S LaDeau; Nature (7145):710-3

35. Equine Cases, United States, 1999-2007
2000
4000
6000
8000
10000
12000
14000
16000
1999
2001
2002
2003
2004
2005
2006
2007
Total Equine: 24,681cases
Vaccine introduced
Equine Case Reports
Year
CDC/NCID/DVBID

36. WN disease

37. Reported incidence of West Nile virus disease by county, United States, 1999–2007
(Total cases)
(1294)
2005
(1495)
2006
(1173)
2007
(62)
(21)
(66)
(4156)
(9862)
(2539)
Hayes EB et al. EID 2006

38. Risk of WN disease in humans seroprevalence studies in US (CDC)
1 of 140 infections neurologic disease
1 of 5 infections febrile illness
4 of 5 infections subclinical
Asymptomatic (subclinical) lead to life-long immunity
Fever:Fever, headache, rash, fatigue; Mild cases often undiagnosed; Median time to recovery ~60 days
NID: WNV Neuroinvasive Disease
Meningitis (~40%), encephalitis (~60%), poliomyelitis (~10%)
Mild disorientation to coma and death (~10% mortality)
Long term sequelae may occur
10% CFR
Most mosquito bites not
by infected mosquito

39. WNV neuroinvasive disease cases in United States (by year)
Regional epidemics
Avg = 1295/year
No. NID cases
Graphically, 10 years of WNND in the US looks like this
Characterized by two years of regional epidemics in midwest through the Mississippi valley to the gulf coast, followed by the epidemic through the plains states
In the 4 full years the virus has been present through most of the country, WNND cases have average almost 1300 each year. 687 NID 2008
Year

40. WNV neuroinvasive disease cases and deaths
No. of NID cases
% mortality

41. WNV Widespread and Pervasive in Environment
Reported WNND Cases and WNV Deaths in Humans, United States, *
Year
Encephalitis/
Meningitis
(includes some AFP)
Non-Encephalitis/
Meningitis AFP
Total AFP
Total WNND
Deaths
3,088 --
303
2003
2,866
264
2004
1,142 6 33
1,148
100
2005
1,294 15 82
1,309
119
2006
1,459 36
101
1,495
177
2007
1,217 10 63
1,227
124
2008
665 1 21
687 44
Total
11,616 68
300
11,820
1,114
11,820 WNND Cases
x 140 infections/WNND
~ 1.65 Million Infections
WNV Widespread and Pervasive in Environment
Produced Widespread and Pervasive Impact
* Reported as of 11/04/2008

42. West Nile virus neuroinvasive disease cases by age group and gender, 1999-2006*25
Male
Incidence 20
Female
Incidence 15
Incidence per 100,000 10 5
0-9
10-19
20-29
30-39
40-49
50-59
60-69
70-79
80-89
90-99
Age Group (yr)
* Reported as of 5/2/2007
Sejvar J CDC

43. Proportion of viremic blood donors developing West Nile fever Colorado, 2003
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
18-29
30-39
40-49
50-59
60-69
70-79
Age Group
Proportion with WNF
Vector Borne Zoonotic Dis 2007;7:479

44. Risk factors for neuroinvasive disease
Strong evidence
Age
Risk increases ~1.5 times per decade
Organ transplant recipients
~40% develop neuroinvasive disease (>40 times the risk as population-at-large)*
Hematological malignancies
Experimental infection and individual case reports (risk remains undefined)
Age discussed in previous slide
A serological study conducted in Canadian transplant clinic patients showed that the risk of severe neurological disease after infection was 40%, a rate approximately 40 times that of the population-at-large.
Individual case reports suggest that persons with hematological malignancies are at increased risk for development of severe disease, but it is not possible to determine the extent of that risk from these reports. In addition, WNV was used as an experimental cancer therapy in the 1950s, and these studies suggested that patients with hematological malignancies were more likely to develop severe disease.
Surveillance data have consistently shown a slight preponderance of cases among men. It is unknown whether this is due to increased mosquito exposure or a true increase in risk of acquiring severe disease.
* Kumar et al. Am J Transplant 2004;4:1883-8

45. Risk factors for neuroinvasive disease
Weaker evidence
Diabetes
Hypertension
Alcohol abuse
Chronic renal disease
Cardiovascular disease
Age discussed in previous slide
A serological study conducted in Canadian transplant clinic patients showed that the risk of severe neurological disease after infection was 40%, a rate approximately 40 times that of the population-at-large.
Individual case reports suggest that persons with hematological malignancies are at increased risk for development of severe disease, but it is not possible to determine the extent of that risk from these reports. In addition, WNV was used as an experimental cancer therapy in the 1950s, and these studies suggested that patients with hematological malignancies were more likely to develop severe disease.
Surveillance data have consistently shown a slight preponderance of cases among men. It is unknown whether this is due to increased mosquito exposure or a true increase in risk of acquiring severe disease.

