West Nile Virus Lyle R. Petersen, M.D., M.P.H.
Family Flaviviridae,, Genus Flavivirus, (~68 viruses) ssrna (positive-sense), sense), ~11,000 nucleotides Human pathogens Hemorrhagic fevers (flavi( 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
West Nile Virus before 1994 Isolated in 1937 from blood of febrile woman in West Nile district of Uganda Commonly found in humans, birds, and other vertebrates in Asia, Eastern Europe, Africa Sporadic cases of febrile illness, meningitis, or encephalitis reported in CAR, Egypt, France, India, Madagascar, Senegal, Tunisia Outbreaks of varying size Israel 1941, 1951-1954, 1954, 1957,, 1980 South Africa, 1974 Outbreaks in yellow associated with many CNS disease cases
West Nile Virus Outbreaks in the Old World since 1994 Algeria, 1994 Romania, 1996 Tunisia, 1997 Russia, 1999, 2000, 2001 Israel, 2000 Sudan, 2002 Outbreaks in yellow associated with many CNS disease cases Outbreaks underlined associated with avian mortality
Phylogenetic Tree of West Nile Viruses-2001 (Envelope gene) 1 2 Kunjin India Egypt 1951 France 1965 South Africa Israel 1952 Romania 1996 M Kenya 1998 Senegal 1993 Morocco 1996 Italy 1998 Volgograd 1999 New York 1999 Israel 1998-A NY2000 3282 NY2000 3356 NY 1999 equine NY 1999 hum Conn 1999 MD 2000 NJ 2000 Israel 1999 H C.Afr.Rep 1989 Senegal 1979 Algeria 1968 C.Afr.Rep 1967 Iv.Coast 1981 Kunjin 1960 Kunjin 1973 Kunjin 1984b Kunjin 1991 Kunjin 1984a Kunjin 1966 Kunjin 1994 India 1955a India 1980 India 1958 India 1955b Kenya Uganda Senegal 1990 Uganda 1937 C.Afr.Rep 1972a C.Afr.Rep 1983 Uganda 1959 C.Afr.Rep 1972b Madagascar 1988 Madagascar 1986 Madagascar 1978 JE SA 14 Bird mortality, mouse neuroinvasive US/ Israel LIN-1 LIN-2
West Nile Virus: Basic Transmission Cycle Enzootic (Maintenance/Amplification) Epidemic Incidental hosts Epizootic Amplifying hosts
WNV Surveillance - ArboNET Only combined human-veterinary, national surveillance system Real-time electronic reporting Humans Clinically ill Viremic blood donors Dead birds (especially crows and jays) Mosquitoes Equines Live captive sentinels (e.g., chickens)
WNV Surveillance, United States, 1999-2006*: Summary of Mosquito and Dead Bird Data 1999-2006: 62 WNV-positive mosquito species reported Culex species account for >98% of the total reported Infection rates measured in percents, rather than per thousand 1999-2006: 317 spp. WNV-positive dead birds reported 2006: American crows and blue jays accounted for 62% of the dead birds reported * Reported as of 5/2/2007
Spatio-temporal Declines, American Crow North American Breeding Bird Survey Source: S. LaDeau; Nature. 2007 Jun 7;447(7145):710-3
Equine and Human WNV Neuroinvasive Disease Cases, United States, 1999-2006 16000 4000 14000 Total Equine: 24,213 cases Vaccine introduced 3500 12000 3000 Equine Case Reports 10000 8000 6000 Total Human: 9,906 cases 2500 2000 1500 Human Case Reports 4000 2000 Equine Human 1000 500 0 1999 2000 2001 2002 2003 2004 2005 2006 0
Year 1999 Reported WNV Disease Cases in Humans, United States, 1999-2006* Total WNND 59 Fever 3 Other clinical/ Unspec 0 Total cases 62 Deaths 7 2000 19 2 0 21 2 2001 64 2 0 66 9 2002 2,946 1,160 50 4,156 284 2003 2,866 6,830 166 9,862 264 2004 1,148 1,269 128 2,539 100 2005 1,309 1,607 99 3,000 119 2006 1,495 2,616 194 4,269 177 Total 9,906 13,489 637 23,975 962 * Reported as of 5/2/2007
West Nile Virus Clinical Syndromes Asymptomatic (Approx. 75%) West Nile fever (Approx. 25%) Neuroinvasive disease (Approx. 1/140) Encephalitis Meningitis Acute flaccid paralysis
The Hidden Epidemic WNV Infections (n=1.4 million), 1999-2006 Not reported Reported Fever 322,800 Fever 13,484 Asymptomatic 1,040,300 Neuroinvasive, Non-fatal 8,942 Fatal, 962
WNV Neuroinvasive Disease Incidence, by County, US, 1999 N=54 Incidence per million.01-9.99 10-99.99 >=100 Any WNV activity
WNV Neuroinvasive Disease Incidence, by County, US, 2000 N=19 Incidence per million.01-9.99 10-99.99 >=100 Any WNV activity
WNV Neuroinvasive Disease Incidence, by County, US, 2001 N=64 Incidence per million.01-9.99 10-99.99 >=100 Any WNV activity
