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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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Suggested Citation:"2 Vector-Borne Disease Detection and Control." Institute of Medicine. 2008. Vector-Borne Diseases: Understanding the Environmental, Human Health, and Ecological Connections: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/11950.
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2 Vector-Borne Disease Detection and Control OVERVIEW Several workshop presentations focused on specific vector-borne diseases, permitting participants to explore them not only as diverse and unique public health challenges in their own right, but also more generally as examples that might inform the detection and control of other vector-borne disease agents. Workshop speakers described opportunities, successes, and obstacles in managing dengue, West Nile virus (WNV), Rift Valley fever (RVF), malaria, bluetongue, hantavirus pulmonary syndrome, and Sudden Oak Death (SOD). Epidemiologists investigating infectious disease outbreaks seek to determine the route of transmission; in the case of vector-borne diseases, their efforts nec- essarily focus on the presence, abundance, and ecology of the vector, which in turn are frequently influenced by environmental conditions and human behavior. To illustrate these connections, Ned Hayes, of the Centers for Disease Control and Prevention (CDC), described his experiences investigating three different vector-borne diseases in diverse settings: pneumonic plague in Ecuador, 1998; dengue at the Mexico-Texas border, 1999; and tularemia in Martha’s Vineyard, Massachusetts, 2000. The investigation of each outbreak proceeded according to the following principles, as defined by Hayes: • Determine that an outbreak exists. • Categorize the outbreak by time, person, and place. • Establish surveillance using an appropriate case definition. • Collect and test diagnostic samples. 127

128 VECTOR-BORNE DISEASES • Formulate hypotheses to explain risk of disease. • Test hypotheses with one or more epidemiologic studies. • Implement preventive interventions. • Communicate results of the investigation through written reports or pub- lished papers. Through the application of these principles, investigators attempt to determine the presence, abundance, and ecology of the vector; to identify reservoirs of infec- tion; to evaluate modes of transmission and the ways in which they are influenced by the environment; and to implement disease control and prevention measures. The plague outbreak in Ecuador occurred in a remote high mountain com- munity with “medieval” housing conditions, in some ways reminiscent of Europe at the time of the Black Death. Based on their analyses, the researchers concluded that the first people infected had acquired plague from fleas that had previously bitten infected guinea pigs (which are raised locally for meat), and that the patho- gen was subsequently transmitted directly among humans, abetted by primitive living conditions and poor access to health care. Hayes said that local climatic conditions, influenced by El Niño, had apparently influenced rodent popula- tion dynamics so as to favor the epizootic of plague that preceded the human outbreak. A post-outbreak comparison of dengue incidence in the contiguous cities of Nuevo Laredo, Mexico, and Laredo, Texas, further illustrated the profound influ- ence of environment on vector-borne disease (Reiter et al., 2003). There, Hayes and coworkers found that although the dengue vector, the mosquito Aedes aegypti, was abundant in the U.S. city, disease incidence was higher in its poorer Mexican neighbor, where far fewer houses were equipped with intact window screens and air conditioners. An investigation of a pneumonic tularemia outbreak on Martha’s Vineyard, Massachusetts, which affected 10 adults, found that mowing lawns or cutting brush was the predominant risk factor for illness. The researchers’ find- ings point to small mammals, which presumably contaminated the foliage with the pathogen; the bacteria was then aerosolized and inhaled by workers during mowing. The single fatal case in this outbreak was a man who had limited access to health care. However, the ecological determinants that might explain why this outbreak—the second ever reported in the United States—occurred at that par- ticular time remain unclear. Turning from outbreak investigation to disease prevention, the authors of the chapter’s first paper, workshop speaker Thomas Scott and Amy Morrison, of the University of California, Davis, present considerable evidence in favor of the use of locally adaptable tools and strategies for dengue prevention, a detailed set of goals for defining and measuring risk factors for human dengue infection, and four “conceptual shifts” in vector control strategy that, they argue, “will substan- tially improve dengue prevention.” Central to the authors’ recommendations are the observations that (1) dengue transmission risk is strongly associated with

VECTOR-BORNE DISEASE DETECTION AND CONTROL 129 adult (but not immature) vector population densities, and (2) that the vast major- ity of human dengue infections occur in the home. Advantages to insect control strategies focused within homes can transcend Ae. aegypti and dengue—and even vector-borne disease—by decreasing population densities and lifespans of various disease-transmitting insects, as well as those of pests such as bed bugs, cockroaches, and filth flies. Thus, Scott and Morrison conclude, “what was originally conceived as an Ae. aegypti control program can be leveraged into a cost and operationally effective public health program that reduces a variety of diseases and pest problems.” The second essay in this chapter, from Lars Eisen and workshop presenter Barry Beaty of Colorado State University, discusses initiatives by a private-public partnership, the Innovative Vector Control Consortium (IVCC; see also Summary and Assessment section, “Disease Prevention Strategies”), to reduce the impact of dengue. The consortium is funding the construction of a computer-based decision support system to inform the design and implementation of effective local and regional vector control programs, as well as the development and dissemination of proactive indoor vector control measures. A second paper by Beaty and Eisen in Chapter 3 reviews public health and scientific responses to a broad range of vector-borne disease issues raised in the Institute of Medicine report Microbial Threats to Health (2003). A subsequent paper, by presenter Lyle Petersen of the CDC, describes the history and impact of WNV in the United States and identifies challenges to the surveillance and prevention of this emerging vector-borne disease in his con- tribution to this chapter. As part of its response to the 1999 WNV outbreak in New York City, the CDC established ArboNET, the first national human-animal disease surveillance system. Administered by the CDC, ArboNET is a real-time electronic reporting system that captures data on WNV in humans, dead birds, mosquitoes, horses, and live captive sentinels of disease (chickens). “A combina- tion of human and veterinary surveillance will be essential to monitor the ongoing ecological impact of WNV and to guide disease prevention efforts,” Petersen con- cludes. The experience with WNV demonstrates that the epidemiological pattern in areas of importation of an exotic arbovirus may bear little resemblance to that which occurred in its previously endemic area. As discussed in the Summary and Assessment (see “Weather, Climate, and Prediction”) and in Chapter 1, a climate-based model predicted a recent outbreak of RVF in Kenya, significantly improving response time and outcome. In his contribution to this chapter, workshop presenter C. J. Peters, of the University of Texas Medical Branch, Galveston, discusses the epidemiology and ecology of RVF—essential factors in its status as an emerging arboviral disease agent—and describes work in progress toward the development of veterinary and human vaccines to achieve better control of this deadly and costly disease. Peters warns of the potential of the RVF virus to expand its geographic range to the United

130 VECTOR-BORNE DISEASES States and urges greater appreciation for the threat it poses to people and livestock throughout the world. A combination of vector control and treatment with an effective drug are currently used to control malaria, the most burdensome of vector-borne diseases with regard to morbidity and mortality. In the chapter’s fifth essay, presenter Michael Coleman of the Medical Research Council of South Africa and co- author Janet Hemingway of the Liverpool School of Tropical Medicine, United Kingdom, describe the use of routine entomological surveillance to increase the effectiveness of malarial vector control. Such surveillance permits earlier detec- tion of, and response to, increases in pathogen transmission, which may indicate the development of insecticide resistance. The authors review vector surveillance techniques and describe their successful application to guide local vector control efforts. They also discuss potential uses of these techniques in modeling disease transmission and by decision support systems that inform national or regional vector control efforts. Bluetongue, a viral disease transmitted primarily among ruminant animals (sheep and cattle) by biting midges of the genus Culicoides, results in economic losses worldwide of approximately $3 billion per year due to morbidity and mor- tality of animals, trade embargoes, and vaccination costs (FAO, 2007; Osburn, 2007). In his contribution to this chapter, presenter Bennie Osburn of the Uni- versity of California, Davis, describes the history, distribution, and impact of the disease, which is present on six continents. Bluetongue has become established in Europe only within the past 5 years, coincident with abnormally high summer temperatures, and thus may provide insights into the behavior of other vector- borne diseases potentially expanding their geographic range with increasing temperatures associated with global climate change. Osburn notes that bluetongue has so far been adequately controlled in eastern and southern Europe; however, this has been achieved primarily through the use of modified live virus vaccines, which pose the threat of reassortment, via vector transmission, with wild-type viruses. The chapter’s final paper, by presenter Charles Calisher of Colorado State University and co-authors, describes a comprehensive, longitudinal study of the transmission of Sin Nombre hantavirus (SNV), the pathogen that causes the rodent-borne viral disease hantavirus pulmonary syndrome (HPS) among deer mice (Peromyscus maniculatus) in Colorado. The first human epidemic of HPS, reported in the spring of 1993, and a subsequent outbreak in 1998, occurred in the Four Corners region of the continental United States, where the borders of Utah, Colorado, New Mexico, and Arizona meet. Research by Calisher and coworkers on the transmission and maintenance of SNV reveals important environmental influences on these processes and thereby provides a model that may be extrapo- lated to other vector-borne zoonotic agents. Such longitudinal studies, they con- clude, “may be the only current means available to identify predictors of risk for rodent acquisition of this virus and for subsequent transmission to humans.” In

VECTOR-BORNE DISEASE DETECTION AND CONTROL 131 addition, they note, “although particular zoonotic diseases have particular etio- logic agents, the controlling conditions for each may have enough similarities to provide us with predictors of risk for acquisition and, therefore, with bases for prevention and control measures.” As a rodent-borne viral disease, HPS has invited consideration of nonarthro- pod vectors of infectious disease. The role of “vector” might be further expanded to include humans in the case of SOD, an infectious plant disease that has been spread across wild lands by hikers, mountain bikers, and equestrians. Speaker David Rizzo, of the University of California, Davis, has worked to understand and mitigate the effects of SOD in California since shortly after its emergence there in the mid-1990s (see Summary and Assessment section, “Lessons Learned: Case Studies of Vector-Borne Diseases”). The disease was first recognized after it caused widespread dieback of several tree species in West Coast forests; it also causes nonfatal leaf disease in many other plants, including rhododendrons and California bay laurel, and has been detected in the United Kingdom and Europe (Rizzo and Garboletto, 2003). The infectious agent of SOD is the fungus-like water mold Phytopthora ramorum, which thrives in the cool, wet climate of California coastal forests. Human visitors to these forests—who pick up P. ramorum spores on their clothes and shoes, equipment, and companion animals—appear to be the main “vectors” for the spread of this pathogen over long distances. However, because the SOD pathogen was identified only 7 years ago, researchers are still learning about its disease cycle and transmission dynamics. As they probe the ecological context and epidemiology of SOD, Rizzo and colleagues are also working to manage the disease in natural ecosystems and in the nursery trade. To target monitoring efforts, they developed risk models based on findings from laboratory studies of the pathogen’s sporulation behavior, com- bined with data on the distribution of host species and climate. Areas identified by the models are investigated by various methods, including aerial imaging, plot-based monitoring, and sampling streams to determine whether the pathogen is present within a watershed. If the pathogen is detected at a sufficiently early stage, the affected vegetation may be clear-cut and burned in hopes of eradicat- ing the disease. While this approach has not yet proven completely successful, Rizzo observed, it has significantly limited the spread of SOD. For areas where the pathogen is established, he and coworkers attempt to develop management schemes that avoid deleterious ecological consequences, such as the growth of invasive plant species following clear-cutting. In order to anticipate the potential effects of such management strategies, Rizzo collaborates with many ecologists. “Understanding the ecology of the forest is absolutely critical [to managing areas with established disease],” he said. “We’ve been doing a lot of work on how we can manipulate these [infected] forests, whether it’s reintroducing fire [or] removing some hosts [through clear-cutting], to figure out a way that we can live with this disease.”

132 VECTOR-BORNE DISEASES LONGITUDINAL FIELD STUDIES WILL GUIDE A PARADIGM SHIFT IN DENGUE PREVENTION Thomas W. Scott, Ph.D. University of California Amy C. Morrison, Ph.D. University of California Introduction When done properly, vector control is a well-documented and effective strategy for prevention of mosquito-borne disease. Familiar examples of success- ful mosquito vector interventions include the worldwide reduction of malaria in temperate regions and parts of Asia during the 1950s and 1960s (Curtis, 2000; Rugemalila et al., 2006), yellow fever during construction of the Panama Canal, yellow fever throughout most of the Americas during the 1950s and 1960s (Soper, 1967), dengue in Cuba and Singapore (Ooi et al., 2006), and more recently den- gue in parts of Vietnam (Kay and Nam, 2005). That these programs significantly improved public health is indisputable. Why then is disease burden from vector- borne diseases like malaria (Sachs and Malaney, 2002) and dengue increasing (WHO, 2006a)? Why has vector control not been effectively applied more often so that it reduces or appreciably minimizes disease? Unsuccessful programs are often attributed to a lack of resources, lack of political will, or ineffective imple- mentation (Attaran, 2004; Gubler, 1989b; Halstead, 1993; Killeen et al., 2002). Just as responsible for control failures are deficiencies in understanding relation- ships between vector ecology and pathogen transmission dynamics, the most appropriate methods for assessing and responding to appreciable risk, and the failure to use existing knowledge or surveillance information to make informed control decisions. It is reasonable to conclude that despite more than a century of vector-borne disease investigation, fundamental concepts in disease prevention remain incompletely defined and underutilized. The goal of this paper is to illustrate the power of improved ecologic and epi- demiologic understanding for increased effectiveness of vector control for dengue. The concepts and processes we discuss are not limited to dengue and, therefore, consideration should be given for their application to other vector-borne diseases. We assert that ����������������������������������������������������������������� a better understanding of virus transmission dynamics, concepts, and tools and strategies for disease prevention will fundamentally change and significantly improve public health programs for dengue prevention. Current programs, which emphasize universally prescribed surveillance and control, have hindered development of an appropriate conceptual and factual foundation for   Department of Entomology, Davis, California. E-mail: twscott@ucdavis.edu. ��������������������

VECTOR-BORNE DISEASE DETECTION AND CONTROL 133 adaptive disease prevention programs and help to explain why contemporary vec- tor control programs too often fall short of public health expectations. Our principal recommendation is that enhancing dengue prevention will require locally adaptable tools and strategies. To accomplish this there is an urgent need for more comprehensive, longitudinal field studies of vector-borne diseases that������������������������������������������������������������������ (1) quantitatively define relationships between the most meaning- ful measures of risk and human infection and (2) use that information to direct public health measures that prevent or minimize disease. Information necessary to fill this knowledge gap should be obtained in the framework of interrelated longitudinal cohort studies that progressively build on one another, providing an increasingly detailed understanding of fundamental processes in pathogen transmission, epidemiology, and disease control. Based on our experience, criti- cal missing knowledge of risk assessment and disease prevention can only be gained by carrying out integrative research that embraces the vector, pathogen, and human host. Too often vector-borne disease specialists study the arthropod vector, disease, or pathogen separately. Only by studying the system in total over a considerable period of time will we gain the greater insight into the complexity of interactions between components of transmission and disease that are essential for design, implementation, and evaluation of increasingly more successful dis- ease prevention programs. In the case of dengue, until a vaccine or chemotherapy become available, control programs will continue to be limited to vector control, which in most cases means reducing mosquito vector populations. But do we understand Ae. aegypti and dengue virus (DV) transmission well enough to make specific recommendations for modifications in vector populations, short of vector eradication, that will result in a predictable public health outcome? Review of rel- evant literature clearly indicates that the answer to this critical question is no. Dengue Epidemiology and Ecology Worldwide, DV infections cause more human morbidity and mortality than any other arthropod-borne virus disease (Farrar et al., 2007; Gubler, 2002c, 2004; Gubler and Kuno, 1997; Kuno, 1995; MacKenzie et al., 2004; Monath, 1994). It is estimated that 2.5 to 3 billion people are at risk of infection in tropical parts of the world each year. In urban centers of Southeast Asia, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are among the leading causes of pediatric hospitalization. During the last 30 years dengue has emerged as a major international public health threat in the Americas (Rigau-Perez et al., 1998; WHO, 2006b). Dengue fever (DF), DHF, and DSS are caused by four closely related, but antigenically distinct, single-stranded RNA viruses (DV-1, DV-2, DV-3, and DV-4) in the genus Flavivirus, family Flaviridae. All four serotypes cause a range of human disease, including asymptomatic infections, undifferentiated fever, and classic DF (Gubler, 2002c, 2004; Gubler and Kuno, 1997; Rothman and Ennis,

134 VECTOR-BORNE DISEASES 1999). Sequential infections with different serotypes are possible because infec- tion with one serotype provides lifelong protection from a homologous infection, but is only briefly cross-protective against heterologous serotypes. The etiology of serious illness is not completely understood but is suspected to be due to immune enhancement and/or variation in virus virulence (Gubler, 2002c, 2004; Kochel et al., 2002; MacKenzie et al., 2004; Monath, 1994; Rothman and Ennis, 1999; Watts et al., 1999). It is estimated that annually there are between 50 and 100 mil- lion DF cases and 250,000 to 500,000 DHF/DSS cases worldwide. If untreated, the case fatality rate for DHF/DSS can approach 30-40 percent; with supportive therapy, less than 1 percent of severely ill patients die (Halstead, 1993). DVs generally persist in endemic foci by a horizontal Ae. aegypti-human transmission cycle (Gubler, 1989a; Rodhain and Rosen, 1997). After an incuba- tion period of 3-15 days (typically 4-7 days) in the human, disease symptoms are first observed (Focks et al., 1995; Waterman and Gubler, 1989). Viremia often precedes fever, typically lasts ~5 days, and usually subsides in concert with the inability to detect virus in the blood (Vaughn et al., 2000). Mosquito vectors become infective after biting a viremic individual and surviving an extrinsic incu- bation period of 7-14 days (Watts et al., 1987). Although other mosquitoes in the subgenus Stegomyia have been incriminated as vectors, Ae. aegypti is the most important dengue vector worldwide (Gubler and Kuno, 1997). Once infective, Ae. aegypti can transmit virus each time it probes its mouthparts into a human or imbibe a blood meal (Putnam and Scott, 1995a,b). Ae. aegypti is uniquely adapted to a close association with humans and efficient transmission of DV. Immature forms develop primarily in artificial, man-made containers (Gubler, 1989a). Highly anthropophilic, females rest inside houses where they feed frequently and preferentially on human blood (Scott et al., 1993b, 2000b), which confers a fitness advantage (Scott et al., 1997; Morrison et al., 1999; Harrington et al., 2001a). Because food, mates, and substrates for laying eggs are readily available within the human habitations where female Ae. aegypti reside, dispersal beyond 100 m is not necessary and is detected in only a very small proportion of the adult population (Morland and Hayes, 1958; McDonald, 1977; Trpis and Hausermann, 1986; WHO, 1997, 1999; Edman et al., 1998; Harrington et al., 2001a,b, 2005). This indicates that most dispersal of DV occurs via movement of viremic human hosts. These features make Ae. aegypti an efficient vector and DV transmission can occur even when Ae. aegypti population densities are very low (Kuno, 1995). Dengue Control Presently, dengue control is dependent on the reduction or elimination of Ae. aegypti. Although dengue vaccines are a focus of attention (Pediatric Dengue Vaccine Initiative funded by the Bill and Melinda Gates Foundation), currently   See http://www.pdvi.org.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 135 there is no licensed vaccine. Developing a dengue vaccine is a challenge because it will need to be tetravalent to avoid the risk of immune enhancement. Even after a vaccine or drug is available, we expect that vector control will remain impor- tant. The benefits of a vaccine will be limited by its safety profile, efficacy, cost, and capacity for delivery (DeRoeck et al., 2003; Shepard et al., 2004). Although a variety of dengue vaccines are being developed and there are promising leads for antidengue drugs at the time of this writing (Farrar et al., 2007), none of the vaccine candidates have been evaluated in Phase III trials, and licensing is not imminent for clinical use of prospective drugs. Critical information on efficacy and cost was, therefore, not available. Even with superior efficiency, which con- sidering the complexity of dengue disease we can not assume without rigorous evaluation, a dengue vaccine will clearly not protect against infection with other mosquito-borne viruses. Furthermore, in order for there to be widespread applica- tion of a dengue vaccine in endemic countries the cost would need to be low (no more than $0.50 per dose) and preferably applied in a single dose (DeRoeck et al., 2003). In a best-case scenario there will be perfect protection against all DVs and perhaps some cross-protection for other Ae. aegypti-borne viruses in the genus Flavivirus (i.e., yellow fever). A dengue vaccine will not protect against infection with nonflaviruses and, realistically, complete vaccine coverage seems unlikely. Conversely, effective vector control reduces risk of infection for all Ae. aegypti- borne arboviruses (e.g., dengue, yellow fever, and chikungunya) across the human population. This alone is a compelling reason for continuing Ae. aegypti control after an effective DV vaccine becomes available. Current vector control methodologies for Ae. aegypti surveillance and control emphasize techniques that were developed for mosquito eradication to prevent yellow fever (see “Measuring Mosquito Density,” below). Although those pro- grams were initially successful in helping to define the role of vector eradication in disease prevention, the approach taken provided little insight into quantitative relationships between mosquito abundance and DV transmission (PAHO, 1994; Gubler and Kuno, 1997; Reiter and Gubler, 1997; Scott and Morrison, 2003). For a variety of reasons, mostly changing urban environments and limited economic resources, in 1994 the Pan American Health Organization (PAHO) departed from the eradication paradigm and declared eradication of Ae. aegypti an unattainable goal (PAHO, 1994). The new goal of dengue control programs is cost-effective utilization of limited resources to reduce vector populations to levels at which they are no longer of significant public health importance (Gubler, 1989b; PAHO, 1994). Aedes aegypti control programs worldwide vary widely, in many cases driven by country-specific economic constraints on local health agencies. Most coun- tries use a combination of vector surveillance, chemical treatment of Ae. aegypti larval habitats, and either regular or emergency applications of ultra low vol- ume (ULV) space sprays. Aerosol insecticides are effective if they reach female Ae. aegypti resting indoors, where they otherwise avoid insecticide contact (Reiter and Gubler, 1997). This means that space sprays need to be applied inside houses

