HORARIO

The cases of LACE over the 13-year study period are typical of other cases, in that the majority of cases are white, non-Hispanic, male, and under the age of 18. As previously known, the highest incidence occurred in western NC but census tract-level analyses revealed significant heterogeneity across the study region. The clusters of high LACE incidence identified in this study occur at the sub- county level, and may not have been identified using traditional county-level analyses. These clusters are spread throughout the western NC region and 3 of the 4 clusters identified represent areas of high LACE risk which see over 10 times the expected number of cases. The 4th cluster is located in downtown Asheville, outside of where one might typically expect endemic LACE.

2. Public health implications

Several of these areas span multiple counties and would have required coordinated efforts by local and state health officials to identify these areas as contiguous locations of high risk. The clusters identified in this study indicate areas of LACE risk, and their detection will allow for targeted public health interventions within these areas to reduce the future occurrence of LACE in western NC. When the North Carolina General Assembly dissolved the Public Health Pest Management section of the NC Department of the Environment and Natural Resources, it significantly constrained the capacity to monitor endemic areas of vector-borne disease. In its absence, NCDPH must rely on human cases to identify endemic areas of disease. This study, therefore, fills an important void in the surveillance and investigation of LACE in North Carolina.

80 3. Future research

The existence of high incidence clusters in the absence of measured risk factors presents an opportunity to further investigate the potential for disease occurrence beyond the typical rural forested habitat. Mosquito trapping and small mammal seroprevalence studies within these high risk areas may identify shifting transmission dynamics into urban areas, given the potential for Ae albopictus to outcompete the primary vector Ae triseriatus in peridomestic areas. This study did not attempt any entomologic studies, but this would be the logical extension of this research.

Another extension of this analysis would be to estimate the LACE risk across western NC given the existence of risk factors and the locations of known cases. The cluster analysis identified high risk census tracts, but the LACE risk outside of those census tracts should not be considered null, rather, there is likely a gradient of decreasing risk with increased distance from risk factors and known cases. Spatial interpolation methods would provide an estimation of LACE risk that accounts for spatial autocorrelation and risk factors throughout the area. The estimated LACE risk would be another tool to identify high risk areas and translate this research into practical, easily communicable information to increase knowledge and awareness of LACE in western NC.

81 REFERENCES

1. Whitley RJ. Viral encephalitis. N Engl J Med. 1990;323(4):242-250.

2. Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens. The Lancet. 2002;359(9305):507-513.

3. Gaensbauer JT, Lindsey NP, Messacar K, Staples JE, Fischer M. Neuroinvasive arboviral disease in the United States: 2003 to 2012. Pediatrics. 2014;134(3):e642-50.

4. Calisher CH. Medically important arboviruses of the United States and Canada. Clin Microbiol Rev. 1994;7(1):89-116.

5. Gargano LM, Engel J, Gray GC, et al. Arbovirus Diseases, Southeastern United States. Emerg Infect Dis. 2013;19(11).

6. Nasci RS. Movement of chikungunya virus into the Western hemisphere. Emerg Infect Dis. 2014;20(8):1394-1395. doi: 10.3201/eid2008.140333 [doi].

7. Centers for Disease Control & Prevention (CDC). La Crosse Encephalitis. http://www.cdc.gov/lac/. Updated 2009. Accessed 3/31, 2014.

8. Thompson WH, Evans AS. California Encephalitis Virus Studies in Wisconsin. Am J Epidemiol. 1965;81(2):230-244.

9. Thompson WH, Kalfayan B, Anslow RO. Isolation of California encephalitis group virus from a fatal human illness. Am J Epidemiol. 1965;81(2):245-253.

10. Haddow AD. The incidence risk, clustering, and clinical presentation of La Crosse virus infections in the eastern United States, 2003-2007. PLoS One. 2009;4(7):e6145.

11. Tsai T. Arboviral infections in the United States. Infect Dis Clin North Am. 1991;5(1):73-102. 12. Reimann CA, Hayes EB, DiGuiseppi C, et al. Epidemiology of neuroinvasive arboviral disease in the United States, 1999–2007. Am J Trop Med Hyg. 2008;79(6):974-979.

13. Grimstad PR, Barrett CL, Humphrey RL, Sinsko MJ. Serologic evidence for widespread infection with La Crosse and St. Louis encephalitis viruses in the Indiana human population. Am J Epidemiol.

1984;119(6):913-930.