WNV Neuroinvasive Disease Incidence, by County, US, 2002 N=2946 Incidence per million.01-9.99 10-99.99 >=100 Any WNV activity
WNV Neuroinvasive Disease Incidence, by County, US, 2003 N=2866 Incidence per million.01-9.99 10-99.99 >=100 Any WNV activity
WNV Neuroinvasive Disease Incidence, by County, US, 2004 N=1142 Incidence per million.01-9.99 10-99.99 >=100 Any WNV activity
2004: Outbreaks in the Desert
WNV Neuroinvasive Disease Incidence, by County, US, 2005 N=1294 Incidence per million.01-9.99 10-99.99 >=100 Any WNV activity
WNV Neuroinvasive Disease Incidence, by County, US, 2006 N=1495 Incidence per million.01-9.99 10-99.99 >=100 Any WNV activity
Cumulative Incidence of WNND by State, 2002 to 2006
Cumulative Incidence of WNND By County, 2002 to 2006
Median Rank of Annual WNND Incidence, by State, 2002 to 2006
Median Rank of Annual WNND Incidence, by County, 2002 to 2006
3000 Reported Number of St. Louis and West Nile Neuroinvasive Disease Cases, U.S., 1932-2006 2500 2000 1500 1000 500 0 1932 1942 1952 1962 1972 1982 1992 2002
Human WNV Disease Cases, by Week of Onset, United States, 2006* 600 550 500 450 400 350 300 250 200 150 100 50 0 7-Jan 21-Jan 4-Feb 18-Feb 4-Mar 18-Mar 1-Apr 15-Apr 29-Apr 13-May 27-May 10-Jun 25-Jun 8-Jul 22-Jul 5-Aug 19-Aug 2-Sep 16-Sep 30-Sep 14-Oct 28-Oct 11-Nov 25-Nov 9-Dec 23-Dec * Reported as of 5/2/2007 Week ending # cases
Reported Human West Nile Virus Cases, by Date of Symptom Onset; and Date of First Positive Surveillance Event, Colorado, 2003 110 100 90 human No. of cases 80 70 60 50 40 chicken mosquito horse Fever (n=2323) Neuroinvasive (n=621) 30 20 bird 10 0 6-Jun 20-Jun 4-Jul Source: John Pape, CO DOH 18-Jul 1-Aug 15-Aug 29-Aug 12-Sep Symptom onset date 26-Sep 10-Oct 24-Oct
West Nile Virus in Latin America 2003 2004 2002 2002 2002 2004 2003 2001 2002 2004 2002 2003 2003 2004 2004 2006 Argentina
Clinical Spectrum of WNV Illness: Revised WN Meningitis WN Fever WN Encephalitis Economic impact of acute costs for WNV inpatients and governmental response in Louisiana in 2002: $20.1 million EID 2004;10:1735 WN Poliomyelitis GBS-like syndrome Radiculopathy / plexopathy
WNV: The Other Iceberg Acute WNV Illness WNV Long-term effects
WN Fever-- --Outcomes Persistent symptoms common in 98 patients with WN Fever during Chicago 2002 outbreak* 63% self-reported persistent symptoms at 30 days; median duration of symptoms 60 days 30 hospitalized (median stay: 5 days) Colorado 2005: Quality of life measures (SF-36) significantly reduced among 16 WNF patients at 2 years post-infection # Fatigue, concentration problems, mood disorders frequently reported Significant enough to impact daily activities and functioning (*Watson et al. Ann Intern Med, 141; 2004) (#Sejvar et al., in press)
WN Encephalitis Outcomes Persistent disabling neurologic sequelae Tremors, movement disorders in ~50% of WN Encephalitis survivors # Over 2 years after initial illness Neurocognitive outcomes Subjective memory, concentration difficulties frequent Objective cognitive dysfunction still unclear Increased all-cause mortality within 1 year following West Nile encephalitis^ # Sejvar et al., in press; Carson et al., CID 2006 ^Greenberg et al., EID 2005
WNV-Associated Poliomyelitis Long-Term Outcomes Range of outcomes rule of thirds 1/3 near-baseline recovery by 1 year 1/3 significant improvement (>1 increment on MMT* in all affected limbs) 1/3 little or no recovery by >2 years Persistent weakness, functional impairment the rule *Sejvar et al, EID 2006 *Manual muscle testing using Medical Research Council 1 5 scale
West Nile virus neuroinvasive disease cases by age group and gender, 1999-2006* Incidence per 100,000 25 20 15 10 5 0 Male Incidence Female Incidence 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
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 at-large)* Hematological malignancies Experimental infection and individual case reports (risk remains undefined) * Kumar et al. Am J Transplant 2004;4:1883-8
Risk Factors for Neuroinvasive Disease Weaker evidence Diabetes Hypertension Alcohol abuse Chronic renal disease Cardiovascular disease