136 VECTOR-BORNE DISEASES using backpack applicators rather than from high-profile trucks moving down city streets or from airplanes flying over houses. Farther up the product development pipeline, disease control based on genetic manipulation of mosquito vectors is being investigated in the laboratory (Beaty, 2000; James, 2005) and will require extensive field evaluation before it can be deployed (Scott et al., 2002; Louis and Knols, 2006). Successful dengue vector control programs in Singapore and Cuba (Ooi et al., 2006), promising results from trials with insecticide-treated materi- als in Latin America (Kroeger et al., 2006), and cost-effective larval control in Cambodia (Suaya et al., 2007) fortify the notion that properly done vector control effectively prevents dengue disease. Enhancing tools and strategies for vector surveillance and control should be a priority in the fight against dengue. The PAHO strategy emphasizes vector surveillance, with the objectives of maintaining Ae. aegypti populations below or close to transmission thresholds, slowing DV transmission, and accordingly, reducing sequential infections with heterologous serotypes that can increase the incidence of serious disease (Vaughn et al., 2000). Although intuitively reasonable, this approach has not been system- atically validated and the implication is that controlling serious disease rather than all disease is a viable public health goal. No well-controlled field studies have been published that clearly define the key relationships between vector density and human infection. There is an urgent need for entomological and epi- demiological data that refine understanding of relationships among entomological risk factors, incidence of human infection, and clinical disease manifestations. This has rarely been done for any vector-borne disease, exceptions being arbo- virus studies of western and St. Louis encephalitis viruses in southern California by Reeves and his colleagues (Reeves, 1971; Olson et al., 1979). Yet reduction of vector populations remains a prominent, underlying premise of many current public health recommendations for control of a long list of vector-borne diseases, including dengue. Prospective studies are urgently needed to test and refine fun- damental assumptions of this strategy for dengue control. Establishing Goals for Dengue Prevention Programs A fundamental observation in dengue prevention is that there is no single method or approach that works in all situations (Scott and Morrison, 2003). Ecol- ogy and epidemiology of virus transmission vary from one place and/or time to another. To help establish dynamic goals for disease prevention programs that can be adapted across the diversity of situations in which dengue exists, we developed four interrelated questions that assist in goal setting. The concepts discussed are not limited to dengue, and therefore, can be applied to other vector-borne diseases. Location-specific answers to these questions are important steps in the development of adaptive dengue control programs.   See Scott and Morrison (2003) for additional discussion on each topic.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 137 What is an acceptable level of dengue risk? This is a complex question. The answer will be situation- and location-specific depending on historical patterns of local DV transmission, available resources, and competing public health priorities. In order to reach properly informed decisions, entomologic and epidemiologic data will need to be considered. That will require appropriate coordination, shar- ing of relevant information, and teamwork among different public health entities (e.g., vector control and epidemiology departments) (Ooi et al., 2006). Goals will likely change as epidemiologic conditions and public health expectations change. This implies that the definition of what constitutes acceptable risk will vary from eradication of all clinically apparent dengue cases to “living with dengue but not DHF.” Consideration of this issue is an important part of the paradigm shift away from universally prescribed control actions and toward local experts developing a dynamic system for repeatedly reevaluating what are the most effective control tools, strategies, and application protocols for their particular situation. What are the mosquito densities (thresholds) necessary to meet agreed upon risk goals? The new policy for dengue control implies that although there may be some DV transmission, properly applied vector control will reduce or elimi- nate severe disease (Gubler, 1989b; PAHO, 1994). The objective, therefore, is to lower the force of infection and thus minimize severe disease by managing the density of mosquito vector populations. This is a tricky proposition. How does one know when vector populations have been reduced to levels at which they are no longer significant? What constitutes no longer significant? What exactly are the epidemiological objectives that guide this approach? Control strategies that do not aim for vector eradication, like this one, require surveillance (entomological and epidemiological) that informs disease prevention responses. In this case, the objective is to identify an entomological threshold below which there will be no epidemic transmission. Values above the thresholds will trigger control actions. Although the concept is straightforward, implemen- tation is challenging. Without the appropriate knowledge and analytical tools, it can be difficult to distinguish between the mere presence of a vector species and situations when vector control is required to prevent an epidemic (Peterson and Higley, 2002). Operationally friendly systems for estimating action thresholds from locally available surveillance, weather, and human population data would be a significant addition to the armature against dengue. Thresholds for DV transmission can fluctuate depending on mosquito density, overall immunity of the local human population (i.e., herd immunity), introduc- tion of novel virus serotypes or genotypes, the nature of contact between mos- quito vectors and human hosts, human density, and weather (Scott and Morrison, 2003). Temperature is particularly important because of its inverse relationship with extrinsic incubation. Even after key parameters have been identified, estima- tion can require acquisition of data that are hard to obtain (e.g., site-specific herd immunity) or can be encumbered by complicated assumptions (e.g., spatially and

138 VECTOR-BORNE DISEASES temporally explicit knowledge of mosquito density, survival, and human biting behavior). Important features of threshold values are that they are dynamic (i.e., they vary through time and space) and estimation is difficult because they are often based on data that are difficult to obtain or that require assumptions that are difficult to accept. In a practical sense development of thresholds will require the use of models (i.e., Focks et al., 1993a,b, 1995) that can be used to make relative rather than absolute comparisons (Dye, 1992). An appropriate analogy is hurricane prediction, for which there are models that can be used with some degree of error to make life-saving decisions. Due to inherent variability in key dengue transmission parameters and the difficulty in some cases of obtaining accurate measurements, it would not be wise to establish a fixed threshold value for DV transmission even at the same location. We can expect, however, to be able to identify circumstances when the risk of transmission is particularly high and prioritize use of limited vector control resources to sites where they will do the most good. Iterative modeling exercises can be used to systematically identify the most informative surveillance systems and predict intervention approaches with the highest probability of meeting local disease prevention goals. We are cur- rently involved in a project (i.e., the Innovative Vector Control Consortium) (Hemingway et al., 2006) that includes upgrading and making more user friendly existing simulation models for Ae. aegypti population dynamics (Focks et al., 1993a,b) and DV transmission (Focks et al., 1995). Our goal is to make these models freely available as a component of a web-based dengue decision support system so that at a variety of different levels (e.g., national, regional, or local) public health, vector control, or government officials can contrast and select from different surveillance and control options under a variety of site and operationally specific circumstances. Preliminary estimations indicate that entomological thresholds for DV trans- mission are quite low (Focks et al., 2000). The most important reason for this is Ae. aegypti’s uncommon feeding behavior. Most adult female mosquitoes engage in a feeding duality. They feed on plant sugars as a substrate for the synthesis of energy reserves (i.e., glycogen and lipid) that are used for flight and maintenance activities and blood for amino acids that are used for development of eggs (Clements, 1999). Female Ae. aegypti deviate from this pattern in ways that make them particularly dangerous vectors. In dengue-endemic situations where Ae. aegypti live in close association with humans, females seldom feed on plant carbohydrates (Edman et al., 1992; Van Handel et al., 1994; Costero et al., 1998). They meet their energetic and reproductive needs by feeding fre- quently and preferentially on human blood (Scott et al., 1993a,b, 2000a,b; Chow et al., 1993). Patterns of multiple biting on humans are consistent with facilita- tion of DV transmission. Multiple meals are taken from different people, bites are heterogeneously distributed so that some people are bitten more often than

VECTOR-BORNE DISEASE DETECTION AND CONTROL 139 others, and virus can be moved from one place to another by visitors who are bitten in homes where infected mosquitoes reside (Chow-Schaffer et al., 2000; DeBenedictis et al., 2003). Because Ae. aegypti tend not to disperse far (Morland and Hayes, 1958; McDonald, 1977; Trpis and Hausermann, 1986; Edman et al., 1998; Harrington et al., 2005), energy needs for flight are reduced. Nutrients in a diet limited to human blood support mosquito maintenance activities and reproduction as long as females feed multiple times in each egg-laying cycle (Harrington et al., 2001a). The unique feature of human blood that makes this possible is believed to be the low concentration of the amino acid isoleucine compared to other vertebrate sources of blood. From an epidemiologic perspec- tive, frequent human biting increases the opportunities for mosquito vectors to acquire DV by biting an infected person and to transmit virus after becoming infectious. From an entomological point of view, feeding frequently and prefer- entially on only human blood confers a fitness advantage and, therefore, females that engage in that behavior have a selective advantage (Day et al., 1994; Scott et al., 1997; Naksathit and Scott, 1998; Costero et al., 1998; Morrison et al., 1999; Harrington et al., 2001a). Consequently, frequent and preferential human biting makes Ae. aegypti a remarkably efficient and, thus, dangerous mosquito. It does not take many Ae. aegypti to sustain unacceptable levels of DV transmission. The operational implications of efficient transmission are that entomological thresholds will be low and thus for vector control to be effective it will need to be thorough and sustained. What are the most informative measures of dengue risk? To date, attempts to predict dengue epidemics have been largely unsuccessful. Public health depart- ments worldwide remain perplexed and frustrated with their inability to assess dengue risk in a meaningful way. In places where fewer than all four serotypes are transmitted (i.e., Latin America and parts of Asia), surveillance systems have been proposed for detecting the introduction of novel DV serotypes (Gubler and Casta-Velez, 1991). In endemic regions of Southeast Asia, where there is an overall pattern of 3- to 4-year cyclical increases in disease (Hay et al., 2000; Cummings et al., 2004), viral surveillance has been more informative than current entomological techniques for managing DV transmission. Nevertheless retro- spectively—and to some extent arbitrarily—prescribed entomological indices are heavily relied upon to assess dengue risk and the effectiveness of vector control programs (Focks and Chadee, 1997; Focks et al., 2000; Scott and Morrison, 2003). An operationally valuable early warning system for dengue, which is in great demand by public health officials (DeRoeck et al., 2003), will need to include data on human herd immunity, Ae. aegypti and human population densi- ties, contact rates between vectors and humans, and ambient temperature. Human herd immunity A key component in the transmission of an infectious disease is the proportion of people in the affected population that are susceptible

140 VECTOR-BORNE DISEASES to infection (Anderson and May, 1991). This is especially true for a virus like dengue that causes sterilizing immunity (i.e., following exposure and an immune response a person is protected from reinfection with the same DV serotype). Results from dengue models clearly indicate that the vector densities necessary to prevent, interrupt, or decrease DV transmission are inversely proportional to seroprevalence rates of the human population (Newton and Reiter, 1992; Focks et al., 1995, 2000). For example, Focks et al. (2000) predicted that when other factors remain constant entomological threshold estimates necessary for epidemic DV transmission will increase 1.5-fold when the initial seroprevalence increases from 0 to 33 percent, 2.1-fold when it increases from 33 to 67 percent, and 3.2- fold when it increases from 0 to 67 percent. As the proportion of immune people in the population increases it is expected that it will become increasingly difficult for DV to sustain transmission. The most specific assay for detecting serotype- specific antibody responses to a DV infection is the plaque reduction neutraliza- tion test (PRNT) (WHO, 2006b). The PRNT unfortunately requires specialized laboratory facilities and equipment that are beyond the reach of most local public health units. Other serologic methods exist (e.g., enzyme-linked immunosorbent assays [ELISAs]), but they lack serotype specificity and in some cases cross- react with antibodies directed against flaviviruses that are closely related to DV. In most cases, therefore, timely and cost-effective transfer of population-based seroprevalence data is not available. There is a critical need for development of new, more cost and operationally amenable means to estimate herd immunity and, thus, susceptibility of local human populations to epidemic DV transmission. Measuring mosquito density  Below we review the most commonly used measures of Ae. aegypti density that are used to assess dengue risk: • Traditional measures of Aedes aegypti density The shift in focus from eradication to control programs merits a reevaluation of Ae. aegypti surveil- lance techniques. Traditional entomological surveillance techniques are based on the premise/house index (HI; percentage of houses infested with larvae and/or pupae), container index (CI; percentage of water-holding containers infested with larvae and/or pupae), and Breteau index (BI; number of positive containers per 100 houses), which were designed to detect the presence or absence of Ae. aegypti larvae (Conner and Monroe, 1923; Breteau, 1954; Tun-Lin et al., 1995a; Focks and Chadee, 1997). Several investigators discussed the limitations of traditional Stegomyia indices for estimating Ae. aegypti density and noted their poor relation- ship with DV transmission (Tun-Lin et al., 1995a, 1996; Focks and Chadee, 1997; Reiter and Gubler, 1997; Scott and Morrison, 2003; Kay and Nam, 2005). The major problems are that they fail to account for larval mortality, heterogeneity in container productivity, and temporal differences in Ae. aegypti life stages. Put simply, we cannot assume a strong positive correlation between the presence of larvae and adult female mosquitoes in a household. Moreover, factors impacting

VECTOR-BORNE DISEASE DETECTION AND CONTROL 141 larval mortality and development such as container size, crowding, and availabil- ity of nutrients in aquatic larval habitats affect the relationship between larval and adult densities (Reiter and Gubler, 1997; Arrivillaga and Barrera, 2004). • Productivity analysis (Pupal and Demographic Survey) Larval productiv- ity indices (Chan et al., 1971; Bang et al., 1981; Tun-Lin et al., 1995a, 1996) and pupal surveys, which were developed to account for heterogeneity in container productivity (Focks and Chadee, 1997), are advances in entomological surveil- lance methods. Common to both is the quantification of either late instar larvae or pupae by container type or characteristic. Each does, however, have its limita- tions. The distribution of Ae. aegypti-infested containers and households can be highly clustered through time and space, making vector population estimates sensitive to sampling error and variation (Tun-Lin et al., 1995a, 1996; Focks and Chadee, 1997; Getis et al., 2003; Morrison et al., 2004a,b). Some containers are large, inaccessible, and difficult to sample adequately. Quantitative sampling strategies for immature Ae. aegypti include funnel traps (Kay et al., 1992; Nam et al., 1998; Russell and Kay, 1999) and standardized sweep methods using nets or dippers (Zhen and Kay, 1993; Tun-Lin et al., 1995b; Knox et al., 2007). Larval productivity indices are based on quantification of third and fourth instar larvae, which are expected to be subject to less sampling variation than pupae. In contrast, the pupal/demographic survey methodology quantifies pupae rather than larvae (Focks et al., 1993a,b; Focks and Chadee, 1997) because in theory it is more practical to count the absolute number of Ae. aegypti pupae than other life stages (Southwood et al., 1972; Focks et al., 1981) and pupal mortality is slight and well-characterized. The number of pupae per person is correlated with the number of adults per person (Focks et al., 1981, 1995). The relative importance of a container type (i.e., production of adult mosquitoes) is defined as the product of the container abundance multiplied by the average standing crop of pupae (i.e., pupae per wet container). Theoretically, important container types, defined either phenotypically or functionally, can be identified and targeted in vector control campaigns providing a cost-efficient alternative to indiscrimi- nate elimination of all potential habitats for immature Ae. aegypti development. Using pupal surveys as the basis of targeted control strategies is currently being evaluated in a multicountry study sponsored by the World Health Organization (WHO, 2006a). • Mosquito collection Adult Ae. aegypti are difficult to capture; they do not readily enter traps (Jones et al., 2003). Population densities are generally low, which makes it difficult to estimate population sizes and to this point has precluded routine surveillance of adults (Reiter and Gubler, 1997). Adult capture techniques include human bait (e.g., Nelson et al., 1978; Trpis and Housermann, 1986), indoor sweeps with hand nets (e.g., Tidwell et al., 1990), and other manual methods. But these are labor intensive and subject to complex operator and loca-

142 VECTOR-BORNE DISEASES tion influences (Reiter and Gubler, 1997). An attractant trap is being developed but is not yet commercially available. The most effective currently available device for capturing adult Ae. aegypti is the battery-powered backpack aspira- tor (Scott et al., 1993a,b; Clark et al., 1994). Based on assessments in Thailand, backpack aspirators collect ~25 percent of adult Ae. aegypti in a house (Scott and Harrington, unpublished data). Aspirators can be used, therefore, to assess relative differences in adult population density. Entomological surveillance for dengue would be significantly advanced by the development of a simple, cost- effective trap for broad-scale sampling of adult Ae. aegypti. Based on our research in Iquitos, Peru, immature Ae. aegypti indices can be informative for characterizing spatial patterns in vector infestations (Getis et al., 2003). It has been more difficult to associate mosquito density with DV transmis- sion. In Iquitos, only immature indices were correlated with DV seroprevalence. Conversely, only adult indices captured temporal and spatial differences in DV incidence (Morrison and Scott, unpublished data). Oviposition traps (ovitraps) can be valuable for detecting the presence or absence of Ae. aegypti, especially when population densities are very low. We do not, however, recommend them for assessing vector abundance because they are susceptible to significant biases from competition with natural oviposition sites. Ambient temperature Within a biologically amenable range (22-32oC) (Focks et al., 2000), variation in ambient temperature has well-established, important effects on Ae. aegypti biology and seasonal trends in dengue transmission (Watts et al., 1987; Burke et al., 1980). At less than 20oC Ae. aegypti eggs do not hatch. Combined mortality across all developmental stages is too high to allow popu- lations to be sustained (i.e., Ro<1) at temperatures greater than 34oC (Focks et al., 2000). Within the receptive range, temperature is negatively associated with Ae. aegypti development time (Gilpin and McClelland, 1979), survival (Focks et al., 1993a), and extrinsic incubation of DV (Watts et al., 1987). Conversely, blood feeding frequency is positively associated with temperature (Scott et al., 2000a,b). Because increasing temperature reduces the time necessary for pupation, Focks et al. (2000) predicted that increasing temperature only 4oC, from 26 to 30oC, could increase the number of adult Ae. aegypti by 45 percent. With regard to mosquito- virus interactions, Watts et al. (1987) detected DV-2 transmission to primates only at warm temperatures (30-35oC) after 7-12 days of extrinsic incubation. Focks et al. (2000) predicted that 14 and 38 percent of females would survive extrinsic incubation with the potential to transmit virus to a human host when held at 22oC versus 32oC, respectively. Because temperature has the potential to significantly affect many important aspects of Ae. aegypti’s role in DV transmis- sion, it should be considered an operationally viable component of large-scale surveillance programs.   See http://www.biogents.com/en/index.html and Williams et al. (2006, 2007).