14. Kappus KD, Monath TP, Kaminski RM, Calisher CH. Reported encephalitis associated with California serogroup virus infections in the United States, 1963-1981. Prog Clin Biol Res. 1983;123:31-41.

15. Rust RS, Thompson WH, Matthews CG, Beaty BJ, Chun RW. Topical Review: La Crosse and Other Forms of California Encephalitis. J Child Neurol. 1999;14(1):1-14.

82

16. McGowan JE, Bryan JA, Gregg MB. Surveillance of arboviral encephalitis in the United States, 1955- 1971. Am J Epidemiol. 1973;97(3):199-207.

17. Johnson RT. Acute encephalitis. Clinical Infectious Diseases. 1996:219-224.

18. Chun RW. Clinical aspects of La Crosse encephalitis: neurological and psychological sequelae. Prog Clin Biol Res. 1983;123:193-201.

19. McJunkin JE, de los Reyes, Emily C, Irazuzta JE, et al. La Crosse encephalitis in children. N Engl J Med. 2001;344(11):801-807.

20. Centers for Disease Control & Prevention (CDC). La Crosse Encephalitis: Symptoms and Treatment. http://www.cdc.gov/lac/tech/symptoms.html. Updated 2009. Accessed 8/25, 2013.

21. Centers for Disease Control & Prevention (CDC). Information on Arboviral Encephalitides. http://www.cdc.gov/ncidod/dvbid/arbor/arbdet.htm. Updated 2005. Accessed 8/25, 2013.

22. Alatoom A, Payne D. An overview of arboviruses and bunyaviruses. Lab Medicine. 2009;40(4):237- 240.

23. McJunkin JE, Khan RR, Tsai TF. California–La Crosse encephalitis. Infect Dis Clin North Am. 1998;12(1):83-93.

24. Grimstad PR. Mosquitoes and the incidence of encephalitis. Adv Virus Res. 1983;28:357-438. 25. Centers for Disease Control & Prevention (CDC). La Crosse Encephalitis: Transmission.

http://www.cdc.gov/lac/tech/transmission.html. Published 2009. Updated 2009. Accessed 12/14, 2014. 26. Yuill TM. The role of mammals in the maintenance and dissemination of La Crosse virus. Prog Clin Biol Res. 1983;123:77-87.

27. Watts DM, Thompson WH, Yuill TM, DeFoliart GR, Hanson RP. Overwintering of La Crosse virus in Aedes triseriatus. Am J Trop Med Hyg. 1974;23(4):694-700.

28. Reese SM, Beaty MK, Gabitzsch ES, Blair CD, Beaty BJ. Aedes triseriatus females transovarially infected with La Crosse virus mate more efficiently than uninfected mosquitoes. J Med Entomol. 2009;46(5):1152-1158.

29. Leisnham PT, Juliano SA. Impacts of climate, land use, and biological invasion on the ecology of immature Aedes mosquitoes: implications for La Crosse emergence. EcoHealth. 2012;9(2):217-228. 30. Gerhardt RR, Gottfried KL, Apperson CS, et al. First isolation of La Crosse virus from naturally infected Aedes albopictus. Emerg Infect Dis. 2001;7(5):807-811.

31. Westby K, Fritzen C, Huang J, et al. La Crosse Encephalitis in Eastern Tennessee: Evidence of invasive mosquito (Aedes albopictusand Ochlerotatus japonicus) involvement in the transmission of an

83

32. Hughes MT, Gonzalez JA, Reagan KL, Blair CD, Beaty BJ. Comparative potential of Aedes triseriatus, Aedes albopictus, and Aedes aegypti (Diptera: Culicidae) to transovarially transmit La Crosse virus. J Med Entomol. 2006;43(4):757-761.

33. Centers for Disease Control & Prevention (CDC). History of Case Definitions.

http://wwwn.cdc.gov/nndss/script/casedefHistory.aspx. Updated 2013. Accessed 12/14, 2014. 34. Centers for Disease Control & Prevention (CDC). Arboviral diseases, neuroinvasive and non- neuroinvasive: 2014 Case Definition.

http://wwwn.cdc.gov/NNDSS/script/casedef.aspx?CondYrID=946&DatePub=1/1/2014%2012:00:00%20 AM. Updated 2014. Accessed 12/14, 2014.

35. Centers for Disease Control & Prevention (CDC). Arboviral diseases, neuroinvasive and non- neuroinvasive: 2004 Case Definition.

http://wwwn.cdc.gov/NNDSS/script/casedef.aspx?CondYrID=614&DatePub=1/1/2004%2012:00:00%20 AM. Updated 2014. Accessed 12/14, 2014.