46. The West Nile Virus “Iceberg” - 2
Acute WNV
WNV long term effects
Sejvar CDC

47. Temporal profile of recovery— WNV “Poliomyelitis”
Baseline Strength
100 80
Level of recovery (18) 60 40 20
Sejvar J CDC

48. Novel modes of virus transmission
Transfused blood
Blood supply screening began in 2003
More than 1000 viremic blood donors identified
Transplanted organs
Breast milk
One case, infant asymptomatic
Transplacental transmission
Single case 2002 with severe outcome to infant
Percutaneous, occupational exposure
Dialysis?
Greatest risk – exposure to mosquito bite !!

49. Conclusions 1 – North America
Rapid spread across USA (<4 years to Pacific Coast)
Bird migration and random bird movements
Many possible important avian hosts and competent mosquito vectors (unprecedented infection prevalence)
Significant impact on wildlife and domestic animals.
Persistent seasonal outbreaks. Incidence varies regionally.
High infection incidence in humans has led to unusual modes of transmission.
Age and immunosuppression highly significant risk factors for neuroinvasive disease. Role of other risk factors unclear, but possibly important.

50. West Nile Virus in Latin America
2002 –
2004
2006

51. Little evidence of human and animal disease in Latin America
Less virulent virus circulating?
Poor surveillance?
Serological cross reactivity with other flaviviruses?
Previous exposure to other circulating flaviviruses modulating disease expression?
Other causes?

52. West Nile Virus Puerto Rico, 2007
Sentinel chicken surveillance: up to 50% chickens seroconverted per week for over two months
3 viremic human blood donors
7 sick horses; 1 death
Active human surveillance: only one human with West Nile fever; no neuroinvasive disease
WNV isolated from chickens and Culex mosquitoes
Strain identical to that circulating in United States
A sentinel chicken program for West Nile virus (WNV) surveillance was initiated in July 2006 in eastern Puerto Rico, yielding the first seroconversions on June 4, Culex nigripalpus, Culex bahamensis) for the first time in Tropical America. Preliminary sequence analysis of the prM and E genes revealed a 1-amino acid difference (V159A) between the Puerto Rican 2007 and the NY99.

53. Future issues
West Nile virus is endemic in the western hemisphere
Vaccines successful for equines but need to weigh cost effectiveness for humans
Therapeutics / antivirals
Long term sequelae
Control and risk prediction

54. Pools at foreclosed homes raise West Nile threat in Dallas County
10:38 PM CDT on Friday, May 22, 2009
By THEODORE KIM / The Dallas Morning News
As if joblessness and the down stock market weren't enough, the weak economy has led to another problem: mosquitoes.
A growing collection of vacant homes in foreclosure, coupled with a wet spring, has fueled a mosquito resurgence in the region, Dallas County health officials say.
Empty homes with unkempt swimming pools have been especially to blame.
"We're getting a lot of calls on vacant homes that are foreclosed on and have swimming pools that, basically, are breeding grounds for mosquitoes," said Zachary Thompson, director of Dallas County health and human services.
braceforimpactnow.blogspot.com

55. Outline Drivers of emerging diseases Re/emerging flavivirus
West Nile
Re/emerging alphavirus
Chikungunya
Atlantic Monthly, 1997

56. Togaviridae: Alphaviruses
Genome:
Single stranded, positive sense RNA
5’ capped , 3’ polyadenylated
Cytoplasmic replication
Structural proeins encoded at 3’ end in subgenomic message
Insect transmitted
3 disease patterns:
Arthropathy (Sindbis, Ross River, Chikungunya)
Systemic febrile illness (Semliki forest, VEE)
Encephalitis (EEE, WEE, VEE)

57. Chikungunya
In Swahili, “chikungunya” : “ that which contorts
or bends “up”
Disease:
High fever ( F)
Rash
Severe incapacitating arthritis/arthralgia
Generalized
Usually acute
Hemorrhagic manifestations have been reported
Rarely fatal
Arthralgia: (Several days to several weeks, though 20% of individuals have long-term joint complaints)
G. Pialoux et al., 2007, Lancet Infect Dis
A.M. Powers and C.H. Logue, 2007 J Gen Virol,

58. CHIKV Transmission Cycle forested areas in West & Central Africa
Forest Aedes spp.
Ae africanus
Ae luteocephalus
Ae furcifer-taylori
eg. Forest redtail monkey
Modified from Gould EA and Higgs S 2009 Trans Royal Soc Trop Med Hyg