VECTOR-BORNE DISEASE DETECTION AND CONTROL 143 At what geographic scale should dengue surveillance and control activities be carried out? Risk factors, including measures of vector densities, can predict risk differently at different geographic scales. Geographic scale is especially impor- tant because of the modifiable areal unit problem (MAUP). MAUP refers to varia- tion in results when data are combined into sets of increasingly larger areal units or alternative combinations of base units at equal or similar scales (Openshaw and Taylor, 1979). Both phenomena are common problems for dengue surveillance and control programs because data are most commonly reported for areal units defined by political rather than epidemiological boundaries. Historically, most Ae. aegypti ecologists have characterized temporal, rather than spatial, patterns in mosquito abundance (Sheppard et al., 1969; Gould et al., 1970; Yasuno and Pant, 1970). Recent studies utilized a myriad of spatial analytical tools, including point pattern analysis (Gatrell et al., 1996; Getis, 1999). The utility of these ana- lytical tools are two-fold. First, they characterize spatial autocorrelation patterns in variables of interest. Using a practical example, we can ask if vector densities in households are more highly correlated with those in neighboring houses than houses farther away. Autocorrelation can be measured at different distances and the scale at which autocorrelation is no longer significant would represent the minimum geographic unit for which surveillance and control schemes should be applied. Recent studies demonstrate that entomological risk should be measured at a household scale (Getis et al., 2003; Morrison et al., 2004a), but the distribu- tion of infested houses does not follow a normal distribution (Alexander et al., 2006). Consequently, sample sizes need to be high for prospective epidemio- logical studies and evaluation of vector interventions. Second, spatial analyses can reveal underlying patterns in different variables. For example, one can ask whether clustering patterns of dengue cases are primarily due to natural varia- tion in Ae. aegypti population densities at households or whether clusters are merely the result of some a priori heterogeneity in the region where the study was conducted (Gatrell et al., 1996). In this way, specific foci of transmission can potentially be identified or evaluated in relation to proximity to specific features of interest, such as village meeting places, schools, or markets. In the case of dengue, not enough is known about the role of human movement in defining the geographic scale of transmission. Although there is clear evidence of clustering of dengue cases within households (Morrison et al., 1998), how human movement patterns affect the scale of dengue transmission remains a major knowledge gap. Defining the appropriate geographic scale for measuring entomological risk and DV transmission, which will not necessarily be the same, will be an important new contribution to dengue surveillance and control (Getis et al., 2003). Recommendations for Improved Vector Control After the capacity to account for inherent variation in dengue risk has been improved, it will be necessary to use that information to mitigate public health

144 VECTOR-BORNE DISEASES threats. Just as it is for goal setting, enhancing dengue prevention requires rethink- ing current control principles and, in some cases, redirecting emphasis to topics that are presently unexplored or underdeveloped. In this section we examine four conceptual shifts in vector control that will substantially improve dengue prevention. The Paradigm Shift from Top-Down Direction to Local Level Decision The fundamental challenge for contemporary dengue control, regardless of the approach taken, is to develop a framework for determining in different eco- logic and epidemiologic circumstances: (1) what control procedures should be used; (2) how they should be applied; and (3) how they should be evaluated and/ or monitored (Box 2-1). The underlying principle will be that there is no single approach that will work across all locations or circumstances. Although some may counter that the concept of “one size does not fit all” in vector control has been known for a long time, there is no denying that it is presently underdevel- oped and underemployed. Improved dengue prevention will require a paradigm shift away from the currently common practice of universally prescribed and BOX 2-1 Key Questions for Development of Innovative, Sustainable, and Cost-Effective Dengue Prevention • What should the site- and situation-specific goal(s) be for dengue preven- tion programs? • How should control be monitored (i.e., what surveillance and risk assess- ment programs should be used)? • What disease prevention tools are effective and currently available and which ones needed to be developed? • What are the best integrated and adaptive control programs (e.g., dynamic application of vector control in concert with other disease prevention and manage- ment strategies)? • What major steps need to be taken to develop, evaluate, disseminate, and ensure application of effective and sustainable dengue prevention? Application will require: (1) Validation with longitudinal cohort studies that examine mosquito vectors and human DV infection. (2) Capacity for programmatic adaptation to site-specific circumstances.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 145 applied strategies to one in which local control personnel decide for themselves what is the most operationally and cost-effective strategy for their particular situation. The new approach will need to be designed to account for variation in dengue transmission at different geographic locations and at different times at the same place. Local control personnel will need to constantly evaluate their surveil- lance and response methods. Their goals will have to be spatially and temporally specific, accounting for local variation in ecology, epidemiology, and availability of intervention resources. An example of this would be use of pupal productivity analysis to target vec- tor control at containers producing most of the adult Ae. aegypti. In some places most Ae. aegypti production is associated with water storage, and those contain- ers are easily identified and treated with larvicides. In contrast, at other locations most production comes from unmanaged containers that are transient and often missed in routine entomological inspections. Control campaigns for these two extremes would be noticeably different. In Iquitos during a severe 2002 DV-3 epidemic, local health officials deemphasized an entrenched pattern of uniform larvicide applications in preference of enhanced public awareness and container clean-up. The change was motivated by solid entomological surveillance data, which indicated that adult Ae. aegypti were being produced primarily from unmanaged containers rather than water storage containers. The shift from prescribed to adaptable strategies will require application of translational research, basic and applied, to the development of novel products and strategies that reduce disease. For example, dynamic, operational tools like virus transmission models and decision support systems will be necessary to guide site- and situation-specific dengue control. For a meaningful conversion of research to improved public health, it is imperative that those responsible for preventing DV transmission use surveillance information to inform their control decisions. Surveillance and Control of Adult Versus Immature Mosquitoes For more than half a century dengue prevention programs focused on imma- ture Ae. aegypti for surveillance and control (PAHO, 1994). There are theoreti- cal and empirical reasons for no longer strictly following that approach. With regard to surveillance, immature indices of Ae. aegypti density have not proven to be good predictors of DV transmission risk. Moreover, goals for immature Ae. aegypti surveillance are often vague and do not account for temporal and spatial variation in transmission factors. With regard to control, killing larvae is expected to have a relatively small impact on a reduction in the number of new human dengue infections, compared to killing adults. Refocusing dengue surveillance and control on adult Ae. aegypti would be a significant step forward. One of the major road blocks to improved dengue surveillance is our inability to directly monitor the vector life form that transmits

146 VECTOR-BORNE DISEASES virus (i.e., adult females). The need for an operationally and cost-effective way to monitor adult Ae. aegypti population fluctuations cannot be over-emphasized. And, even after we have a useful sampling technique we will need to think carefully about how best to use it. For example, unlike malariologists, dengue specialists do not have an informative measure of entomological risk like the entomological inoculation rate (EIR) (Scott and Morrison, 2003). Two obstacles to a dengue EIR are (1) the difficultly in collecting adult Ae. Aegypti and (2) the fact that virus infection rates in Ae. aegypti are typically too low (Kuno, 1997) to base a surveillance program on an EIR or its equivalent. An alternative approach would be to develop a dengue transmission potential (DTP) index. Leaving out mosquito virus infection status, a DTP could predict entomological risk based on the product of adult mosquito density, human-mosquito vector contact, serotype- specific susceptibility of the human population (ideally this would also include susceptibility to novel genotypes), and ambient temperature. Dengue prevention would similarly benefit from greater attention to adult Ae. aegypti. Adult mosquito density has a positive nonlinear relationship with the basic reproductive number of vector-borne disease (Garrett-Jones and Shidrawi, 1969; Dye, 1992). Control strategies directed at immature mosquitoes can only reduce the density of adult mosquitoes. Killing adults similarly reduces adult density, but more importantly it shortens vector lifespan so fewer mosquitoes survive extrinsic incubation. Because extrinsic incubation for DV is expected to be relatively long compared to an average lifespan (Styer et al., 2007), killing adults before they become infectious has a greater impact on new human DV infections than does larval control. Encouraging the development of novel strate- gies for killing adult Ae. aegypti would exploit this fundamental concept and enhance dengue prevention. We are not recommending abandoning larval control, especially in loca- tions and cultures with strong community participation or where conditions are particularly favorable. For instance, in Vietnam biocontrol agents were available for treating a prominent and easily recognizable container class (Kay and Nam, 2005). Removal of immature Ae. aegypti development sites, through physical or chemical means that are targeted at containers that produce the most adults, should be considered valuable components of integrated dengue vector control programs (WHO, 2006a). Our main point here is that shifting attention from immature to adult mosquitoes for surveillance and control will stimulate develop- ment of more informative and effective methods with greater impact on reducing morbidity and mortality than an immature-centric approach. Emphasis on Intradomicile Vector Control Increased attention on surveillance and control of adult Ae. aegypti reveals the opportunity to attack them in human habitations, where they spend most of their time. Because adult Ae. aegypti rest, feed, mate, and reproduce in houses

VECTOR-BORNE DISEASE DETECTION AND CONTROL 147 (Scott et al., 2000b), it is believed that this is where they make the most frequent contact with humans (DeBenedictis et al., 2003), and thus, where most people are infected. The assumption that the home is the primary point of contact for human DV infection merits rigorous validation in prospective field studies. Nevertheless, based on existing information, attacking this species in homes is well justified. The efficacy of strategies such as indoor residual sprays (IRS) and intradomicile application of insecticide-treated materials (ITM) are strongly sup- ported by encouraging results from a variety of Ae. aegypti field studies (Nam et al., 1993; Nguyen et al., 1996; Igarashi, 1997; Kroeger et al., 2006). Moreover, it has been known for some time that when insecticides do not reach Ae. aegypti inside homes they are ineffective (Reiter and Gubler, 1997). Novel products and systems for delivery of insecticidal products into homes will enhance broad-scale intradomicile dengue prevention programs. It is essential that means for detecting and managing insecticide resistance are incorporated into an overall plan for adult mosquito control programs to prevent dengue. Because intradomicile control is conceptually consistent with the current public health policy for dengue (i.e., managing disease by managing mosquito vector populations) (PAHO, 1994) it should be promoted to enhance disease prevention. Advantages from this approach transcend Ae. aegypti and dengue. Intradomi- cile insect control will decrease densities and lifespans of dengue and nondengue insect vectors and pests and, thereby, help reduce the long list of public health problems that they represent. For example, in addition to dengue, the home is a major point of infection for pathogens like malaria, lymphatic filariasis, leishman- iasis, and Chagas disease. A variety of insect vectors (e.g., Ae. aegypti, Anopheles gambiae, An. funestus, Culex quinquefasciatus, sandflies, and triatomids) bite and infect humans in their homes. Pest insects (e.g., bed bugs, cockroaches, filth flies, and pest mosquitoes) are similarly too often abundant in homes and can lead to the perception that control measures directed at specific vectors (i.e., Ae. aegypti) are not effective. Knowledge gained from an improved understanding of peridomestic insect ecology can be effectively applied in intradomicile control strategies that address a variety of disease and pest problems. In so doing, what was originally conceived as an Ae. aegypti control program can be leveraged into a cost- and operationally effective public health program that reduces a variety of diseases and pest problems. Integrated Disease Prevention: Vector Control and Vaccines It is generally accepted that an integrated, multidimensional control strategy is superior to a single line of attack (Shea et al., 2000). Thus, vector control guide- lines frequently and justifiably include recommendations for disease prevention that combine different vector interventions (WHO, 2006a). We propose to take the notion of integrated disease prevention a step farther, across disciplines that traditionally have not been used in combination by applying vector control and

148 VECTOR-BORNE DISEASES a vaccine together. The justification for our recommendation is that in concert these two methods will act sooner and be more sustainable than either method by itself. The synergetic benefit, from vector control and chemotherapy, has been documented for lymphatic filariasis (Sunish et al., 2007). Proof of principle with another vector-borne disease justifies serious consideration of a similar strategy for dengue prevention. In this approach, we view both strategies as public health tools, rather than something intended to protect individuals. The overall goal is to sustain a lowered force of DV transmission, ideally so that the basic reproductive number (Ro) for dengue is less than one. If that is accomplished, disease would correspondingly decrease and DV transmission could conceivably be eliminated from treated areas. The combined benefit of vector control and a vaccine comes from their complimentary impact on reducing Ro. The critical proportion of a population that must be vaccinated to eliminate transmission of a pathogen is derived by the equation Pc = 1 – (1/Ro) (Anderson and May, 1991). Although, Ro for any pathogen varies through time and space, if we assume that for dengue R o = 10 the critical proportion to vaccinate will be 90 percent. If Ro can be reduced by reduc- ing the density of vector mosquitoes a smaller proportion of susceptible people will need to be vaccinated (i.e., if Ro = 2 then Pc = 50 percent). Vector control, therefore, makes it easier to meet vector-borne disease vaccine delivery goals. The positive impact of a vaccine on vector control concerns the issue of sustainability. There are numerous examples of effective vector control over the short term (Ooi et al., 2006). The big challenge is to sustain disease suppres- sion. This is because effective vector control lowers the incidence rate. The aim of vector control, short of vector eradication, is to lower the force of pathogen transmission. Recruitment into the population of susceptible people by birth is sufficient to gradually decrease herd immunity over time to the point where mosquito densities necessary to avoid unacceptable levels of transmission are so low that operationally they are close to vector eradication. Accordingly, over the long term, vector control becomes increasingly difficult to sustain. If, however, herd immunity can be artificially elevated by vaccination this difficult battle does not need to be fought. Vaccination can be used to sustain artificially elevated levels of herd immunity and at the same time the force of DV transmission can be diminished by vector control. The result is an operational capacity to sustain Ro below 1. Vaccination as a public health tool, therefore, makes sustained vector control a realistic possibility. Clinical cures for dengue will be important for disease management, but are not likely to have a major impact on virus transmission because DV viremia is brief (i.e., 3-7 days), many DV infections are asymptomatic (Waterman and Gubler, 1989; Focks et al., 1995; Rigau-Perez et al., 1998), and most people do not seek medical attention until after they have been viremic for some time or after their viremia has subsided altogether (Vaughn et al., 2000). Drugs will be

VECTOR-BORNE DISEASE DETECTION AND CONTROL 149 valuable in a clinical setting but are not expected to reduce DV transmission unless applied prophylactically on a broad scale. Conclusions The transition from prescribed to adapted dengue prevention will need to be guided by meaningful goals and accomplished with effective tools. Goals will be reached if enhanced vector control is framed by an improved understanding of vector ecology in pathogen transmission. Longitudinal field studies that capture entomologic, virologic, and epidemiologic information are the most effective ways to assess fundamental assumptions and refine new techniques. The follow- ing are key tasks that need to be addressed to meet these objectives: • Design operationally and epidemiologically effective ways to assess risk of DV transmission and set goals for disease prevention. • Create an inexpensive and effective tool for monitoring adult Ae. aegypti population density. • Develop a rapid, sensitive, specific, and inexpensive way to estimate serotype-specific herd immunity that can be used to predict risk of epidemic DV transmission. • Encourage the use of dengue vaccines as public health tools to artifi- cially elevate immunity in an integrated disease prevention program with vector control. • Evaluate more effective and operationally feasible means of reduc- ing adult Ae. aegypti density that can be readily adapted to situation-specific circumstances. • Promote field-based prospective longitudinal cohort research in disease- endemic locations that assesses adaptive intervention strategies based on relation- ships among measures of entomologic and epidemiologic risk, dengue incidence, and severity of disease. Accomplishing these tasks will translate into the most important attributable benefit from vector control for dengue—reduction of disease burden and death.

150 VECTOR-BORNE DISEASES INNOVATIVE DECISION SUPPORT AND VECTOR CONTROL APPROACHES TO CONTROL DENGUE Lars Eisen, Ph.D. Colorado State University Barry J. Beaty, Ph.D.5 Colorado State University Summary Vector-borne diseases (VBDs) remain major threats to human health and well-being. The 2003 Microbial Threats to Health report from the Institute of Medicine challenged the global research and public health community to develop new tools, approaches, and capacities to predict, prevent, and control the emer- gence and resurgence of VBDs. Among these were recommendations to develop new computer-based systems and new approaches for vector control. The Inno- vative Vector Control Consortium (IVCC) is addressing these needs for dengue and malaria; this includes funding a Colorado State University project aiming to develop a computer-based Dengue Decision Support System (DDSS), syndromic surveillance for early detection of and intervention in dengue outbreaks, and a “Casa Segura” safe house proactive vector control approach. The need for a shift toward proactive vector control approaches and integrated vector management strategies also is highlighted. Introduction As an epidemiological group, VBDs, such as dengue, filariasis, leishmani- asis, malaria, onchocerciasis, trypanosomiasis, and other vector-borne bacterial, parasitic, or viral diseases, are the causes of inestimable misery, morbidity, and mortality in humans and impediments to socioeconomic development in many parts of the world (IOM, 2003; see also Beaty and Eisen in this report). A number of actions to address major needs in prediction, prevention, and control of VBDs were suggested in the Microbial Threats to Health report from the Institute of Medicine (IOM, 2003). In this paper, we will describe ongoing initiatives and activities pertinent to two of these recommendations: • Expand efforts to exploit geographic information systems (GIS) and robust models for predicting and preventing the emergence of vector-borne and zoonotic diseases, and exploit innovative systems of surveillance that capitalize on advances in information technology.   Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 151 • Develop new and expand upon current research efforts to enhance the armamentarium for vector control, including improved pesticides and formula- tions, novel strategies to prolong pesticide usage, new repellents, and new biopes- ticides and biocontrol agents to augment chemical pesticides. The IVCC is helping to address these needs for dengue and malaria by fund- ing projects to develop new tools and approaches to enhance vector and disease surveillance and control. This paper will focus primarily on dengue, which is caused by four dengue virus serotypes (DENV 1-4), and is transmitted primarily by the yellow fever mosquito Aedes aegypti. Epidemic dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) have increased dra- matically throughout the tropics in recent decades (Gubler, 2002a, 2004; Guzman and Kouri, 2003; IOM, 2003). There are critical needs and opportunities for new tools and approaches for control of dengue and other VBDs. New Initiatives, Approaches, and Tools for Vector-Borne Disease Prediction, Prevention, and Control The response of the nation and world to the challenges associated with VBDs has been generally positive. The Bill and Melinda Gates Foundation has numer- ous programs involving vector control, including one of the Grand Challenges, and the World Health Organization (WHO) Special Programme for Research and Training in Tropical Diseases (TDR) has initiated a new program—Innovative Vector Control Interventions. The portfolio of vector grants has exploded at the National Institutes of Health (NIH). Finally, the Innovative Vector Control Consortium is directly aligned with the Institute of Medicine recommendations concerning GIS and modeling approaches and the development of new tools, approaches, and public health insecticides for vector control. The Innovative Vector Control Consortium The IVCC was formed to improve control of mosquito-borne diseases (Hemingway et al., 2006). Consortium institutions include the Liverpool School of Tropical Medicine, the London School of Hygiene and Tropical Medicine, the Medical Research Council of South Africa, Colorado State University, and the University of California, Davis. The overarching goal of the IVCC is to improve vector control in and around the home, where many VBDs are preferentially transmitted. Malaria in sub-Saharan Africa, Chagas disease, dengue, filariasis, and leishmaniasis are transmitted to humans principally indoors by endophagic and/or endophilic vectors. The IVCC established two major objectives to address these VBDs:

152 VECTOR-BORNE DISEASES 1. Develop new public health insecticides and formulations for vector control 2. Develop new tools and approaches for vector control In objective 1, the IVCC is partnering with industry to facilitate and expedite discovery, development, and deployment of new public health insecticides and/or formulations for vector control. The rationale and approach for IVCC objective 1 activities are provided by Hemingway et al. (2006). In objective 2, the IVCC is funding projects to develop new tools and approaches for vector control. The current objective 2 project portfolio tar- gets malaria and dengue and includes product development projects focused on operational tools for rapid detection of insecticide resistance (Vector Population Monitoring Tool project) and determination of efficacy of insecticide-treated materials (Pyrethroid Quantification Kit project). Three additional objective 2 projects focus on malaria and dengue modeling and development of decision support systems for vector and disease control program operational management (Malaria Decision Support System, Dengue Decision Support System, and Den- gue Modeling projects). Decision Support System Approaches to Facilitate Control of Vector-Borne Diseases Computer-based decision support systems have been evaluated and used extensively in clinical and diagnostic medicine (e.g., Miller, 1994; Del Fiol et al., 2000; Montgomery et al., 2000; Colombet et al., 2003; Sefion et al., 2003), veterinary medicine (e.g., Stärk et al., 1998; Gu et al., 1999; Sanson et al., 1999), and for agriculture and forestry pest management (e.g., Knight, 1997; MacLean et al., 2000; Hearn and Bange, 2002). This approach has great potential for improving surveillance, prevention, and control of VBDs affecting humans. Vec- tor control programs implementing a decision support system will benefit from improved logistical capacity for data management and analysis and an emphasis on evidence-based and rational decision making, leading to the implementation of effective control program strategies, methodologies, and management. Following the emergence of West Nile virus (WNV) in the United States, the ArboNET system was developed to achieve a rapid flow of information of WNV activity in vectors, domestic and wild animals, and humans from local and state health departments to a national database managed by the Centers for Disease Control and Prevention (CDC). Map outputs showing up-to-date activity of WNV and other arboviruses included in ArboNET are available through a website man- aged by the U.S. Geological Survey. A similar system for WNV surveillance has been implemented in Canada (Gosselin et al., 2005). Other examples from North   See http://diseasemaps.usgs.gov.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 153 America include a web-based multimedia spatial information system to document Ae. aegypti breeding sites and dengue fever risk along the U.S.-Mexico border (Moreno-Sanchez et al., 2006) and the use of GIS for malaria surveillance and control in Mexico (Hernandez-Avila et al., 2006). The Ross River virus Early Detection and Surveillance (RREDS) system managed by the Queensland Institute of Medical Research, Australia, is another example of a web-based system to achieve rapid flow of information regarding arbovirus activity from local health authorities to a central database (Ryan et al., 2006). In addition, the RREDS system generates a near-real-time comparison of the current intensity of virus activity (expressed as activity over a 3-week moving window) to a historical average for the same time period; this allows for early warning of increased virus activity (alert threshold) relative to the “normal” situa- tion. In the global arena, WHO’s DengueNet provides a variety of dengue-related data, which can be accessed in table and map formats. Similar information for malaria in Africa is available from the MARA/ARMA—Mapping Malaria Risk in Africa project and the Malaria Atlas Project. Perhaps the best examples of operationally functional computer-based GIS or decision support systems for VBDs in the developing world comes from sys- tems for malaria surveillance and control and insecticide resistance management developed by the Medical Research Council of South Africa (Booman et al., 2000, 2003; Martin et al., 2002; Coleman et al., 2006; Sharp et al., 2007a). Other positive examples include systems for urban malaria control in India (Srivastava et al., 2003), management of human African trypanosomiasis in Ethiopia and Zambia (Robinson et al., 2002; Sciarretta et al., 2005; Symeonakis et al., 2007), and vector and dengue surveillance and control in Brazil and Singapore (Ai-leen and Song, 2000; Teng, 2001; Rosa-Freitas et al., 2003). Development of a comprehensive decision support system for management of a VBD needs to take into account data related to vector, pathogen, and dis- ease surveillance as well as vector control, pathogen control, clinical infor- mation, diagnostic testing, behavior and education of the human population, and demographic and socioeconomic conditions. We are currently developing a DDSS that will support local and regional vector control programs, will be made freely accessible for self-application by end-users through application packages offered from a website, and will be rationally designed to promote information flow between local, regional, national, and even international stakeholders. The computer-based DDSS will aid and systematize the process of gathering and ana- lyzing information, gaining new insights, generating alternatives, and ultimately, making evidence-based decisions regarding vector and disease surveillance and control (Figure 2-1).   See http://www.who.int/csr/disease/dengue/denguenet/en/index.html.   See http://www.mara.org.za.   See http://www.map.ox.ac.uk/MAP_data.html.