36. Centers for Disease Control & Prevention (CDC). Arboviral diseases, neuroinvasive and non- neuroinvasive: 2011 Case Definition.

http://wwwn.cdc.gov/NNDSS/script/casedef.aspx?CondYrID=616&DatePub=1/1/2011%2012:00:00%20 AM. Updated 2014. Accessed 12/14, 2014.

37. NC Department of Health and Human Services (NC DHHS). Building and Strengthening Epidemiology, Laboratory, and Health Information Systems for Infectious Diseases in North Carolina. 2013.

38. Centers for Disease Control & Prevention (CDC). La Crosse Encephalitis: Epidemiology & Geographic Distribution. http://www.cdc.gov/lac/tech/epi.html#casesbystate. Updated 2011. Accessed 8/26, 2013. 39. Erwin PC, Jones TF, Gerhardt RR, et al. La Crosse encephalitis in Eastern Tennessee: clinical,

environmental, and entomological characteristics from a blinded cohort study. Am J Epidemiol. 2002;155(11):1060-1065.

40. Haddow AD, Bixler D, Odoi A. The spatial epidemiology and clinical features of reported cases of La Crosse virus infection in West Virginia from 2003 to 2007. BMC Infect Dis. 2011;11:29-2334-11-29. doi: 10.1186/1471-2334-11-29; 10.1186/1471-2334-11-29.

41. Miller A, Carchman R, Long R, Denslow SA. La Crosse Viral Infection in Hospitalized Pediatric Patients in Western North Carolina. Hospital Pediatrics. 2012;2(4):235-242.

42. Szumlas DE, Apperson CS, Hartig PC, Francy DB, Karabatsos N. Seroepidemiology of La Crosse virus infection in humans in western North Carolina. Am J Trop Med Hyg. 1996;54(4):332-337.

43. Kappus KD, Calisher CH, Baron RC, Davenport J, Francy DB, Williams RM. La Crosse virus infection and disease in western North Carolina. Am J Trop Med Hyg. 1982;31(3 Pt 1):556-560.

44. Monath TP, Nuckolls JG, Berall J, Bauer H, Chappell W, Coleman PH. Studies on California encephalitis in Minnesota. Am J Epidemiol. 1970;92(1):40-50.

84

45. Deibel R, Srihongse S, Woodall JP. Arboviruses in New York State: an attempt to determine the role of arboviruses in patients with viral encephalitis and meningitis. Am J Trop Med Hyg. 1979;28(3):577- 582.

46. Thompson WH, Gundersen CB. La Crosse encephalitis: occurrence of disease and control in a suburban area. Prog Clin Biol Res. 1983;123:225-236.

47. Woodruff BA, Baron RC, Tsai TF. Symptomatic La Crosse virus infections of the central nervous system: a study of risk factors in an endemic area. Am J Epidemiol. 1992;136(3):320-327.

48. Haddow AD, Bixler D, Schuh AJ. The Demographic and Socioeconomic Factors Predictive for Populations at High-Risk for La Crosse Virus Infection in West Virginia. PloS one. 2011;6(9):e25739. 49. Morgenstern H. Ecologic Studies. In: Rothman KJ, Greenland S, Lash TL, eds. Modern Epidemiology.

Third ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:511.

50. P. Atkinson AM. Geographical analysis of communicable disease data. In: Elliott P, Wakefield J, Best N, Briggs D, eds. Spatial Epidemiology: Methods and Applications. Oxford ;New York: Oxford University Press; 2000:253-266. http://search.lib.unc.edu?R=UNCb3762661.

51. Meade MS, Emch M. Medical Geography. New York: Guilford Press; 2010.

52. Meliker JR, Sloan CD. Spatio-temporal epidemiology: principles and opportunities. Spatial and spatio-temporal epidemiology. 2011;2(1):1-9.

53. Hampton KH, Serre ML, Gesink DC, Pilcher CD, Miller WC. Adjusting for sampling variability in sparse data: geostatistical approaches to disease mapping. International Journal of Health Geographics. 2011;10(1):54.

54. Haddow AD, Jones CJ. Assessing risk in focal arboviral infections: are we missing the big or little picture? PloS one. 2009;4(9):e6954.

55. Eisen L, Eisen RJ. Need for improved methods to collect and present spatial epidemiologic data for vectorborne diseases. Emerging Infect Dis. 2007;13(12):1816-1820.