Novel Modes of West Nile Virus Transmission Transfused blood Transplanted organs (2 instances) Breast milk (one case, infant asymptomatic) Transplacental transmission One instance severe outcome to infant F/U 72 infants: no conclusive evidence of WNV congenital malformation Percutaneous, occupational exposure Conjunctival exposure (1 instance) Dialysis?
West Nile Virus and Transfusion Safety: A New Paradigm Blood supply screened with mini-pool nucleic acid amplification tests (MP-NAT) in 2003 Only infectious agent screened solely by this method ~1800 viremic donors identified to date Viremia in humans very low (median 3500 copies/ml) 9 breakthrough transmissions documented because donor viremia below limit of detection of MP-NAT. Enormous hidden cost: >$4 million annually
Network analysis of E region of WNV by year Source: E. Delwart, M Busch
Network analysis of E region of WNV by region Source: E. Delwart, M Busch
Conclusions Ecology and Geographic Spread Rapid spread across USA (4 years to Pacific Coast) and the Americas (7 years to Argentina) Bird migration and random bird movements Spread by human activity? Many possible important avian hosts and competent mosquito vectors (unprecedented infection prevalence). Significant impact on wildlife and domestic animals Ecologic surveillance provides indicators of impending human outbreaks several weeks in advance Combined human/veterinary surveillance essential for monitoring ecological impact and guiding prevention efforts
Conclusions Incidence Epidemic Persistent epidemic/endemic pattern in USA Unprecedented pattern globally No clear temporal trend in incidence Highest incidence/persistence in Midwest Land use has facilitated persistence and spread Approximately 1.4 million infections to date Epidemiological pattern in areas of importation may have little relation to that in previously endemic regions Suburban/rural pattern with wide variation in annual incidence in any given area challenges traditional clinical trial approach for vaccines and therapeutics. Long-term approach required for surveillance and prevention
Conclusions Clinical Illness Severe underreporting of West Nile fever Chronic sequelae of both WN fever and neuroinvasive disease common Possible risk factors for neuroinvasive disease: Male, increasing age, immunosuppressive drugs, malignancy, diabetes, HTN, alcoholism, cardiovascular disease, chronic renal disease A hidden epidemic long-term medical, economic, and social consequences of WN illness unknown, but likely huge Changing population demographics and medical care likely to greatly increase the population at risk for severe outcomes of infection
Conclusions New Transmission Modes Blood transfusion, organ transplantation, perinatal, breast milk transmission Within three years became the most common transfusion transmissible viral agent New paradigm Risk conferred by high incidence rather than chronicity Blood donor screening relies on MP-NAT screening Breakthroughs due to low viremia Vector-borne pathogens threat to blood safety due to high incidence of asymptomatic infection (model for dengue) Alternate transmission modes may have limited overall public health significance in relation to vector transmission, but may result in considerable cost and public concern New methods required to control them
Conclusions Virology New closely related genetic variants associated with human outbreaks of unusual severity Single nucleotide change in non-structural gene resulted in avian mortality Original NY99 strain was replaced by a strain with apparent increased fitness in birds. Change due to one nucleotide difference in envelope gene. Subsequent temporal and regional viral evolution. Some new variants have appeared and then disappeared (South Texas). Multidisciplinary approach required to understand linkages between ecology, epidemiology, and viral genetics
Acknowledgements Division of Vector-borne Infectious Diseases staff State and local health department investigators Clinicians University-based investigators