154 Dengue Decision Support System Data Data Data Data Data Data Program collection entry storage retrieval analysis display strategy Data Management tool, XHTML files, and methodology Sampling format, SQL data Management GIS software, text files, schemes data entry warehouse tool statistical packages, GIS software, screens modeling Google Earth Outputs: charts, graphs, maps, tables Feedback to program Interpretation strategy and methodology (comparison with local historical data, relation to critical thresholds, etc.) Management decisions FIGURE 2-1  Flow scheme for a Dengue Decision Support System. fig 2-1 Landscape view

VECTOR-BORNE DISEASE DETECTION AND CONTROL 155 The potential for developing decision support systems for management of VBDs has been enhanced by the emergence of GIS technology and the rapidly increasing availability of cartographic, demographic, socioeconomic, and envi- ronmental GIS-based data. Using dengue as an example, GIS provides capacity for the presentation of spatial and spatiotemporal patterns of risk of exposure to vectors and dengue virus based on location-specific information (e.g., Morrison et al., 1998, 2004a; Indaratna et al., 1998; Carbajo et al., 2001; Teng, 2001; Ali et al., 2003; Getis et al., 2003; Muttitanon et al., 2004; Siqueira et al., 2004; Sithiprasasna et al., 2004; Tran et al., 2004; Chadee et al., 2005; van Benthem et al., 2005); and development of predictive spatial risk models based on correlates between GIS-derived data and vector or disease measures (Peterson et al., 2005; Rotela et al., 2007). Free mapping software tools providing access to high-quality satellite imagery (e.g., Google Earth, MS Virtual Earth) are a powerful comple- ment to GIS software for presentation of information overlaid on an image show- ing the physical environment (Figure 2-2). FIGURE 2-2  Example from Chetumal, Mexico, of quality of imagery accessed through Google Earth.

156 VECTOR-BORNE DISEASES Incorporation of a GIS spatial backbone into the DDSS framework and collection of spatial reference information for vector- or disease-related data (see Figure 2-3) will allow the user to readily link information from different data categories (e.g., disease case locations, implementation of vector control measures, and insecticide resistance in local vector populations) for analysis and display. An outline of data categories and data types potentially included in a full- capacity DDSS for implementation in a resource-rich environment, including the downstream potential for a vaccine against dengue virus, is shown in Figure 2-3. The flexibility of the DDSS framework will, however, allow for implementation of locally adapted and scaled-down DDSS versions to fit other resource environ- ments. For example, in a resource-poor environment perhaps only the vector control, vector surveillance, and passive disease surveillance components will be used together with a very basic spatial backbone. Expected key outcomes from implementation of the DDSS include improved capacity for data collection, entry, storage, retrieval, analysis, and display; and evidence-based decision making and use of locally appropriate vector/disease control program strategies and methodologies. Syndromic Surveillance and Use of Priority Areas for Emergency Vector Control to Facilitate Early Dengue Outbreak Response The severity of dengue outbreaks can be exacerbated by slow and unfocused vector control responses. Vector control programs commonly do not initiate reac- tive control measures until they receive laboratory diagnosis of dengue infections. Several weeks to a month may elapse before diagnostic results become available and during that time a dengue outbreak may spread rapidly through a city and overwhelm vector control resources. This underscores the need for implementa- tion of an effective dengue surveillance system (Rigau-Perez and Gubler, 1997; Gubler and Casta-Valez, 1991; Gubler, 2002b), and, indeed, argues for use of a syndromic surveillance approach to achieve early warning of dengue outbreaks. In a computer-based DDSS, we envision clinical data to be entered into an elec- tronic case report form at local health clinics and syndromic surveillance informa- tion, either based on physician diagnosis or an algorithm to separate dengue from other commonly occurring diseases based on symptomology, to reach the vector control program in real time, thus minimizing vector control response time. The feasibility of the syndromic surveillance approach will be operationally tested in Merida, Mexico, in collaboration between Colorado State University, Universidad Autonoma de Yucatan, the Servicios de Salud de Yucatan, Centro Nacional de Vigilancia Epidemiologica y Control de Enfermedades, and Instituto Nacional de Salud Publica. Another problem commonly facing vector control programs is that dengue cases spread rapidly throughout a city and overwhelm vector control response capacity. In this situation, it is critical to have a rational spatial response plan where high-risk priority areas are treated before areas with lower risk. Des-

, etc. Fever of unknown origin DISEASE CONTROL?? Vaccination Knowledge, Attitude, and Practice among population , etc. FIGURE 2-3  Outline of data potentially included in a full-capacity Dengue Decision Support System. 157

158 VECTOR-BORNE DISEASES ignation of priority areas for emergency vector control can be based on historical entomological and epidemiological data and adjusted in near real time based on syndromic surveillance data from the DDSS. Combined, syndromic surveillance and use of priority areas for emergency vector control will provide unprecedented capacity to intervene in impending dengue epidemics. Management of Insecticide Resistance and the Development of New Insecticides Insecticides will remain the front line of control of mosquito-borne diseases for the foreseeable future. Unfortunately, no new public health insecticides for adult mosquitoes have been developed in more than 30 years, and the number of insecticides available for mosquito control is severely limited (Hemingway et al., 2002, 2006). The recent report of reduced efficacy of bednets and indoor residual spraying (IRS) associated with pyrethroid resistance in Benin (N’Guessan et al., 2007) is of great concern. In the case of Ae. aegypti, numerous studies have documented resistance to commonly used insecticides, potentially removing them from the armamentarium used by vector control programs. Increasing resistance to temephos, which is widely used for control of Ae. aegypti immatures, has resulted in a shift toward the operational use of Bacillus thuringiensis israelensis (Bti) in parts of Brazil (Lima et al., 2003; Braga et al., 2004). Resistance to pyre- throids is being documented in many dengue-endemic countries (e.g., Rodriguez et al., 2001, 2005; Houng et al., 2004; da-Cunha et al., 2005; Flores et al., 2005; Paeporn et al., 2005; Ponlawat et al., 2005), with potential ramifications for operational control of adult Ae. aegypti. Routine operational testing for insecticide resistance in dengue virus and malaria vectors is still lacking in many disease-endemic areas, and positive exam- ples of evidence-based insecticide resistance management schemes are scarce. Examples include the switch to Bti in response to tempehos resistance in Brazil mentioned earlier and the development in South Africa of an evidence-based decision support system for rational insecticide choice in the control of African malaria vectors (Coleman et al., 2006; Coleman and Hemingway, 2007). Indeed, decision support systems provide exceptional capacity for monitoring and miti- gating resistance, developing insecticide resistance management schemes, and evaluating the efficacy of new insecticides (Hemingway et al., 2006; Coleman et al., 2006; Coleman and Hemingway, 2007). These systems also will facilitate critically needed evaluations of the operational impact of insecticide resistance on the efficacy of specific insecticide-based vector control measures (for example, use of insecticide-treated bednets or curtains to reduce pathogen transmission in the home environment). The IVCC-funded Dengue and Malaria Decision Support System projects will monitor insecticide resistance in targeted vector populations, thereby permitting better stewardship of insecticides and improved vector control (Hemingway et al., 2006; Coleman and Hemingway, 2007).

VECTOR-BORNE DISEASE DETECTION AND CONTROL 159 The “Casa Segura” Safe House Approach to Control of Vector-Borne Diseases Targeting the vector in the domicile offers great potential for control of VBDs that are transmitted indoors. Indeed, much of the success of DDT in the past was attributed to its ability to kill or repel endophagic vectors (Roberts et al., 1997; Gratz, 1999; Attaran et al., 2000). In this regard, one of few success stories in VBD control in recent times has been the dramatic reduction of Chagas disease (American trypanosomiasis) in South America following implementation of the Southern Cone Initiative (Schofield and Dias, 1999; Dias et al., 2002). This initiative included a combination of IRS to control reduviid vectors and screening blood donors to avoid transfusional transmission. The IRS approach dramatically reduced the prevalence of Triatoma infestans vectors in the domi- ciles and, ultimately, resulted in near elimination of Chagas disease in parts of southern South America. Many other VBDs are also transmitted in large part indoors (e.g., malaria in much of sub-Saharan Africa, dengue, leishmaniasis, and filariasis), and are thus susceptible to similar domicile-targeted interventions. The advent of long-lasting insecticide-treated materials (LL-ITMs), which can remain efficacious for more than 5 years, for use in bednets for malaria control has also been a public health success (e.g., N’Guessan et al., 2001; Hawley et al., 2003; Tami et al., 2004; Dabire et al., 2006); these materials also offer great potential for control of other diseases transmitted in the house. We are exploring a “Casa Segura” safe house approach for control of dengue using LL-ITMs as curtains. This approach is predicated upon previous studies demonstrating the potential for using ITMs as curtains to reduce vector abundance and dengue virus transmis- sion in Southeast Asia (Nam et al., 1993; Nguyen et al., 1996; Igarashi, 1997; Madarieta et al., 1999) and the Americas (Kroeger et al., 2006). Entomological indices were not only dramatically reduced in and near intervention homes, but there was also a community effect on vector abundance (Kroeger et al., 2006). Currently studies are being initiated in an urban setting in Merida, Mexico, in collaboration with local, state, and national public health officials to assess the protective efficacy of LL-ITMs in a 3-year longitudinal study. Conceptually, a “Casa Segura” provides protection similar to a well-built and air-conditioned home. The presence of window screens and air conditioning recently was shown to be a key factor explaining discrepancies between outdoor abundances of Ae. aegypti immatures and dengue incidence between “sister cities” on opposite sides of the U.S.-Mexico border (Reiter et al., 2003). LL-ITMs in the form of curtains or wall hangings can potentially protect homes, schools, or other struc- tures where people are exposed to bites by Ae. aegypti for multiple years at low cost. Protection may also extend to other disease vectors or pest insects, including nuisance-biting Culex mosquitoes, thereby making LL-ITMs a broad-spectrum public health product, rather than one stove-piped to protect against a single dis- ease. For example, use of insecticide-treated curtains in the Americas may offer protection against vectors of dengue, Chagas disease, cutaneous leishmaniasis,

160 VECTOR-BORNE DISEASES and malaria (Xavier and Lima, 1986; Figueiredo et al., 1998; Kroeger et al., 2002, 2006; Herber and Kroeger, 2003). Finally, LL-ITMs and other future low- cost interventions to create a “Casa Segura” also provide a business opportunity since the approach can be implemented both as part of a proactive vector control program and as a private homeowner initiative. The Need for Proactive Vector Control Approaches and Integrated Vector Management Strategies The limited success of reactive vector control approaches (especially vehicle- based ultra low volume [ULV] spraying in response to detection of dengue cases) to combat dengue over the last decades highlights the need for a shift toward more proactive vector control approaches implemented as part of an integrated vector management strategy (Reiter and Gubler, 1997; Gubler, 2002c; Townson et al., 2005; Kroeger and Nathan, 2006). The “Casa Segura” approach discussed earlier is one example of a proactive vector control measure targeting the adult mosquito. In an integrated vector management strategy, the “Casa Segura” could be implemented together with promising proactive approaches for control of immature mosquitoes (i.e., targeting of chemical or biological control measures to especially productive container types [Alexander et al., 2006; Focks and Alexander, 2006; Nathan et al., 2006] and community-based programs for source reduction, such as the Patio Limpio program now being widely implemented in Mexico).10 The latter type of program may, however, need to be supported by legislation and fines for noncompliance to ultimately become an effective and sustainable vector control measure. Although there has been a recent resurgence in dengue, Singapore provides a positive example of how an aggressive, proactive, and multifaceted approach can reduce dengue transmission compared to that in surrounding areas (Goh, 1995; Reiter and Gubler, 1997; Ooi et al., 2006). The Singapore model was based on a program initiated in the late 1960s and combined aggressive implementation of vector surveillance and control measures, health education, slum clearance, improvements in water supply and storage practices to reduce vector breeding sites, and legislation (the 1968 Destruction of Disease Bearing Insects Act, which later was replaced by the 1998 Control of Vectors and Pesticide Act) to ensure public compliance in removal of vector breeding sites from the domestic environ- ment (Chan and Counsilman, 1985; Lok and Bos, 1987; Ooi et al., 2006). This was later complemented by the use of GIS for vector and disease surveillance and to identify dengue virus transmission hotspots for improved targeting of vector control activities (Ai-leen and Song, 2000; Teng, 2001). Several possible explanations for the recent resurgence of dengue in Singapore despite its compre- hensive vector/dengue control program have been offered (e.g., overall lowered 10  See http://www.cenave.gob.mx/dengue/default.asp?id=81/.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 161 herd immunity of the human population and an increase in adult cases, emphasis away from vector surveillance toward detection of dengue case clusters followed by reactive implementation of vector control measures). Further insights into this matter will provide valuable information facilitating the process of restoring the Singapore program to its former level of performance. To achieve a global shift in resource allocation from reactive to proactive vector control approaches, there is a need for partnerships between academic institutions conducting research on outcomes of different proactive vector control approaches and the public health community ultimately charged with deciding how available resources should be allocated between proactive vector control measures, vector surveillance, dengue surveillance, and reactive emergency vec- tor control measures. Conclusion Although the challenges are great, there is currently considerable excitement in the field of VBDs for the development of new tools and approaches to predict, prevent, and control disease. Exciting new advances in information technology, disease modeling, GIS-based risk assessment, and long-lasting insecticide deliv- ery mechanisms (e.g., LL-ITMs) offer great potential for improved management of VBDs. Our new mandate is to translate the explosion of new information into field-relevant tools and management strategies, and to train a new generation of vector biologists and medical entomologists capable of incorporating the new methodologies into daily vector and disease control operations. To facilitate this process, there is a need for new research and training programs, and for partner- ships between academic institutions, business interests, and the public health community. Acknowledgments Funding was provided by the IVCC as part of the DDSS project. We collec- tively thank the DDSS project teams at Colorado State University, Universidad Autonoma de Nuevo Leon, Universidad Autonoma de Yucatan, Servicios de Salud de Yucatan, and Servicios Estatales de Salud de Quintana Roo for their invaluable contributions to and support for the project.

162 VECTOR-BORNE DISEASES WEST NILE VIRUS Lyle R. Petersen, M.D., M.P.H.11 Centers for Disease Control12 The West Nile virus (WNV) is a single-stranded RNA virus belonging to the family Flaviviridae, genus Flavivirus. Several of the nearly 70 known viruses in this genus are human pathogens; some cause encephalitis or febrile illness, including hemorrhagic fevers such as dengue and yellow fever (hence “flavi,” meaning yellow). They are grouped into three phylogenetic clusters: one has no known arthropod vector; one is tick-borne; one, which includes WNV, is mosquito-borne (Kuno et al., 1998). WNV is part of a serocomplex that includes Japanese encephalitis and its close relative, St. Louis encephalitis, a disease with a long history in North America. WNV and its close relatives are primarily bird viruses that produce low viremias in humans and horses, which therefore serve as non-amplifying hosts. WNV was first isolated in 1937 from the blood of a febrile woman in the West Nile district of what is now Uganda. Subsequently, it was commonly found in humans, birds, and other vertebrates in Asia, Eastern Europe, and Africa, and was associated with sporadic cases of febrile illness, meningitis, and encephali- tis in numerous countries (Murgue et al., 2002). From the 1940s through 1980, outbreaks of varying size occurred throughout these regions and mainly in Israel (Marberg et al., 1956); only one, which occurred in an Israeli nursing home in 1957 (Spigland et al., 1958), was associated with a high incidence of severe morbidity. A major WNV outbreak in South Africa in 1974 caused tens of thou- sands of cases of febrile illness without a single reported case of meningitis or encephalitis. Beginning in 1994, WNV outbreaks with a high incidence of severe morbid- ity occurred in Algeria (1994), Romania (1996), Tunisia (1997), Russia (1999, 2000, and 2001), Israel (2000), and Sudan (2002) (Mackenzie et al., 2004). The 2000 Israeli outbreak is notable because it was accompanied by bird mortality. It was this neuroinvasive strain, or its very close relative, that was imported into the United States to cause the first domestic outbreak in 1999, in New York City (Lanciotti et al., 1999). Similar strains, all of which are associated with bird mor- tality and mouse neurovirulence, constitute a new group within the phylogenetic tree of WNV, as shown in Figure 2-4. Researchers (Brault et al., 2007) have sub- sequently demonstrated that increased bird mortality due to these strains resulted from a single nucleotide change in a nonstructural protein. 11  Director, Division of Vector-Borne Diseases, Fort Collins, Colorado. 12  The findings and conclusions in this report are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 163 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 U.S./ Israel MD 2000 NJ 2000 Israel 1999 H C.Afr.Rep 1989 Senegal 1979 Algeria 1968 C.Afr.Rep 1967 Iv.Coast 1981 Kunjin 1960 1 Kunjin Kunjin 1973 Kunjin 1984b Kunjin 1991 Kunjin 1984a Kunjin 1966 Kunjin 1994 India India 1955a India 1980 India 1958 India 1955b LIN-1 Kenya Uganda 2 Senegal 1990 Uganda 1937 C.Afr.Rep 1972a C.Afr.Rep 1983 LIN-2 Uganda 1959 C.Afr.Rep 1972b Madagascar 1988 Madagascar 1986 Madagascar 1978 JE SA 14 FIGURE 2-4  Phylogenetic tree of West Nile virus. Only lineage 1 viruses are frequently associated with human or animal disease. Note the genetic similarity of isolates identi- fied from recent human outbreaks in Romania, Senegal, Morocco, Russia, Israel, and the 2-4 United States. The U.S. isolates are nearly genetically identical to those found in Israel, suggesting importation from the Middle East. SOURCE: From Lanciotti et al. ���������������������������������������������������� (1999). Reprinted with permission from the American Association for the Advancement of Science. Surveillance Response to the 1999 New York City outbreak included the creation of the first and currently only national human-veterinary disease surveillance system, called ArboNET. Administered by the Centers for Disease Control and Prevention (CDC), ArboNET is a real-time electronic reporting system that captures data on WNV in humans, dead birds, mosquitoes, horses, and live captive sentinels (chickens) (Gubler et al., 2000). These data are collected and reported to CDC