56. Kitron U, Michael J, Swanson J, Haramis L. Spatial analysis of the distribution of LaCrosse encephalitis in Illinois, using a geographic information system and local and global spatial statistics. Am J Trop Med Hyg. 1997;57(4):469-475.

57. Ord JK, Getis A. Local spatial autocorrelation statistics: distributional issues and an application. Geogr Anal. 1995;27(4):286-306.

58. Song C, Kulldorff M. Power evaluation of disease clustering tests. Int J Health Geogr. 2003;2(1):9. 59. NC Department of Health and Human Services (NC DHHS). Virology/Serology: Arbovirus.

85

60. Calisher CH, Pretzman CI, Muth DJ, Parsons MA, Peterson ED. Serodiagnosis of La Crosse virus infections in humans by detection of immunoglobulin M class antibodies. J Clin Microbiol.

1986;23(4):667-671.

61. Byrd B. Personal communication concerning American Indian populations and LACE in western NC. 2012.

62. Centers for Medicare and Medicaid Services. ICD-9-CM Diagnosis and Procedure Codes: Abbreviated and Full Code Titles. https://www.cms.gov/Medicare/Coding/ICD9ProviderDiagnosticCodes/codes.html. Updated 2014. Accessed 3/31, 2014.

63. Goldberg D, Wilson J, Knoblock C, Ritz B, Cockburn M. An effective and efficient approach for manually improving geocoded data. International Journal of Health Geographics. 2008;7(1):60.

64. Wey CL, Griesse J, Kightlinger L, Wimberly MC. Geographic variability in geocoding success for West Nile virus cases in South Dakota. Health Place. 2009;15(4):1108-1114.

65. US Department of Commerce, Bureau of the Census. 2010 Census Urban and Rural Classification and Urban Area Criteria. http://www.census.gov/geo/reference/ua/urban-rural-2010.html. Updated 2013. Accessed 11/2, 2013.

66. US Geological Service Land Cover Institute, National Gap Analysis Program. Land Cover Data Portal. http://gapanalysis.usgs.gov/gaplandcover/data/download/. Updated 2013. Accessed 11/2, 2013. 67. North Carolina Center for Geographic Information and Analysis (NC CGIA). NC Onemap Statewide Orthoimagery 2010.

http://data.nconemap.com/geoportal/catalog/search/resource/details.page?uuid={89BC136A-D247- 4E7A-AB52-794CABED3F7E}. Updated 2013. Accessed 10/13, 2013.

68. Maldonado G, Greenland S. Simulation study of confounder-selection strategies. Am J Epidemiol. 1993;138(11):923-936.

69. North Carolina Office of State Budget and Management. County estimates.

http://www.osbm.state.nc.us/ncosbm/facts_and_figures/socioeconomic_data/population_estimates/c ounty_estimates.shtm. Updated 2014. Accessed 1/5, 2015.

70. US Department of Commerce, Bureau of the Census. Relationship files: geographic relationships over time (comparability). https://www.census.gov/geo/maps-data/data/relationship.html. Updated 2014. Accessed June/28, 2014.

71. Kulldorff M. A spatial scan statistic. Communications in Statistics-Theory and methods. 1997;26(6):1481-1496.

72. Kulldorff M. SaTScan user guide for version 9.0. http://www.satscan.org/. Updated 2010. Accessed July/8, 2013.

86

73. Jin S, Yang L, Danielson P, Homer C, Fry J, Xian G. A comprehensive change detection method for updating the national land cover database to circa 2011. Remote Sens Environ. 2013;132:159-175. 74. US Geological Survey (USGS). La Crosse Encephalitis: Historical.

http://diseasemaps.usgs.gov/lac_historical.html. Updated 2013. Accessed 8/26, 2013.

75. Selvin S. Analysis of Contingency Table Data: Logistic Model I. In: Statistical Analysis of Epidemiologic Data. 3rd ed. New York, NY: Oxford University Press; 2004:190-235.

76. WNC Healthy Impact Collaborative. 2012 WNC Community Health Assessment Report . 2012. 77. NC Department of Health and Human Services (NC DHHS). Mosquito-Borne Illnesses (Arboviruses). http://epi.publichealth.nc.gov/cd/diseases/arbo.html. Updated 2013. Accessed 8/25, 2013.

78. Kitron U, Michael J, Swanson J, Haramis L. Spatial analysis of the distribution of LaCrosse encephalitis in Illinois, using a geographic information system and local and global spatial statistics. Am J Trop Med Hyg. 1997;57(4):469-475.