59. CHIKV Transmission Cycle urban in Asia
Aedes aegypti
& Ae. albopictus

60. Powers AM, Logue CH J Gen Virol. 2007 88:2363.

61. identifi ed in a given country
identifi ed in a given country. India is shaded in green (Asian genotype) as outbreaks from 1963 to 1965 and 1973 were confirmed to have
been caused by members of the Asian clade; however, reports from India during 2005–2007 indicate this outbreak was caused by the same
CHIKV strains detected during the Indian Ocean outbreaks (Central/East African genotype). Asterisk indicates a location from which
CHIKV was isolated (courtesy: Powers and Logue 2007).
The precise reasons for the re-emergence of chikungunya in the Indian subcontinent as well as the other small countries in the southern Indian Ocean are an enigma. Although, it is well recognized that re-emergence of viral infections are due to a variety of social, environmental, behavioural and biological changes, which of these contributed to the re-emergence of chikungunya virus would be interesting to unravel. Genetic analysis of chiungunya viruses have revealed that two distinct lineages were delineated,[12] one containing all isolates from western Africa and the second comprising all southern and East African strains, as well as isolates from Asia. Phylogenetic trees corroborated historical evidence that the virus originated in Africa and subsequently was introduced into Asia

62. Recent outbreaks of Chikungunya 2004-2007
Endemic Chikungunya
Congo: 2004 (re-emergence after 39 years)
Malaysia: 2007 (re-emergence after 7 years)
Reunion Island 266,000 clinical cases . Approximately 1/3 of population. Vector, Aedes albopictus. Groups within Central/East African CHIK
strains 
266,000 cases
Enserink, M. (2007) Science 318:

63. Chikungunya Virus Outbreak 878 imported cases to France
Pialoux et. al 2007 Lancet Inf Dis, 7:

64. Recent outbreaks of Chikungunya 2004-2007
>1.4 million cases
Enserink, M. (2007) Science 318:

65. Recent outbreaks of Chikungunya 2004-2007
New emergence in 2007: >200 cases
Enserink, M. (2007) Science 318:

66. Mosquito species were different in various outbreaks
Ae. aegypti
Ae. albopictus
Italy: autochthonous transmission; 234 cases
Enserink, M. (2007) Science 318:

67. Historical and geographical variations in CHIKV ecology and associated risks for human health. Viral phylogenetic groups of genotypes are color coded: the ancestral West African group is in green; the second African cluster (or CSEA cluster, for Central, Southern, East African viruses) is in blue; the primarily Asian group is in red, and the CHIK viruses involved in Indian Ocean outbreaks since 2000 are represented in yellow. For each group, a box summarizes the knowledge acquired on CHIKV ecology and human infection risks (see details in text).
Re-emergence in the 2000s
Domestic epidemic cycles
Ae albopictus on islands and Italy
Ae. aegypti in India

68. Mosquito-borne virus hits 20,000 HEALTH MINISTRY ISSUES ALERT OVER CHIKUNGUNYA DISEASE By: APIRADEE TREERUTKUARKUL
Bangkok Post 05/24/09

69. Charrel et al. 2007. N Engl J Med 356;8

70. Presence of Aedes albopictus in Europe, 2007
ECDC/WHO Mission report Sept 2007

71. Expansion of world distribution of Aedes albopictus
Charrel et al N Engl J Med 356;8

72. Factors involved in re-emergence of Chikungunya virus
Biologic and genetic
Non-immune population
Adaptation of virus to new mosquito: Ae. albopictus
Ecologic conditions
Standing water due to droughts
Warm European summer
Mosquito abundance
Social, economic, political
International travel
Previous introduction of Ae. albopictus into Reunion Island & Italy
Delayed identification and control of initial outbreaks
Physical environment
Stored water/atificial breeding sites
High mosq abundance due to warm summer and artificial breeding sites from stored water
Chretien JP, Linthicum KJ. Lancet Dec 1;370(9602):1805-6
Modified from Chretien JP, Linthicum KJ. Lancet. 2007

73. Can Chikungunya virus emerge in US?
37 imported cases in
No autochthonous transmission so far
Components of the transmission cycle?
Climate in southern states 
Humans 
Monkeys X
Mosquitoes ????

74. Distribution of Ae. aegypti in Americas
1970 – after mosquito eradication
2002

75. Distribution of Ae. albopictus in US, year 2000

76. Can Chikungunya virus emerge in US?
37 imported cases in
Components of the transmission cycle?
Climate in southern states 
Humans 
Monkeys X
Mosquitoes 
Human behavior ???

77. Can we predict the next new emerging zoonosis?
“In general, there is no way to predict when or where the next important new zoonotic pathogen will emerge or what its ultimate importance might be.”
F.A. Murphy, ICEID 1998
Emerg. Infect. Dis :

78. Malaria, yellow fever, dengue, West Nile virus, chikungunya,
WHAT’S NEXT?

79. Thank you!
QUESTIONS???????