164 VECTOR-BORNE DISEASES 16,000 Equine Vaccine Introduced 4,000 14,000 Equine 3,500 Human Equine Case Reports (N=24,213) Human Case Reports (N=9,906) 12,000 3,000 10,000 2,500 8,000 2,000 6,000 1,500 4,000 1,000 2,000 500 0 0 1999 2000 2001 2002 2003 2004 2005 2006 Year FIGURE 2-5  Equine and human West Nile virus neuroinvasive disease cases, by year, United States. by health departments across the country. Between 1999 and 2006, ArboNET has detected 62 species of mosquitoes that are positive for WNV—a huge number for 2-5 an arbovirus—although more than 98 percent of infected mosquitoes collected belong to the genus Culex (CDC, 2007a). WNV is associated with an enormously high prevalence of virus in mosquitoes, such that during WNV outbreaks, infec- tion rates are measured in percents of mosquitoes infected, rather than per thou- sand, a more typical rate of infection for an arboviral vector. From 1999 through 2006, 317 species of WNV-positive dead birds were reported to ArboNET (CDC, 2007a). In 2006, American crows and blue jays accounted for 62 percent of the total reported (however, some reporting bias is likely as both species are relatively common in urban settings, large, and morphologically distinct). Recent data indicate that declines in crow and other susceptible bird populations have accompanied the introduction of WNV into an area (LaDeau et al., 2007). Figure 2-5 illustrates trends in cases of neuroinvasive WNV disease among humans and horses. The introduction of an equine WNV vaccine before the 2003 transmission season has markedly decreased the inci- dence of disease in horses. A Hidden Epidemic Table 2-1 summarizes reports of human WNV cases in the United States to date, including more than 9,900 cases of neuroinvasive disease in the form of

VECTOR-BORNE DISEASE DETECTION AND CONTROL 165 TABLE 2-1  Reported West Nile Virus Disease Cases in Humans, by Clinical Syndrome, United States, 1999-2006 Year WNNDa Fever Otherb Total Deaths 1999 59 3 0 62 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 aWNND = West Nile virus neuroinvasive disease. bOther = Other clinical syndrome or syndrome unspecified. encephalitis, meningitis, and acute flaccid paralysis. These numbers are probably accurate because the vast majority of patients with neuroinvasive disease are hospitalized and reported. On the other hand, the 13,000 reported cases of West Nile fever significantly underestimate the number of actual cases. Serosurveys show that about 75 percent of WNV infections are asymptomatic; the other 25 percent develop West Nile fever, and about 1 in 140 of these individuals develops neuroinvasive disease (Tsai et al., 1998; Mostashari et al., 2001). Extrapolations of these ratios to the number of neuroinvasive disease cases reported indicate that approximately 1.4 million infections have occurred in the United States (thus, the actual number of fever cases to date is approximately 323,000). This “hidden epidemic” of WNV poses a serious threat to the U.S. blood supply, as will be subsequently discussed. Geographic Patterns of WNV Neuroinvasive Disease Incidence The series of maps shown in Figure 2-6 depicts the incidence of WNV neu- roinvasive disease in U.S. counties each year since the inception of surveillance in 1999. In that year, all of the cases occurred around New York City, but WNV activity was detected in animals and mosquitoes across a much wider area. In 2000, WNV moved northward in the spring along with migrating birds, then southward again in the fall (CDC, 2000). This is the only really clear evidence, provided by ArboNET data, for the importance of bird migration to the spread of WNV in the continental United States. In 2001, as expected, an enzootic area formed in the southeastern United States, resulting in sporadic human cases of WNV neuroinvasive disease (CDC, 2001). Although human cases were limited to this region as well as the Northeast, the virus spread to the Mississippi River and beyond. The first large outbreak

166 VECTOR-BORNE DISEASES FIGURE 2-6  West Nile virus activity and human neuroinvasive disease incidence per million population, by county, United States, 1999-2006. SOURCE: CDC (2007c).

VECTOR-BORNE DISEASE DETECTION AND CONTROL 167 of WNV disease occurred in Chicago and other cities near the Great Lakes, Mississippi, and Louisiana in 2002 (O’Leary et al., 2004); like the 1999 New York City outbreak, this outbreak occurred during a heat wave, as did outbreaks that spanned much of the Midwest in 2003, and again in 2005 and 2006 (CDC, 2007a). By 2004, WNV had become endemic in much of the United States and had reached the West Coast. Outbreaks occurred in desert locations, such as Phoenix, Arizona; this seems remarkable until one realizes that these places have been transformed by humans—who have built golf courses, swimming pools, and reservoirs—into urban oases capable of supporting extensive mosquito breed- ing. An analysis of data from 2002 through 2006 showed that North and South Dakota, Wyoming, Colorado, and Nebraska had a cumulative incidence of human neuroinvasive disease of more than 15 per 100,000 population, while Montana, Louisiana, and Mississippi had cumulative incidences from 10 to 14 per 100,000. These same states historically have had high incidence of St. Louis encephalitis (SLE) virus, a related flavivirus with similar ecology to WNV. A ranking of the counties in terms of mean annual incidence for WNV neuroinvasive disease reveals a pattern of persistent high incidence of disease in counties along the Platte and Missouri Rivers and the southern Mississippi River. Predicting Future Outbreaks As illustrated by the epidemic curve for WNV in 2006 (Figure 2-7), human case incidence increases very quickly in mid-summer; often, human epidemics 600 550 500 450 400 No. of Cases 350 300 250 200 150 100 50 0 No 1 5 Ju 0 5 Oc 4 No 8 De 9 3 1 Au 2 Ja 7 l8 Ma 8 Ma 3 Ju 7 Se 9 Fe 4 Se 6 Oc 0 Au 5 Ap 5 Ma 2 9 Se 2 8 Ap 1 Ma 4 v1 v2 t1 t2 c2 n1 n2 n2 l2 b1 y1 y2 g1 p1 p3 r1 r1 c n b g p r r Ju Ap De Ja Fe r Ju Week Ending FIGURE 2-7  Reported number of human West Nile virus disease cases, by week of symptom onset, 2006, United States. 2-07

168 VECTOR-BORNE DISEASES are not recognized until they are well under way. Thus, predicting where and when epidemics are likely to occur is a key goal of ArboNET. For clues to WNV behavior in the future, one might look at long-term SLE incidence patterns. Unfortunately, as shown in Figure 2-8, such a pattern is not discernable from 70 years of SLE incidence data. Because WNV has an ecology similar to that of SLE, it is likely that WNV will behave in a similarly unpredict- able pattern. However, WNV produces considerably higher levels of viremia in birds, affording it much greater epidemic potential (Komar et al., 2003). Although both WNV and SLE outbreaks, particularly in the northern United States, have often occurred during heat waves, it is noteworthy that the largest U.S. outbreak of SLE was not associated with a heat wave or with any other readily identifiable weather anomaly. Ecological surveillance can be somewhat helpful in predicting WNV out- breaks. In North America, chickens, mosquitoes, horses, and birds have dem- onstrated increased activity prior to the onset of, or early in, human outbreaks of WNV illness (Eidson et al., 2001; Kulasekera et al., 2001). However, at best, ecological surveillance provides only a few weeks’ warning before a human WNV outbreak. In Latin America, extensive serological data from ecological surveillance in birds and horses shows that WNV has spread from the Carib- bean as far south as Argentina (Morales et al., 2006; Komar and Clark, 2006), 3,000 West Nile virus 2,500 St. Louis encephalitis virus 2,000 Number of Cases 1,500 1,000 500 0 1932 1942 1952 1962 1972 1982 1992 2002 Year FIGURE 2-8  Human cases of West Nile virus and St. Louis encephalitis neuroinvasive disease, by year, 1932-2006, United States. 2-8

VECTOR-BORNE DISEASE DETECTION AND CONTROL 169 yet relatively little human or horse morbidity has occurred in these areas. Since considerable serological cross-reactivity exists among flaviviruses, interpretation of such serological data is difficult. Perhaps an unknown serologically cross- reactive WNV-related flavivirus is actually circulating in the region, or it could be that, for some yet-unknown reason, WNV produces relatively little morbidity in this part of the world. Outcomes and Impact of WNV Illness The clinical spectrum of WNV illness is complex. Whereas fever, meningitis, encephalitis, and acute flaccid paralysis were initially considered to be sepa- rate outcomes of WNV infection, there now appears to be considerable overlap among these syndromes (Sejvar and Marfin, 2006). Many people with fever also have some meningitis symptoms; likewise, both encephalitis and meningitis are present in many patients. Acute flaccid paralysis can occur with any of the other three syndromes, but some people have developed WNV paralysis in the absence of any other symptoms. It is perhaps not surprising, then, that the full impact of acute WNV illness in the United States remains to be determined. A 2002 study in Louisiana, limited to people with neuroinvasive disease, estimated the economic impact of that year’s outbreak on the state at $20 million (Zohrabian et al., 2006). The economic impact of long-term effects of acute WNV illness has not been studied but may be considerable. For WNV encephalitis, long-term effects include persistent disabling neurological sequelae, tremors, and movement disorders in about half of all patients 2 years post-diagnosis; these patients also often report that they have difficulty with memory and concentration (Sejvar, 2007). Nearly all patients with WNV paralysis experience persistent weakness and functional impairment. Within a year of diagnosis, about one-third of patients approach baseline recovery; another third improve significantly but still have severe functional disability; the remaining third experience little or no recovery (Sejvar et al., 2006). The considerable underreporting of WNV fever and misunderstanding of its true morbidity have created the perception that WNV fever has little public health significance. Recent studies show that West Nile fever, initially considered to be a mild febrile illness, can result in hospitalization and/or symptoms that often last weeks to months (Watson et al., 2004; Patnaik et al., 2006). Nearly four-fifths of persons with WNV fever missed work for a median of 16 days. Finally, deaths due to WNV illness are also probably underreported in our surveillance system since persons with a delayed death from WNV may not be reported or deaths attributed to their primary cause (e.g., cardiovascular disease) may have been precipitated by WNV.

170 VECTOR-BORNE DISEASES Risk Factors for Infection and Illness According to data accumulated from 1999 to 2006, a person’s risk of acquiring WNV neuroinvasive disease steadily increases from birth through advanced age—a risk that is, overall, significantly higher in males than in females (CDC, 2007a; O’Leary et al., 2004). In addition, organ transplant recipients have about 40 times the risk of the population at large for developing severe neurological disease after WNV infection (Kumar et al., 2004a,b). Patients with hematological malignan- cies also appear to be especially vulnerable to severe WNV neurological disease (Southam and Moore, 1954), but relative risk has not yet been calculated for this population. Weaker evidence suggests that diabetes, hypertension, alcohol abuse, chronic renal disease, and cardiovascular disease increase the risk for developing WNV neuroinvasive disease (Patnaik et al., 2006; Bode et al., 2006; Murray et al., 2006). Novel Modes of Transmission Several instances of non-mosquito-borne WNV transmission have been reported, including two cases resulting from organ transplants (Iwamoto et al., 2003; CDC, 2005), and one case from breast milk in which the infant remained asymptomatic (CDC, 2002a), although this mode of transmission seems to be rare (Hinckley et al., 2007). One case of transplacental transmission in which the infant experienced a severe outcome has been reported (CDC, 2002a); however, a study of 72 cases in which mothers were infected with WNV during pregnancy showed no conclusive evidence linking WNV infection to congenital malforma- tion (O’Leary et al., 2006). Percutaneous, occupational exposure to WNV has been well described (CDC, 2002b); there was also one case of infection follow- ing conjunctival exposure to the brain tissue of an infected bird (Fonseca et al., 2005). WNV and Transfusion Safety The risk of WNV infection via blood transfusion has led to a new paradigm in blood donation screening. It was proven in 2002 that WNV could be transmit- ted via transfused blood (Pealer et al., 2002). At that time, models indicated that WNV was the most common, unscreened, transfusion-transmissible viral agent by far, due to its extraordinarily high incidence (particularly since viremia due to WNV lasts only approximately 6 days) (Biggerstaff and Petersen, 2003). All proven transmissions of WNV via the blood supply have occurred in patients transfused with IgM- and IgG-negative blood (Pealer et al., 2002; CDC, 2007b), thus the virus could not have been detected with antibody tests such as those used to identify human immunodeficiency virus (HIV) or hepatitis C virus (HCV). As a result, in 2003, the U.S. blood supply was screened by

VECTOR-BORNE DISEASE DETECTION AND CONTROL 171 mini-pool nucleic acid amplification tests (MP-NATs), a technique that is also used to detect HIV and HCV as a supplement to antibody testing; WNV is cur- rently the only infectious agent to be screened solely by this method. To date, approximately 1,800 viremic donors have been identified, but nine breakthrough transmissions have occurred through donors whose viremia was lower than the detection limit for mini-pool MP-NAT (CDC, 2007b). Screening the U.S. blood supply for WNV is enormously costly: cost estimates range from about $2.5 to $7 per donation screened (Custer et al., 2005; Korves et al., 2006), which would amount to $34 to $95 million annually. This is greater than the approximate $33 million budget spent by CDC in 2006 for WNV surveillance, prevention, and control programs. Viral Evolution WNV has spread rapidly across the Americas since its introduction in 1999, arriving at the Pacific Coast within 4 years and in Argentina within 7 years. Figure 2-9 depicts network analyses of viral isolates obtained from blood banks and other sources that show the relatedness of WNV strains, both by year and by region (Herring et al., 2007). Chronological analysis indicates that the 1999 New York strain has been replaced by descendants of the 2002 strain, which have a single nucleotide change in the envelope gene (Herring et al., 2007; Davis et al., 2005). Compared to the 1999 virus, this newly emergent genotype is transmitted earlier and more efficiently in Culex mosquitoes (Ebel et al., 2004; Moudy et al., 2007). Regional analysis suggests that new WNV clades are emerging in different areas of the country, most notably the Pacific Coast (Herring et al., 2007). Summary and Conclusions In the years since WNV was introduced to the United States, we have gained considerable knowledge of the virus in several key areas. We know that bird migration and random bird movement profoundly influence viral spread; the role of humans in this process remains to be determined. Many possible important avian hosts and competent mosquito vectors have been identified for WNV, many of which contribute to its unprecedented epizootic activity. WNV has also had a significant impact on wildlife and domestic animals. In some cases, ecological surveillance can provide indicators of impending human outbreak several weeks in advance. Clearly, a combination of human and veterinary surveillance will be essential to monitor the ongoing ecological impact of WNV and to guide disease prevention efforts. An estimated 1.4 million WNV infections have occurred in the United States to date. The resulting incidence of WNV illness reveals a persistent epidemic/ endemic pattern without a clear temporal trend. No other region of the world experiences repeated WNV outbreaks, year after year, as have occurred in the

172 VECTOR-BORNE DISEASES FIGURE 2-9  Phylogenetic analysis of West Nile virus E gene sequences, by (A) year and (B) location, United States. SOURCE: Reprinted from Herring et al. (2007), with permission from Elsevier. United States. The experience with WNV demonstrates that the epidemiological pattern in areas of importation of an exotic arbovirus may bear little resemblance to that which occurred in its previously endemic area. WNV has had considerable regional and local variation in incidence and persistence in the United States. Incidence appears to be highest in the midwest-

VECTOR-BORNE DISEASE DETECTION AND CONTROL 173 ern United States and, in part, has been facilitated by land use, such as irrigation of farm land. Such wide temporal and geographic variations in WNV incidence challenge traditional clinical trial-based approaches to evaluating vaccines and therapeutics, which are usually based in a few centers, often in urban areas. A different strategy is clearly required—one reliant on surveillance to rapidly iden- tify areas where outbreaks are occurring or likely to occur and that allows rapid recruitment of patients in rural and suburban hospitals in those areas. Severe underreporting of WNV fever, and of the apparently common chronic sequelae of both WNV fever and neuroinvasive disease, are hiding a serious epidemic of which the consequences remain to be fully understood. Changes in patient population demographics and medical care are likely to increase the popu- lation at risk. A variety of nonvector transmission modes have been discovered for WNV, most notably via blood transfusion. WNV has become a significant and costly threat to blood safety in the United States due to the high incidence of asymptomatic infection; in a similar scenario, another vector-borne viral patho- gen, dengue, now appears to be compromising blood supplies in Puerto Rico and other endemic areas. While alternate transmission modes for vector-borne patho- gens may be of limited overall public health significance, they could result in con- siderable public concern and expense (as demonstrated by the cost of screening the U.S. blood supply for WNV) and thus require new methods of control. Genetic variation in WNV, including relatively small changes in the virus, has been associated with avian mortality and human outbreaks of unusual sever- ity. The original New York 1999 strain has disappeared and has been replaced by a strain that is transmitted earlier and more efficiently in vector mosquitoes; there has been subsequent temporal and regional viral evolution, with variants appear- ing and disappearing. In such a complex and fluid situation, a multidisciplinary approach will be required to understand the linkages between WNV ecology, epidemiology, and genetics. RIFT VALLEY FEVER IS AN EMERGING ARTHROPOD-BORNE VIRUS C. J. Peters, M.D.13 University of Texas Medical Branch Epidemiology and Ecology Rift Valley fever (RVF) appeared at the turn of the 20th century as an epidemic disease of domestic livestock in Kenya. The virus (RVFV) was isolated in 1930 (Daubney et al., 1931) and shown to cause the acute febrile disease that occurs in 13  John Sealy Distinguished University Chair in Tropical and Emerging Virology; Director for Biodefense in the Center for Biodefense and Emerging Infectious Diseases.

174 VECTOR-BORNE DISEASES most infected humans. In the 1950s the virus began to cause widespread epidem- ics in South Africa and nearby Zimbabwe (Swanepoel and Coetzer, 2004). The common ecologic denominator among the three areas was the presence of depres- sions that filled with water only when heavy rainfall occurred; these were known as damboes in Kenya (Linthicum et al., 1985), vleis14 in Zimbabwe (Swanepoel and Coetzer, 2004), and pans in South Africa (Gargan et al., 1988b). The previ- ous concepts of RVFV were based on movement of the virus from areas of heavy rainfall into regions with intermittently strong precipitation where it might utilize several different mosquito vectors for intensive epidemic transmission (Meegan and Bailey, 1988), but later data showed that there was a very different model that has more explanatory power. The virus was transovarially transmitted in floodwater breeding Aedes mosquitoes, and this formed the basis for persistence of RVFV in the environment (Linthicum et al., 1985). Heavy rainfall led to the accumulation of water in these depressions, which connect with groundwater aquifers, and this saturation in turn triggers the hatch of transovarially-infected Aedes ova and the introduction of RVFV into the environment. Later hatches of these and other species of mosquitoes provide vectors that are efficient in hori- zontal transmission of the virus. One of the important characteristics of RVFV is that it readily orally infects many species of mosquitoes found worldwide, and then can be transmitted when they feed on laboratory hosts, demonstrating their potential vector competence in propitious ecological circumstances (Gad et al., 1987; Gargan et al., 1988a; Jupp et al., 2002; Jupp and Cornel, 1988; McIntosh et al., 1973; Turell and Kay, 1998). These alternate vectors are very important in continuing propagation of epidemics. The finding of Aedes mcintoshii as an important transovarial host of RVFV in East Africa (Linthicum et al., 1985) left questions about the ecology of RVFV else- where. It is clear that low levels of RVFV transmission occur in many areas during interepidemic periods (Davies, 1975; Davies et al., 1992; Fontenille et al., 1995; Swanepoel, 1976; Thonnon et al., 1999). The best example is in the Senegal River basin. A serosurvey conducted as part of an environmental impact study before the construction of a dam at the mouth of the river showed ~7 percent seroprevalence in human populations, establishing the presence of the virus even though it had never been described in that region (Digoutte et al., 1989). When the dam was closed in 1987, there was flooding that resulted in a major epidemic of RVF in that area. This massive epidemic would likely not have been detected if it were not for two French army physicians posted to Rosso, Mauritania; even then, they thought the epidemic of hemorrhagic fever they observed was yellow fever. Fortunately, they connected with the Pasteur Institute in Senegal and the correct virological diagnosis was made. Interestingly, the epidemic that called attention to the situation in West Africa was only part of the story; remote sensing shows that there was increased moisture in a much broader area. When transmission was sought, virus activity 14  Fertile wetland areas.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 175 was found to occur far away from the river flooding including the Ferlo region of Senegal (Wilson et al., 1994) and as far south as The Gambia (Ksiazek et al., 1989). Subsequent studies in the area isolated RVFV from new species of flood- water Aedes mosquitoes, which are candidates for the transovarial reservoirs of the virus (Fontenille et al., 1998). With improved surveillance low-level endemic and intermittent epidemic virus activity has been found (Nabeth et al., 2001; Thonnon et al., 1999; Zeller et al., 1995, 1997). While the finding of transovarial transmission of RVFV provided a key find- ing in the natural history of the virus, many other questions remain. Although vertical transmission of the virus can explain persistence at some level, it proved impossible to colonize Ae. mcintoshii mosquitoes to study the efficiency of the process or any of its quantitative aspects; Rickettsia (now Orientia) tsutsugamushi and its trombiculid mite host provide the only known system which has 100 percent vertical transmission. Thus, we infer that there is almost certainly a ver- tebrate amplifier involved; but viruses are “old” and we also suppose RVFV must have been present for hundreds or thousands of years. To date, there has been no native African vertebrate amplifier identified, and it is believed that sheep, cattle, and goats were only introduced into Africa 3,000 to 5,000 years ago. In addition, most arboviruses generally are not pathogenic for their amplifier host, whereas domestic animals have a substantial case fatality rate and a very high abortion rate (Swanepoel and Coetzer, 2004). One possibility is that the virus we know as RVFV has evolved only recently. Nichol and colleagues have recently published an analysis of 33 strains using a Baysian approach and believe that the oldest common progenitor of our modern virus strains emerged in the late 1800s (Bird et al., 2007). This is a time when major changes in sheep and cattle raising occurred, including introduction of new breeds from Europe and raising of large herds. Although we lack the strains to test it, this hypothesis would put RVFV in the same category as Venezuelan equine encephalitis virus (VEEV) (Weaver, 2005). This agent evolved to produce high viremias and change mosquito vectors after the introduction and proliferation of equines with the Conquistadores in the 1500s. In fact, there are several similarities, including adapting from a defined set of endemic vectors (Culex in the subgenus Neomelanoconion versus floodwa- ter Aedes) to utilize multiple epidemic vector species, using a “new” vertebrate amplifier (equines versus sheep and cattle), incidentally infecting humans, and having great human economic impact on the amplifer species. Like VEEV, RVFV also has the potential for emergence in distant areas. VEEV exhibited this through its march up Central America through Mexico to reach Texas in 1971. RVFV has been making tentative gestures in this direction since 1977 when it caused a massive epidemic in Egypt (Meegan, 1979). It has now spread from continental Africa for the first time; in the wake of the large East African epidemic in 1997- 1998 (Woods et al., 2002), the same strain was found in an epidemic in nearby Yemen and Saudi Arabia (Shoemaker et al., 2002) and may have been reintro- duced into Egypt as well (Abd el-Rahim et al., 1999).

176 VECTOR-BORNE DISEASES Control Through Prediction Undoubtedly one of the reasons RVFV has not been introduced into the United States is that in Africa it is a rural disease, and the movement of domestic livestock and rural dwellers is not common. Contrast this with West Nile virus that came to the United States during an epidemic in Israel caused by a strain of virus that seems to be unusually virulent and that is vectored by an urban mos- quito. Thus, the ability to predict, monitor, and control RVFV in Africa could be of extreme importance, and some progress has been made in this area. The first observations related to the high, prolonged precipitation associated with epidemics in Kenya (Davies et al., 1985). Then it was shown that this could be assessed in a dambo in Kenya by using the National Oceanic and Atmospheric Adminstration (NOAA) satellite and Advanced Very High Resolution Radiometer (AVHRR) readings to measure leafy biomass (Linthicum et al., 1987). Several studies (Anyamba et al., 2006a,b; Linthicum et al., 1999) culminated in a system that can combine AVHRR readings (which are readily available and inexpensive to obtain). This system, which is maintained on the Department of Defense Geographic Emerging Infections Surveillance website (Al Hazmi et al., 2003), utilizes the historical information on RVFV epidemics and the NOAA databases. Real-time sattelite observations make it possible to predict immediately arising problems, but this system can be linked to long-term climate prediction, which is becoming increasingly accurate. It has become clear that the East African epi- demics are linked to El Niño/Southern Oscillation conditions. Climate prediction in turn can be coupled with the detailed geographic information systems map- ping of Africa as developed by many institutions, including the U.S. Agency for International Development Famine Early Warning System, to examine the impact of issues such as water accumulation, run-off, soil types, and groundwater consid- erations. In addition, there are evolving modeling systems using the susceptible- exposed-infected-resistant (SEIR) modeling system (Gaff et al., 2007). These eventually will be linked to climate and satellite data to help in control decisions such as deployment of vaccines, mosquito larviciding, and other strategies in Africa and in the case of introduction into the United States. Clinical Disease and Therapy Most Americans fail to grasp the huge gaps between our understanding of many important diseases in developing countries and our information on diseases that are much less common but are studied in medical centers in the United States. In addition to the lack of infrastructure and skilled observers, many cultures do not permit post-mortem examinations. This understanding is, of course, basic to developing therapeutic approaches to RVFV. Only a handful of human RVFV patients have been studied in detail. As one example of this, the recent Saudi Arabian epidemic resulted in severe cases being moved to tertiary care hospitals

VECTOR-BORNE DISEASE DETECTION AND CONTROL 177 that, for the first time, performed systematic renal function, hepatic function, and coagulation tests on patients (Al Hazmi et al., 2003; Madani et al., 2003). These tests and clinical observations suggested there was an association between severe systemic disease and central nervous system involvement. Isolated renal disease was also seen in virus-confirmed cases. Because of the hiatus in clinical description of cases, we took the 2006-2007 outbreak in Kenya as an opportunity to make first-hand clinical observations on patients with a U.S.-trained infectious disease physician. He was linked to the United States using telemedicine so that the institutional base at the University of Texas Medical Branch at Galveston could support him (Kahlon, Peters, King, White, and LeDuc, unpublished obser- vations). New descriptions of clinical manifestations were obtained, broadening our understanding of the pathogenesis of the disease and also educating U.S. physicians in understanding the clinical presentation of RVFV infection through direct telemedicine observation. It is also unappreciated that we actually know very little about the actual incidence of the different severe manifestations of infection, such as hemorrhagic fever, encephalitis, and retinal disease. Retinal vasculitis has been said to occur in 1-10 percent of patients with most suggestions being toward the low end. A recent retrospective combined serological and ophthalmological study in Kenya suggested that seropositive persons were much more likely to have retinal dis- ease and optic atrophy than controls, perhaps several percent of total infections (LaBeaud, King, Muchiere, and Peters, unpublished observations). Vaccines The rapidity with which RVFV moves in epidemics makes a safe potent vaccine with rapid onset of immunity after a single dose basic to control of livestock disease. No such vaccine now exists (Botros et al., 2006; Coetzer and Barnard, 1977). We have begun to work with an attenuated strain developed in the mid-1980s (Caplen et al., 1985) as such a vaccine and also as a human vaccine. We have developed a reverse genetic system to be able to manipulate the vac- cine and the wild-type virus (Ikegami et al., 2006) and are exploring the critical mutations and seek deletions to define attenuation. The major obstacles we have found are the presence of the predictable mutability of RNA virus genomes and the existence of quasispecies or multiple polymorphisms in viral populations (Lokugamage, Makino, Ikegami, Morrill, and Peters, unpublished data). The outlook is nevertheless good for the human vaccine because it seems to be overall genetically stable, and other successful RNA virus vaccines also have multiple polymorphisms in their populations (e.g., yellow fever, mumps, measles, polio vaccines). We believe it will be possible to develop such a tool for control of dis- semination to mosquitoes via viremic domestic animals and to protect humans in laboratory, veterinary, and endemic settings.

178 VECTOR-BORNE DISEASES Conclusions RVFV has been emerging in our consciousness since the beginning of the 20th century and continues to cause devastating human and animal epidemics in Africa. It has the potential to extend its range and it is very likely that the United States and other areas are receptive to virus transmission. Research has been slow for lack of appreciation of the threat and lack of infrastructure in involved areas. It seems likely that some measure of control in endemic areas could be achieved by prediction of epidemics and application of live attenuated vaccines for animals and humans. This would also decrease the risk of distant natural spread. If either natural or intentional introduction of the virus to this country should occur, then these vaccines would be urgently needed, and successful vaccine development is likely to be possible using newly developed reverse genetics systems. THE IMPLICATIONS OF ENTOMOLOGICAL MONITORING AND EVALUATION FOR ARTHROPOD VECTOR-BORNE DISEASE CONTROL PROGRAMS Michael Coleman, Ph.D.15 Medical Research Council Janet Hemingway, Ph.D.16 Liverpool School of Tropical Medicine Malaria control currently relies on the use of an effective drug and an effective vector control program. Most National Malaria Control Programmes (NMCPs) focus their resources on monitoring morbidity and mortality of people, neglecting the implications that insecticide-based vector control is having on the mosquito population. Routine entomological monitoring allows for the earlier detection and response to potential insecticide failure and increases in malaria transmission. Through this rapid response it is possible to avert increases in mor- bidity and mortality that currently occur before program failure is recognized. This paper reviews some of the simple entomological techniques available for use by NMCPs and indicates how they can be successfully implemented. This paper focuses on entomological surveillance aspects for malaria control. The concepts presented here have cross-cutting implications to other arthropod vector-borne diseases. 15  Malaria Research Programme. 16  Director.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 179 Introduction There are a large number of human pathogens in nature that are transmit- ted by arthropods. These vector-borne pathogens typically infect, replicate, and develop in both the vector and human host. There are over 100 countries at risk from malaria encompassing almost 50 percent of the world’s population (Hay et al., 2004; WHO, 2002). There are up to 300 million episodes and 1 to 3 million deaths a year from malaria (Breman et al., 2004; Snow et al. 2005). This disease has major economic and health impacts for a disease-endemic country (Gallup and Sachs, 2001). A public health surveillance system, based on the systematic collection of relevant information and the analysis and timely dissemination of data, to those responsible for controlling the disease, is essential. For a vector-borne disease, a good surveillance system should include the following: • Disease detection via passive (patient data from health facilities) or active surveillance (visiting the community and testing individuals) • Entomological surveillance through monitoring of species density, infec- tivity (sporozoite rate), and insecticide resistance • Environmental surveillance including climate and geographical data Successful malaria control currently relies on effective drug treatment and vector control. Vector control is insecticide-based mainly through indoor residual spraying (IRS) or deployment of insecticide treated bednets (ITNs). Entomological Surveillance There are over 100 species of anopheline mosquito that are able to transmit malaria. Anopheles gambiae, An. Arabiensis, and An. funestus are the three main vectors in Africa. Species Density Only older adult female mosquitoes are able to transmit malaria. Vector control aims to reduce the numbers of mosquitoes in a population that are able to transmit malaria. Vector population species density can be reduced to a threshold that interrupts transmission. Our ability to reduce vector populations varies with species and locality. An. funestus is highly endophilic, and hence, susceptible to IRS and has been eradicated from parts of southern Africa (Sharp et al., 2007a,b; Maharaj et al., 2005). Vector density surveillance measures the direct impact of the control program on vector population size. There are a number of methods available for collect- ing vectors. Collection methods are varied and dependent on the questions that

180 VECTOR-BORNE DISEASES are being answered. For example, collecting resting mosquitoes will give a more representative idea of the population for sexes and the feeding states than a trap that will predominantly catch feeding or recently fed females. However, sampling resting mosquitoes is time-consuming and more suited to research projects than an NMCP, which would favor a less-intensive collection method such as passive window exit traps. For an in-depth review of methods see Service (1971, 1993). Relative vector density is an adequate surveillance method for most NMCPs. Collections should ideally be assessed against a baseline and established before the onset of control activities. A good example of how relative species density is informative is from the ongoing malaria control program on Bioko Island, Equatorial Guinea. Species density is measured through a series of window traps at sentinel sites; in year one the IRS program with a pyrethroid had a significant impact on the An. funestus population but not the An. gambiae population. This was shown to be due to knockdown resistance (kdr) in the An. gambiae population; when the insecticide changed to a carbamate it had a significant impact on both vector species (Figure 2-10) (Sharp et al., 2007b). The sustainability of IRS is controversial. However, this mode of control has been linked to some of the world’s most successful malaria campaigns including the near eradication of malaria from Sri Lanka in the 1960s, South America in 60 50 per Trap per 100 Nights 40 Average Mosquitoes 30 An. funestus 20 An. gambiae s.l. 10 0 Months 12 01 02 03 04 05 06 07 08 09 10 11 12 01 02 03 04 05 06 07 08 Years 2003 2004 2005 FIGURE 2-10  By monitoring the species density on Bioko Island, Equatorial Guinea, the malaria control program was able to detect a reduced impact of IRS with pyrethroid on An. gambiae compared to An. funestus. Further investigation detected kdr resistance in 2-10 An. gambiae and a change in insecticide policy that resulted in a reduction of both vector species. SOURCE: Sharp et al. (2007b).

VECTOR-BORNE DISEASE DETECTION AND CONTROL 181 1950-1960 (Alilio et al., 2004; Carter and Mendis, 2002), and Mexico in the 1990s (Chanon et al., 2003). Sporozoite Rate Transmission of malaria varies with location and vector species. Parameters may vary depending on factors such as the human biting rate, sporozoite rate (infectivity of mosquitoes) and entomological inoculation rates (EIRs). EIR is the number of infective bites that an individual receives over a set period of time (Killeen et al., 2000; Antonio-Nkondjio et al., 2002). Determining these aspects of entomology is labor-intensive and time-consuming, which is not compatible with NMCP continuous surveillance activities. Operationally, a more passive format of mosquito collection via fixed traps is preferred. Monitoring the vector infectivity, or sporozoite rate, can be achieved using exit traps on houses. Mosquitoes can be analyzed for sporozoite by dissec- tion or more sophisticated techniques of polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) (Bell and Ranford-Cartwright, 2004; Moreno et al., 2004). Various studies demonstrate that transmission can be interrupted by reduc- ing vectorial capacity. This was achieved in Bioko, where sporozoite rates in An. gambiae were reduced despite the control measure having a lower impact on this species than on An. funestus (Sharp et al., 2007b). This is most likely due to the impact of control measures on the age structure of the mosquito population. A second threshold measure that can be achieved is a reduced daily mosquito survi- vorship. If this is reduced significantly, so that death occurs before the mosquito becomes infective (typically 10 days after an infected blood meal), then vectorial capacity is reduced and transmission is blocked. Insecticide Resistance Insecticide resistance in mosquitoes threatens the long-term ability to con- trol disease vectors. The numbers of insecticides formulated for indoor resid- ual treatment and recommended by the World Health Organization (WHO) via its Pesticide Evaluation Scheme (WHOPES) (WHO, 2001) are severely lim- ited. Insecticide resistance surveillance was recently reviewed (Coleman and Hemingway, 2007). The WHO-led malaria eradication campaign (1955-1969) was built on the twin pillars of DDT-based control of the insect vectors and chloroquine treatment of malaria cases. This campaign had many notable successes, eradicating malaria from several countries and dramatically reducing transmission in others (Trigg and Kondrachine, 1998), but the campaign was ultimately seen as a failure, with issues of DDT resistance often cited as a major reason for the lack of eradication in many malaria-endemic countries (Coleman et al., 2006).

182 VECTOR-BORNE DISEASES Resistance to DDT was first noted just 10 years after its introduction (WHO, 1957). As DDT resistance spread, the faster-acting pyrethroids were introduced; this class of insecticides replaced DDT in many malaria control programs. As pyrethroid resistance started to develop, many control programs attempted to revert back to DDT. However, because these insecticide classes share a common target site (Soderlund and Bloomquist, 1989), the sodium channel and cross- resistance had developed to both insecticide classes in many locations (Martinez- Torres et al., 1998; Ranson et al., 2000). The spread of pyrethroid resistance may be critical for sustainability of ITNs, as this is currently the only insecticide group recommended for net impregnation. Figure 2-11 shows insecticide resistance in Africa between 1950 and 2006. The economics of developing, registering, and marketing insecticides means that new insecticides are primarily developed for large agricultural markets. Some of these insecticides eventually cross over into the public health arena, which means that vectors breeding in agricultural areas may have previously been FIGURE 2-11  Resistance in Africa, 1950-2006. SOURCE: Reprinted from Coleman et al. (2006), with permission from the Entomological Society of America. Copyright 2006.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 183 Collection blood fed females from houses F1 generation reared Species WHO Biochemical identification susceptibility and molecular assay assays Management/policy change FIGURE 2-12  Insecticide resistance monitoring methods. SOURCE: Adapted from information in Coleman and Hemingway (2007). 2-12 exposed to these chemicals. In West Africa, DDT and pyrethroid resistance due to kdr is widespread. This resistance was selected for by the evolutionary pressure of DDT used in growing cotton and other cash crops (Mouchet, 1988). Surveillance of resistance within a population can be done by several meth- ods. The simplest is to measure insecticide dose response, where insects are exposed to a range of concentrations of insecticide and the dose that kills either 50 or 95 percent (LD50 and LD95, respectively) of the population. Populations may be compared by calculating the resistance ratio. Alternatively, and more commonly in an NMCP, a single diagnostic dose of insecticide is used that kills susceptible insects. Alternatively, resistance may be measured at a mechanis- tic level using biochemical or molecular methods. Although technically more demanding, these methods provide more predictive and accurate information (see Figure 2-12). Studies to determine the baseline of resistance should ideally be completed before an insecticide is selected (Casimiro et al., 2006a,b). Changes in this baseline can be monitored over time and insecticide treatments switched when required. This has been a component of the Lubombo Spatial Development Initiative (LSDI), a tri-national malaria control program between South Africa, Swaziland, and Mozambique to control malaria (Sharp et al., 2007a). Prior to

184 VECTOR-BORNE DISEASES 1999, there was no systematic collection of entomological information on the susceptibility levels of malaria vectors. In 1999, Maputo Province, Southern Mozambique, became part of the LSDI and an insecticide susceptibility baseline was established. A high level of pyrethroid resistance was detected in the vectors (Casimiro et al., 2006a,b). This resulted in a policy change and the carbamate bendiocarb® replaced lambda cyhalothrin in 2000. As dependence on the use of a single insecticide class in the long term was likely to be problematic, an extensive resistance surveillance program was initiated. Based on data from this surveillance and a requirement to reduce costs (Conteh et al., 2004), DDT was reintroduced in 2006 for IRS in malaria control in southern Mozambique. The insecticide susceptibility profile continues to be monitored operationally in the two major vectors in this region (see Figure 2-13) (Casimiro et al., 2007; Coleman et al., in press). Resistance in Mozambique is monitored by both bioassay and biochemical and molecular assays. Metabolic resistance involves a small number of enzyme families (Hemingway et al., 2002). Elevated levels of these enzymes are detect- able using simple biochemical assays (Hemingway and Smith, 1986; Penilla et al., 1998). Resistance to insecticides may also be due to an alteration in the target site. Kdr gives cross-resistance between DDT and pyrethroid. This has been studied extensively in West Africa (Coleman et al., 2006; Coetzee et al., 1999). Monitor- ing has been simplified by the development of a simple PCR to detect this single- point mutation (Martinez-Torres et al., 1998; Ranson et al., 2000). Simpler and more cost-effective tools to monitor insecticide resistance moni- toring are required to sustain this component of routine monitoring for an NMCP. Currently research is underway to develop simple PCR methods that are able to detect associated markers of insecticide resistance by replacing the biochemical assays and reducing the need for live or frozen insects. This will increase the ability of an NMCP to complete resistance surveillance without the reliance on external scientific research. Monitoring of resistance allows for resistance management policies to be implemented that will result in the extended life span of insecticides for vector control. This work was pioneered in Mexico, where a 7-year program demon- strated that at an operational level, annual rotation of insecticide groups was efficient (Figure 2-14) (Hemingway et al., 1997). Models Models help us to understand how a disease outbreak, epidemic, and spread may occur by understanding each component of the system (Bailey, 1982). A modified Reed-Frost equation (Fine, 1980) describes the dynamics of vector- borne disease through the average number of infective bites an individual may experience. This is intrinsically linked to the vectorial capacity (i.e., the number

FIGURE 2-13  Monitoring of insecticide resistance in Mozambique has resulted in several policy changes on the insecticide of choice for the country’s IRS program. Ultimately this will result in the sustainability of malaria control. 185 SOURCE: Adapted, with permission from Casimiro et al. (2006b). Courtesy of the Medical Research Council.

186 VECTOR-BORNE DISEASES Year 1 Year 2 Year 3 Single Traditional A A A insecticide Unrelated Rotation A B C insecticides Two unrelated Mosaic insecticides FIGURE 2-14  Insecticide rotation. of infective bites that an individual may receive in 1 day). McDonald (1977) pio- neered the use of vectorial capacity to study the transmission of malaria dynamics in Africa. Today we are left with a 2-14 modified form of this (Garrett-Jones, 1964). Using this model McDonald predicted that adulticides rather than larvicides would best reduce malaria transmission in Africa. ITNs were not an option at the time. However, models have flaws due to assumptions that must be made. McDonald’s model for instance, does not account for fluctuations in vector den- sity caused by seasonality effects, survivorship, or age composition. Ultimately models help our understanding of the factors that may affect a control program and predict what the outcome will be. Analysis of large data sets such as those generated in the Garki Project (Molineaux and Gramiccia, 1980) or the LSDI (Sharp et al., 2007a) will shed more light on the role of models in control. In order to be utilized, models must be incorporated into surveillance systems and not require a mathematical background. Decision Support Systems Sustainable malaria control is often jeopardized by insufficient public health resources. By utilizing information in a geographic information system (GIS) it is feasible to rationally target limited resources. Although GIS has been advocated for NMCP (Sharma and Srivastava, 1997) there has been little use of its capabili- ties for entomological surveillance (Coleman et al., 2006). GIS has been used most often in research to identify environmental factors responsible for vector and pathogen survival; it has been combined with a malaria

VECTOR-BORNE DISEASE DETECTION AND CONTROL 187 notification system to plan a malaria control program (Booman et al., 2000). This system creates risk maps of disease incidence at town level, allowing for more focused vector control. Larviciding is not generally used for large-scale malaria vector control, due to difficulties in targeting breeding sites and the numbers of larvae that need to be killed to reduce the subsequent numbers of adult females able to transmit disease. However, targeted larviciding can add value to an ITN or IRS program. Studies have identified variations in environmental factors at the village level, which, if mapped, would be amenable to focal larviciding strategies (Smith et al., 1995; Singh et al., 1990). Similar systems are being created in other areas to assess entomological malaria risk factors, including EIR and locality of vector breeding sites in order to effectively target control measures (Srivastava et al., 2003; Vanek et al., 2006; Dev et al., 2004). In Sri Lanka, where malaria is sea- sonal, focused larviciding of river banks as water levels recede in the post rainy season, the NMCP can offset the peak malaria vector abundance by 3 weeks (Wijesundera et al., 1990; Wickramasinghe, 1981). The result is a delayed and shorter malaria season. The usefulness of GIS for making control decisions and planning depends on the availability of accurate and timely data. A key component to the success is the integration of such systems into the NMCP itself. Control programs that utilize IRS and ITNs to interrupt the transmission cycle are only effective if a high coverage of the community is achieved. Monitoring and evaluation is needed if IRS is used to ensure effective application and avoid wastage (Goodman and Mills, 1999). A successful computerized IRS surveillance system has been developed utilizing a database and spatial mapping GIS tool (Booman et al., 2003). ITN coverage has traditionally focused on the number of bednets distributed, with little focus on actual use until recently. While usage has in some cases been determined during Malaria Indicator Surveys (WHO, 2000; Korenromp et al., 2003), these surveys are not appropriate for surveillance. The complex interrelationship between data and information needs to be inte- grated and simple analysis tools developed to aid control programs to assess and monitor malaria control and decide how best to respond to changes in informa- tion that is received. This can all be accomplished via a decision support system (Figure 2-15). Disease Surveillance Although not within the scope of this paper, it is essential to measure malaria prevalence to determine the impact of vector control on disease. Monitoring disease can be either passive, through cases presenting within the health system, or through active surveillance by going into the community and searching for cases. The speed at which it is possible to monitor for malaria parasites in blood smears has increased with the advent of sensitive rapid diagnostic tests (RDTs)

Health • clinically diagnosed cases SPATIAL Summary HMIS 188 Management • treatment and referral MODELLING Information • definitively diagnosed Case-specific System Spatial statistics HMIS • treatment and referral Mathematical ¥ vector species and densities • vector species and densities modelling ¥ specimen analysis • specimen analysis Entomological Vector Data Vector data Entomological ¥ Infectivity • infectivity Information Information System Insecticide Insecticide ¥ susceptibility to specific • susceptibility to specific System resistance insecticide groups DOCUMENTATION Resistance insecticide groups SQL protocols, ITN • quantities, distribution, and Intervention usage user manuals, Management process diagrams • insecticide quantities, and Information types System IRS • spray personnel • application rates of active MANAGEMENT ingredients TOOL • parasite type and infectivity • dynamic query tools Parasitemia and anaemia • anaemia • reports, tables, DATA WAREHOUSE Malaria graphs Indicator • socio-demographic data • maps, spatial Survey • illness, treatment, and birth Household analysis histories survey • under 5 mortality SDE cross-query datasets by region and over time • knowledge of malaria DATA MALARIA DECISION SUPPORT SYSTEM DISSEMINATION • provincial, district, sub-district, and locality boundaries Vector (points, • dynamic query tools Spatial • towns, villages, health lines, polygons) facilities, sentinel sites, • desktop mapping Decision window traps Support • web mapping Raster System Population surfaces, climate • web-based data (surfaces and coverages, elevation models coverages) serving FIGURE 2-15  Malaria Decision Support System. Courtesy of the Medical Research Council. 2-15 Landscape view

VECTOR-BORNE DISEASE DETECTION AND CONTROL 189 replacing microscopy (Craig and Sharp, 1997; Craig et al., 2002). This has led to a drive to put RDTs into clinics in Africa, but it has been a slow process and clinical diagnosis remains the norm for malaria case information. Summary Countries need to build field entomological capacity. It is the field entomolo- gist that should be involved in routine surveillance and interpretation of data for the NMCP. The aim of a public health surveillance system is to provide relevant infor- mation to make informed and timely decisions guiding interventions. Increased sharing of data is essential in the fight to prevent disease. A number of networks and databases have been developed, including AnoBase,17 MARA,18 and Vec- torBase,19 to do just that. The Innovative Vector Control Consortium (IVCC) (Hemingway et al., 2006) is facilitating the refinement and practical implemen- tations of entomological decision support systems (DSS). Currently the IVCC project portfolio has DSS being developed for malaria and dengue. To date these systems have relied on an interaction with a set of special- ized and skilled scientists including entomologists, spatial epidemiologists, and statisticians. These skills are not found in the average malaria control program, resulting in nonintegration of systems. Newer systems are looking at ways of simplifying data collection and interpretation to reduce the need for these skills at a local level. Research projects are generally intensive and concentrated on a few aspects of malaria in a small area. In order to fully understand the implications of research there is a need to scale research up to operational levels in an NMCP. Few examples of large-scale operational malaria research projects exist and those that do are slow in publishing results due to the pressure on scientists for novel publications. We are addressing the balance through new operational research in Malawi, Mozambique, and Zambia. Open-source databases are currently being developed that will allow relevant research to be shared with the malaria community ahead of schedule. Practical, affordable, and effective surveillance systems for inte- grated vector management in an NMCP will be developed. Researchers cannot support every NMCP operational activity in Africa; they cannot equally support routine surveillance—this must be an integral part of the NMCP if the NMCP is to succeed. 17  See http://www.anobase.org. 18  See http://www.mara.org.za. 19  See http://www.vectorbase.org.

190 VECTOR-BORNE DISEASES VECTOR-BORNE ZOONOTIC DISEASES AND THEIR ECOLOGICAL AND ECONOMIC IMPLICATIONS: BLUETONGUE DISEASE IN EUROPE Bennie I. Osburn, Ph.D., D.V.M.20 University of California, Davis Introduction Vector-borne diseases are of increasing importance because they are associ- ated with new and emerging diseases. Many of the viral and microbial agents associated with vector-borne diseases are zoonotic, affecting both animals and humans. The close association of the viral agents with vectors limits the distribu- tion of these agents and the diseases associated with them. The appearance of West Nile virus in the United States in 1999 serves as a prime example of how arboviruses can be picked up by susceptible vectors in the United States and spread rapidly across the country. In its wake are countless losses of wild bird populations, equine and companion animal disease, and deaths as well as human suffering and death. This paper will focus on an animal disease, bluetongue (BT) disease, which primarily effects ruminants and is transmitted by the biting midge, Culicoides spp. BT is caused by one of the 24 bluetongue viruses (BTVs) (Erasmus, 1985; Walton, 2004). BTVs are segmented double-stranded RNA viruses consisting of 10 genome segments. Although BTVs are found on six continents, the selective distribution of the viruses on continents is controlled by the vectors and specific genome segments. The confinement of the various serotypes of virus to continents depends on a variety of factors including weather, environmental conditions, and vector competence and capacity. BTVs on occasion move outside of recognized zones when climatic condition changes carry the vectors into areas where there are susceptible mammalian host species. The Disease BT was first recognized as a disease entity in the late 1800s when European sheep were introduced into South Africa (Erasmus, 1985). Many of these sick animals developed facial edema and, at the time of death, there was often a protruding swollen blue tongue, hence the name bluetongue. In the early 1900s, South African veterinary scientists were able to demonstrate that the disease was of infectious origin. The typical clinical signs in sheep were those of depression, facial edema, high fever, erosions of the oral mucosa, arched back, reluctance to move, difficulty walking, reddened coronary bands, and 30 percent mortal- ity. Less frequently, there were reports of clinical bluetongue in cattle. These 20  Dean, School of Veterinary Medicine.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 191 animals rarely died; however, they would show signs of vesicular lesions on the oral mucous membranes, which evolved into erosion. In addition, the cattle would have a vesicular dermatitis, which would often lead to erosions and dermal ulceration (Anderson et al., 1985). The skin was often thickened from edema, and the cows developed lameness because of coronitis. BT also affects some species of wild ruminants where the disease is associated with a hemorrhagic syndrome and sudden death (Stallknecht and Howarth, 2004). These animals also show depression and a high fever. Bluetongue has also been associated with congenital lesions and death in newborn ruminants and dogs (MacLachlan and Osburn, 1983; Akita et al., 1994). Fetal lambs and calves infected in utero early in gestation will develop a necrotiz- ing lesion in the developing brain, leading to hydranencephaly or porencephaly and retinal dysplasia (Osburn and Silverstein, 1972). Although the lambs and calves may be born alive, the lesions are incompatible with life. Pregnant bitches, accidentally infected with live virus vaccines containing BTV-contaminated fetal calf serum will abort infected fetal pups or the pups will die shortly after birth (Akita et al., 1994). Chick embryos used to culture BTVs develop a hemorrhagic syndrome associated with their death (Tyler et al., 1980). It appears that the BTV associated with the fetal deformities and neonatal deaths have been modified or selectively adapted in cell or chick embryo cultures. The pathogenesis of BTV in susceptible sheep, wild ruminants (white-tailed deer and prong-horned antelope), and chick embryos is centered on the predilec- tion of the virus for vascular endothelium (Mahrt and Osburn, 1986; MacLachlan et al., 1992; MacLachlan, 2004). This is associated with hemorrhagic lesions and edema. Some of the hemorrhagic lesions will lead to necrosis of striated muscles in the heart and skeletal muscles. A hallmark feature of sheep dying of BTV infections is pulmonary edema. This is brought about because of cardiac necrosis as well as the virus attack on vascular endothelium in the lungs (Mahrt and Osburn, 1986; MacLachlan, 2004). The pathogenesis of the fetal lesions in the developing nervous system appears to be neuronal and microglial necrosis due to virus infection of these developing cells and possibly, vascular invasion by the virus leading to infarction and liquefaction necrosis of nervous tissue (Osburn and Silverstein, 1972; MacLachlan, 2004). Cattle sensitized with inactivated BTV followed by challenge virus infection developed an IgE response with the subse- quent release of prostaglandins and cyclooxyengases leading to edema (Anderson et al., 1985). It is not known whether this occurs in acute infections in naturally occurring field outbreaks. The Viruses BT is caused by arthropod-borne viruses which are the prototype of the Orbivrus genera in the family Reoviridae (Murphy et al., 1999). Globally, there are 24 distinct serotypes based on serotyping. BTVs are icosahedral in structure

192 VECTOR-BORNE DISEASES and 69 nm in diameter. The genome consists of 10 double-stranded RNA seg- ments that can be observed on polyacrylamide and agarose gels. Seven of the genes code for structural proteins and three segments for nonstructural proteins, listed in Table 2-2. The genome is surrounded by 32 caposomeres in the nucleo- capsid. The diffuse outer layer coat of proteins is made up of viral structural protein (VP) 2 and VP5 with VP2 serving as the neutralizing protein in mam- mals. VP3 and VP7 are the major internal core proteins. VP7 is important for viral attachment in the insect vector and plays an important role in the ecological distribution of the viruses. This viral protein is often used as the group antigen for serological testing of BTVs. Even though 24 serotypes of BTVs have been identified throughout the world, not all serotypes have been identified on a single continent. The genetic heterogeneity of BTVs occurs as a result of genetic drift and shift (Bonneau and MacLachlan, 2004; deMattos et al., 1994). These two phenomena result in a remarkable heterogeneity among strains of BTVs that circulate or cocirculate in endemic regions. BTVs reassort gene segments, both in the infected ruminant as well as in the insect vector following infection with different strains or serotypes of viruses leading to the genetic shifts (deMattos et al., 1996). The accumulation of nucleotide substitutions within individual BT genes leads to genetic drift. The Vectors Early in the 20th century, South African scientists recognized that BTV was transmitted by midges (Erasmus, 1985; Walton, 2004). Later studies revealed TABLE 2-2  Viral Proteins and Functions Function Characteristics Structural Proteins VP1 RNA polymerase Replication and capping VP2 Outer capsid Cell attachment and penetration VP3 Core structural protein Topotyping VP4 RNA capping Replication and transcription VP5 Outer capsid Destabilization of endocytic vesicle Infective for culicoides VP6 Helicase VP7 Core protein Replication and transcription Nonstructural Proteins NS1 NS2 Inclusion body NS3 Morphogenesis and release Topotyping Influences vector transmission

VECTOR-BORNE DISEASE DETECTION AND CONTROL 193 that the most important vector was a small fly of the Culicoides species. Initially, BT disease was thought to be confined to Africa, and the principle means of transmission in Africa was by C. imicola. However, when BT was recognized outside of Africa in the 1940s and 1950s, it was assumed that the introduction of the virus into other countries of the world was by animals carrying the virus. This then led to extensive quarantine and trade restrictions involving the movement of animals. The fear was compounded by reports of persistently infected cattle and the global dissemination of BTV through semen of bulls (Luedke, 1985). These reports pushed the emphasis of insect vectors as disseminators of BTV into the background. Extensive research failed to verify the early reports of persistent infection in cattle, and the failure to confirm shedding of virus in bull semen then led to reevaluation of the insects as important vectors of BTV (Bowen et al., 1985; Sawyer et al., 1992). In addition to these observations, it was recognized that BTVs were present in many countries on all continents with the exception of Antarctica (MacLach- lan and Osburn, 2006). Of the 1,254 Culicoides spp. recognized around the world, only 30 have been incriminated in transmitting BTVs to some degree (Tabachnick, 2004). There are nine species of Culicoides that have been identified as the major transmitters of BTVs, as shown in Table 2-3. The distribution of the different Culicoides spp. in the different parts of the world is also associated with different serotypes of BTVs (Figure 2-16). This has led to the concept of episystems, which is used to describe the species and envi- ronmental aspects of an epidemiological event in a particular ecosystem, which affects the distribution and dynamics of a pathogen and disease (Tabachnik, 2004). This is an important concept in complex systems such as that of BTVs. Bluetongue viruses in these episystems are integral to the maintenance and trans- mission of the viruses to susceptible ruminant animals, leading to economically important disease. The distribution of BT-infected Culicoides spp. in episystems is not fully understood. However, it appears to include phylogenetic relationships, vector competence, vector capacity, environmental temperatures, and breeding sites. The TABLE 2-3  Location of Culicoides Vectors for Bluetongue Virus Vectors Countries / Continents C. imicola Africa, Mediterranean Europe C. sonorensis North America and northern Mexico C. insignis Central and South America C. brevitaris, wadii, fulvus Southeast Asia C. brevitaris, wadii Australia, Java C. obsoletus, pulicaris Central and southern Europe C. dewulfi, obsoletus complexa Northern Europe aMeiswinkel et al. (2007).

194 C. obsoletus complex, C. obsoletus, pulicaris dewulfi C. brevitaris, wadii, fulvus 1, 2, 4, 9, 16 1-4, 9, 12, 14-21, 23 C. sonorensis 2, 10, 11, 13, 17 C. imicola C. insignis 1-19, 22, 24 1, 3, 6, 8, C. brevitaris, wadii 12, 14, 17 1, 3, 9, 15, 16, 20, 21, 23 FIGURE 2-16  Distribution of Culicoides episystems and bluetongue virus topotypes. Created by John Gardiner, School of Veterinary Medi- cine, University of California, Davis. 2-16

VECTOR-BORNE DISEASE DETECTION AND CONTROL 195 vectors appear to adapt to certain ecosystems and the ruminant or other animal species that serve as blood meal sources for the insects. Some of the factors are undoubtedly genetically controlled, whereas environmental factors will impact the ability of the vectors to survive and actively produce infective virus. Until recently, the rule of thumb was that Culicoides spp. carrying infected viruses were confined to 40°N and 35°S latitudes (Sellers, 1992; Walton, 2004). Distribution The worldwide distribution of the 24 different serotypes of BTVs is governed by the virus and insect vector. Two different gene segments, VP3 and VP10, play roles in expressing the viral structural protein VP3 and the nonstructural proteins (NS) NS3 and NS3A, respectively, which make up the topotype classification controlling the distribution of the viral serotypes in the different episystems on the six continents (Figure 2-16) (Bonneau and MacLachlan, 2004; Gould et al., 1992). VP3 is a structural protein in the inner core of the virus, which is associ- ated with the topotypes. NS3 and NS3A play an important role in viral release from the cells and appear to have evolved with the competent Culicoides spp. vectors. The other factors which play an important role in viral distribution include climatic conditions such as environmental temperature, soil, water, and vertebrate host populations, which serve as sources of blood meals (Sellers, 1992; Mellors, 2004). Although BT disease is primarily limited to the temperate regions of the world, the introduction of susceptible animals (sheep) from temperate or northern climates readily come down with BT disease. The inference is that animals in tropical and subtropical areas of the world develop herd immunity to the BTVs in their areas. Most likely, the passive immunity in the maternal colostrum bestows immediate immunity to the newborn. Circulation of endemic BTVs continually reimmunizes these newborn animals through adulthood. Hence, the immune ani- mals are not incapacitated by active infections during their life. BT disease is seasonal and dependent upon the infected Culicoides spp. vectors, which are in the ecosystem (Figure 2-17). Viral replication in the Culi- coides spp. vectors requires warm temperatures. Although virogenesis can occur in Culicoides spp. at 15 to 25ºC, the ideal temperature range is from 25 to 32ºC (Mullens et al., 2004). The high virus titers require more blood meals, which in turn brings higher virus loads to the ruminants upon which they feed. The first animal cases usually show up in the late summer and early fall and persist until the first frost or freezing temperatures. Late summer and fall are the very time that the Culicoides spp. vectors are at their peak in numbers, and the virus titers in ruminants are also high. The combination of elevated virus titers in both the insect and the ruminant populations sets the stage for acute infections and disease in the recipient animal hosts. Once the killing frost reduces the population of infected vectors, the outbreaks and transmission of viruses stops.

196 VECTOR-BORNE DISEASES Latent virus Fro s t Winter e m ergence Fall Culicoides Spring °C -25 tor Summer 15 e Pe c ak nc Ve 25-3 vir 2 °C us I nf ge er ec ve m le ti cy Vector season a cle V ir FIGURE 2-17  Bluetongue virus and Culicoides vector cycle. Created by Rick Hayes, School of Veterinary Medicine, University of California, Davis. The appearance of BT disease in ruminants is usually the first indication that 2-17 the virus is circulating in the ecosystem. Unless an active surveillance system of virus isolation or serological testing is in place, disease manifestation is the only indication that the virus is in the region. Viral identification is complicated by the need for rapid methodology, such as PCR identification. Virus isolation by chick embryo or cell culture is slow and laborious. Serological results are delayed until after an immune response has taken place; most susceptible animals will have already shown clinical signs of disease. The means by which the virus is introduced into the ecosystem is wind, which transports BT-infected Culicoides (Sellers, 1992). This concept is thought to be the way that incursions of C. imicola carried BTVs into southern Europe from North Africa in the mid-1950s and in the 1980s. Fortunately, the vectors and the virus did not persist, as the climatic conditions did not permit their estab- lishment in succeeding years. BTVs also may appear in new areas by transport of viremic BT-infected animals, which then serve as a source of virus-infected

VECTOR-BORNE DISEASE DETECTION AND CONTROL 197 blood meal for susceptible local Culicoides. These vectors may then feed on other animals in the ecosystem and quickly serve as a new outbreak of BT infection and disease. This is the principal way that the viruses become established in temperate climates that have resident susceptible Culicoides populations. There is also some evidence that BTVs may survive over winter through transovarial transmission of the viruses in Culicoides (White et al., 2004). These midges may then be a source of virus during the next summer season. In the temperate and northern climates, BTVs vary each year depending on climatic conditions and the distribution of the infected Culicoides spp. vectors. Many of the newborn animals may be born during the winter months, and the passive immunity in the colostrum will have been depleted by the time the vec- tors carrying BTVs are circulating in the ecosystem. This new susceptible naïve population is available for BT infection and disease. The distribution of BT disease, caused by the BTVs, is directly associated with the insect vectors critical to viral transmission. It is important that the appro- priate medium for the incubation of eggs and larvae be used for virus isolation and identification. These breeding sites depend on the species of Culicoides. For instance, C. sonorensis breeds in streams with slow-moving water with a mix of cow dung and silt along the edge, whereas C. brevitarsis utilizes cow dung or patties as its primary breeding site (Mellors, 2004). Case Study: Progression of Bluetongue Disease in Europe BTV infection and disease appears to have been established in Europe over the last 5 years (Mellors, 2004; Goffredo and Meiswinkel, 2004). Although the cause for this is not entirely clear, there are some factors that are becoming more apparent, such as changing climatic conditions including the possibility of global warming, and the adaptation of virus to a new species of Culicoides. The sequence of events is depicted nicely by the movement of the C. imicola boundary in 1999 from North Africa, Spain, Portugal, and Turkey to the southern European countries of Greece and Italy in 2001. Along with the incursion of the vectors was the appearance of BT disease in sheep (Goffredo and Meiswinkel, 2004). By 2005, BT disease was reported in sheep at nearly 45°N latitude; and in 2006, BT disease in sheep and cattle had reached above 50°N latitude (Figure 2-18). Culicoides imicola remained at around 40°N latitude and was the primary vector of BTVs up to that location (Baylis et al., 2004). Two other Culicoides appeared to be the primary vectors above 40°N latitude. Culicoides obsoletus and C. pulicaris appeared to have fed on BTV-infected animals, and in turn, became the vectors of importance in transmitting BTV serotypes 1, 4, 9, and 16. Over 500,000 sheep were infected in Italy (WAHID-OIE, 2007). BTV serotype 2 was introduced into the western part of southern Europe from North Africa. In 2006, the appearance of BTV serotype 8 in over 2,000 cattle and sheep in northern Europe was unexpected (Goffredo and Meiswinkel, 2004). The vectors

198 VECTOR-BORNE DISEASES complex FIGURE 2-18  Progression of bluetongue viruses emergence in Europe. Created by Rick Hayes, School of Veterinary Medicine, University of California, Davis. 2-18 were different, possibly C. dewulfi and C. obsoletus complex, and appeared to be the primary vectors in Germany, France, the Netherlands, Belgium, and Luxem- bourg (Meiswinkel et al., 2004). These vectors are well-adapted and acclimated to northern Europe. The other environmental factors that appear to have played a role were global warming and more importantly, the unusual flow of warm weather from southern Europe. The temperature in northern Europe was 3°C warmer during the 2006 autumn than had been recorded before (WMO, 2007). Also, the vector season was extended into November because of unusually warm temperatures. This elevated temperature may have permitted virogenesis to easily occur in C. dewulfi and C. obsoletus complex. Another factor of interest was the appearance of BTV serotype 8 in north- ern European countries. Serotype 8 had not been reported north of Nigeria. It is unusual for serotypes to move over such a great distance. The explanation for the appearance of serotype 8 in northern Europe has not been resolved. It is of interest that BT disease has been reasonably well controlled in east- ern and southern Europe; whether this is due to the effectiveness of vaccines or whether BTVs 1, 2, 4, 9, and l6 have not been able to become established with C. imicola, C. obsoletus, and/or C. pulicaris in that environment, only time will tell.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 199 Vaccines The control of BTV infection in animals is based primarily on vaccination with modified live virus directed to the serotypes in the area. Since this type of vaccine virus has been associated with modified live vaccines, it is recommended that the vaccines be administered during the winter months when the vectors are inactive. The use of these vaccines protects the susceptible animals from disease as long as the appropriate serotypes are included in the vaccine. In Italy, modified live virus vaccine containing serotypes 2 and 9 was used to control the disease (Santi et al., 2004). Both sheep and cattle were vaccinated. In the Mediterranean islands, vaccination with modified live virus vaccines including serotypes 2 and 4 was also effective in preventing disease. There is a need for effective recombinant vaccines that can be used in the face of an outbreak. Inactivated viral vaccines have not been effective in preventing disease. Summary The biology of BTV infections is complex: 24 serotypes of virus carried by at least 9 different Culicoides spp. on 6 different continents presents a variety of scenarios that must be dealt with. BTV is a double-stranded RNA virus which easily reassorts the segments during dual infections, and the virus is also subject to mutations and genetic drift. The distribution of BTV serotypes is controlled by the Culicoides spp. (episystems) and the genetic characteristics of the virus (topotypes). Many other factors have an interplay including climatic conditions, water, and mammalian host species required for blood meals. In order for the virus to be successful in the vectors requires favorable vector capacity and vector competence. The impact of the virus on mammalian systems includes devastating hemorrhagic disease in sheep and wild ruminants, an IgE-mediated response in cattle, and a necrotizing and liquefying neuronal lesion in fetal lambs and calves leading to retinal dysplasia and hydranencephaly. The challenges facing BTV infections include disease control, which for the most part is vaccines. At this time, the most widely accepted and efficacious vaccines are modified live virus vaccines. These vaccines present problems since they may be picked up by vec- tors and transmitted to other ruminants where they can reassort with wild-type viruses in nature. There is a need to better understand the biology of the vectors; vector competence and capacity; the epidemiology of the infections; and the effects of climatic and global warming on these viruses, their vectors, and the disease in animal species. In this regard, there are aspects of the virus and the related vec- tors and environmental changes that can be used as models for other vector-borne diseases.

200 VECTOR-BORNE DISEASES ENVIRONMENTAL FACTORS INFLUENCE TRANSMISSION OF SIN NOMBRE HANTAVIRUS BETWEEN RODENTS (AND TO HUMANS?) Charles H. Calisher, Ph.D.21 Colorado State University James N. Mills, Ph.D.22 Centers for Disease Control and Prevention23 J. Jeffrey Root, Ph.D.24 U.S. Department of Agriculture Jeffrey B. Doty, M.S.21 Colorado State University Barry J. Beaty, Ph.D. 21 Colorado State University The factors that condition the transmission and maintenance of zoonotic agents in reservoir and tangential vertebrate hosts are poorly understood. This is particularly true for vector-borne zoonotic agents because of their complex trans- mission cycles. Risk assessment, prevention, and control of zoonotic diseases would be enhanced by understanding the determinants of emergence of these pathogens into human populations. Unfortunately, in many cases we do not even know what all the variables are and these variables may differ between agents, from time to time, and geographically, at the very least. Hantaviruses, which are transmitted between rodents (and shrews), and thereby to humans, may provide model systems for investigation of these diverse factors. Long-term (longitudinal) studies of Sin Nombre virus in deer mice (Peromyscus maniculatus) in Colorado have provided insight into the maintenance and amplification of this virus in nature. Lessons learned may be extrapolated to other zoonotic agents, including those transmitted by arthropod vectors. 21  Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology & Pathology, College of Veterinary Medicine and Biomedical Sciences, Fort Collins, CO 80523. Phone: (970) 491-2987; Fax: (970) 491-8707; E-mail: calisher@cybersafe.net. 22  Special Pathogens Branch, National Center for Infectious Diseases, Atlanta, GA 30333. E-mail: jum0@cdc.gov. 23  The findings and conclusions in this report are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention. 24  U.S. Department of Agriculture, Wildlife Services, National Wildlife Research Center, 4101 La Porte Avenue, Fort Collins, CO 80521. E-mail: jeff.root@aphis.usda.gov.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 201 Natural Cycles of Arthropod-Borne and Rodent-Borne Viruses The classical definition of an arthropod-borne virus (“arbovirus”) is that it is a virus maintained in nature through biological transmission between suscep- tible vertebrate hosts by hematophagous arthropods (mosquitoes, psychodids, ceratopogonids, and ticks). That is, these viruses replicate both in an arthropod host and a vertebrate host; vertebrate infection occurs when the infected arthro- pod takes a blood meal. Most human, livestock, and wild animal diseases occur when the arbovirus is transmitted to these hosts from the enzootic vertebrate host by the arthropod vector. Few arboviruses are transmitted directly from human to human by arthropod vectors; for example, dengue viruses, yellow fever virus, and Chikungunya virus are among these exceptions. The life cycles of these viruses are very complex, given that these viruses have the ability to replicate in both an arthropod and a vertebrate. The arthropod is either unaffected or minimally affected and usually is infected for life, whereas the vertebrate may be unaffected, mildly affected, or severely affected. Although the arthropod host has little effect on the virus, other than serving to amplify the virus, the vertebrate host responds to infection with viremia and by manufacturing antibody, cytokines, chemokines, and other products with antiviral activities. Viruses that are strictly rodent-borne (i.e., without arthropod components to their life cycles) are transmitted directly and biologically (not mechanically) between rodents or from rodents to vertebrates of other taxa, including humans. The natural cycles of both arboviruses and rodent-borne viruses are conditioned by features of the ecology, environment, host, and virus, factors which vary tem- porally and geographically, perhaps in a complex and ephemeral interrelationship that Yates et al. (2002) called a “trophic cascade” (vide infra). Among the exclusively rodent-borne viruses are hantaviruses (family Bunyaviridae, genus Hantavirus) and arenaviruses (family Arenaviridae, genus Arenavirus), both of which include serious human pathogens. These viruses appear to replicate in their rodent hosts with some, usually minor, effects but do not cause disease in them. Hantaviruses may cause persistent infections, with or without virus shedding, and antibody to them does not quench those infections. Thus, the presence of antibody to a hantavirus may serve as a surrogate indicator of current, recent, or remote infection with that virus. Introduction to the Hantaviruses Hantaviruses (family Bunyaviridae, genus Hantavirus) are first known from Chinese medical records of 1,000 years ago, describing what is now known as hemorrhagic fever with renal syndrome (HFRS). Reports of this or similar diseases were made during World War I, the Japanese-Chinese war, and among German soldiers during 1941-1942 in Russia and Finland, although the latter likely was a mild form of HFRS called nephropathia epidemica. Korean hemor-

202 VECTOR-BORNE DISEASES TABLE 2-4  Recognized Hantaviruses (to April 2007) Virusa Sourceb Distributionc Diseased Hantaan Apodemus agrarius Asia HFRS (mantchuricus) Seoul Rattus norvegicus Nearly worldwide HFRS Soochong Apodemus peninsulae Asia None Dobrava Apodemus flavicollis Europe HFRS Thai Bandicota indica Asia HFRS Saaremaa Apodemus agrarius Europe HFRS (agrarius) Amur Apodemus peninsulae Asia HFRS Puumala Myodes glareolus Europe NE Prospect Hill Microtus pennsylvanicus North America None Bloodland Lake Microtus ochrogaster North America None Isla Vista Microtus californicus North America None Tula Microtus arvalis/M. levis Europe HFRS Khabarovsk Microtus fortis Asia None Topografov Lemmus sibericus Asia None Sangassou Hylomyscus simus Africa None Sin Nombre Peromyscus maniculatus North America HPS (several subspecies) New York Peromyscus leucopus North America HPS Black Creek Canal Sigmodon hispidus North America HPS (spadicipygus) Bayou Oryzomys palustris North America HPS Catacamas Oryzomys couesi Central America None Muleshoe Sigmodon hispidus (texianus) North America HPS Monongahela Peromyscus maniculatus North America HPS (nubiterrae) Limestone Canyon Peromyscus boylii North America None Blue River Peromyscus leucopus North America None El Moro Canyon Reithrodontomys megalotis North America None Río Segundo Reithrodontomys mexicanus Central America None Caño Delgadito Sigmodon alstoni South America None rhagic fever and Epidemic hemorrhagic fever (China) are other names for HFRS. In 1978, Lee et al. reported that they had isolated the etiologic agent of Korean hemorrhagic fever (Hantaan virus) from striped field mice (Apodemus agrarius) captured in South Korea. The discovery of other hantaviruses in other rodents soon followed, and with increasing frequency, each virus was shown to have an association with a principle rodent host, suggesting a coevolutionary relation- ship. Table 2-4 provides a list of the hantaviruses recognized to date (J. N. Mills, unpublished summary). Hantaviruses may cause persistent infections in their rodent hosts, even in the presence of antibody to the infecting virus.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 203 TABLE 2-4  Continued Virusa Sourceb Distributionc Diseased Juquitiba Oligoryzomys nigripes South America HPS Araraquara Necromys lasiurus South America HPS Castelo dos Sonhos Unknown South America HPS Río Mamoré Oligoryzomys microtis South America None Anajatuba Oligoryzomys fornesi South America HPS? Rio Mearim Holochilus sciureus South America None Laguna Negra Calomys laucha South America HPS Andes Oligoryzomys longicaudatus South America HPS Lechiguanas Oligoryzomys flavescens South America HPS Bermejo Oligoryzomys chacoensis South America HPS Orán Oligoryzomys longicaudatus South America HPS Maciel Necromys benefactus South America None Hu39694 Unknown South America HPS Pergamino Akodon azarae South America None Central Plata Oligoryzomys flavescens South America HPS Choclo Oligoryzomys fulvescens Central America HPS (costaricensis) Calabazo Zygodontomys brevicauda Central America None (cherriei) Maporal Oligoryzomys fulvescens South America None Thottapalayam Suncus murinus Asia None Tanganya Crocidura theresae Africa None aOther viruses are known but have not been sufficiently studied to warrant a name; these may be newly recognized viruses or subtypes of recognized viruses. bPrincipal or only known hosts are listed; other rodents may serve as hosts. cThe distribution of these viruses generally parallels the distribution of the principal rodent host. Thus, whereas general locations are given, the virus and its host may be found only in limited areas. dHFRS: hemorrhagic fever with renal syndrome; HPS: hantavirus pulmonary syndrome; NE: ne- phropathia epidemica; None: no disease recognized. Discovery of Sin Nombre Virus and of Hantavirus Pulmonary Syndrome In April 1993, an outbreak of adult respiratory distress syndrome occurred among some residents of the Four Corners area of the southwestern United States (where Colorado, New Mexico, Arizona, and Utah are contiguous). It was soon thereafter shown that the etiologic agent of this disease, called hantavirus pul- monary syndrome (HPS), is a hantavirus hosted by deer mice (Peromyscus man- iculatus); the virus eventually was named Sin Nombre virus (Nichol et al., 1993; Butler and Peters, 1994; Elliott et al., 1994; Ksiazek et al., 1995; Schmaljohn et al., 1995). Deer mice, the most common mammal in North America, invade houses, breed prolifically, and are distributed throughout much of North America, with

204 VECTOR-BORNE DISEASES most of the eastern (Atlantic) coasts of the United States and Canada being an exception. Their populations fluctuate from season to season and from year to year, which is an important epidemiological characteristic. Longitudinal Studies of Sin Nombre Virus in Colorado Until recently, most studies of rodent-borne viruses have provided informa- tion on changes in abundance and prevalence of viral infection in host popula- tions. While epidemiologically informative, these data do not explain the series of events leading to human disease and comprise, in effect, point prevalence studies, yielding snapshots of the situation at specific time points. Yates et al. (2002) provided data suggesting and supporting the hypothesis that, in the southwestern United States, there is a “trophic cascade”—climatological, ecologic, and demo- graphic events—leading, somehow, from significant occurrences of precipitation to human disease. This trophic cascade is apparently very complex and involves weather, rodent population densities, and many other factors, some, perhaps many, unrecognized to date. In 1994, under contract with the U.S. Centers for Disease Control and Pre- vention, research groups in northern and southern Arizona, New Mexico, and Colorado began long-term studies of the prevalence of Sin Nombre virus, the densities of rodent populations, and the environmental factors that may influence both. We terminated the Colorado studies in October of 2006, when funding was no longer available. During those 12 years, however, we studied numerous ecologic aspects of Sin Nombre virus transmission and were able to accumulate a huge database regarding Sin Nombre virus and its deer mouse host. Scores of publications regarding various aspects of this work have been published; refer- ences to some of them can be found interspersed below. Studies were conducted at sites in southwestern (Fort Lewis, La Plata County) and west-central (Molina, Mesa County) Colorado and at the Pinon Canyon Maneuver Site (PCMS) in Las Animas County, southeastern Colorado. For serologic tests (IgG ELISA) we used the nucleocapsid antigen of Sin Nombre virus (Feldmann et al., 1993). For reasons not yet understood, and which may be related to deer mouse genetic differences, the prevalence of antibody to Sin Nom- bre virus at PCMS was much lower than that at the western Colorado sites. We already had observed a positive association of rodent abundance and prevalence of antibody to Sin Nombre virus at the Fort Lewis site (Calisher et al., 1999b). We have analyzed in detail many of the specifics of rodent populations, virus (antibody) prevalence, air and ground temperatures, precipitation and ground moisture, vegetational surveys, terrestrial insect biomass, deer mouse genetics, and deer mouse cytokine analyses at PCMS (Calisher et al., 2005a,b), but have not yet done the same for the western Colorado sites. Therefore, the data to be described and discussed here are those from the PCMS. The PCMS, which comprises more than 1,040 km2, was acquired by the U.S.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 205 Department of the Army in 1983 and is under the management of the Directorate of Environmental Compliance and Management, Fort Carson, Colorado. Prior to that acquisition, the area had been grazed by domesticated and wild ungulates and had supported small populations of humans since it was pioneered in the late 1870s. PCMS has been described as an area of dry continental climate and with elevation ranges from 1,300 to 1,700 m (Shaw et al., 1989; U.S. Department of the Army, 1980; Anderson et al., 1989). The topography consists of broad, moderately sloping uplands bordered by the Purgatoire River canyon on the east, limestone hills on the west, and a basalt hogback on the south. Vegetation is dominated by short-grass prairie but includes pinyon pine (Pinus edulis)-one- seeded juniper (Juniperus monosperma) woodland (Costello, 1954); the pinyon- juniper association is concentrated along the Purgatoire River canyon and its side canyons, in the limestone hills, and on parts of the basaltic hogback. The Fort Carson authorities have made concentrated and successful efforts to maintain and improve wildlife habitat, archaeologic sites, roads, and facilities. We trapped rodents at various locations but the results reported here were from two principal sites: one in Red Rocks Canyon and the other about 2 km from there, at the head of Red Rocks Canyon (Figures 2-19 and 2-20). The data reported herein will be used to exemplify the effects of climatologi- cal variations on rodent populations. Our intent was to accrue sufficient data from these longitudinal studies to determine environmental risk factors for transmis- sion of Sin Nombre virus to rodents and to humans. Major Findings Concerning Sin Nombre Virus Transmission and Maintenance at Colorado Sites Long-term studies at these varied sites inevitably led to many observations not made previously and revealed many aspects of rodent and virus characteristics and relationships not observed previously: • We observed an association between gender and antibody prevalence (more males than females infected). • We determined that infection status was associated positively with observed wounds, which likely were the result of intraspecific aggressive behav- iors (Calisher et al., 2007). • A similar correlation between prevalence of antibody to Sin Nombre virus and wounds has been observed with Limestone Canyon hantavirus and its prin- ciple host, the brush mouse (Peromyscus boylii), but not between western harvest mice (Reithrodontomys megalotis) and El Moro Canyon hantavirus or meadow voles (Microtus pennsylvanicus) and Prospect Hill hantavirus, suggesting dif- ferent transmission mechanisms for the latter two and the former two viruses (unpublished data). • We observed that antibody to (infection with) Sin Nombre virus is acquired

206 VECTOR-BORNE DISEASES FIGURE 2-19  Overview of Red Rocks Canyon, Pinon Canyon Maneuver Site, southeast- ern Colorado. Note shallow canyon, one-seeded juniper, and otherwise arid short-grass prairie. FIGURE 2-20  Close-up view of rocky area in Red Rocks Canyon, Pinon Canyon Maneu- ver Site, southeastern Colorado. Note the abundance of grasses, forbs, small one-seeded junipers, and rocky outcroppings.

VECTOR-BORNE DISEASE DETECTION AND CONTROL 207 by males, mostly during the late summer to late fall period (when aggressive behavior peaks) and that antibody to Sin Nombre virus is acquired by females more frequently during the period from winter to early spring (when breeding commences). • We found that antibody titers are about the same in male and female deer mice (unpublished data). • Simultaneous multiple captures of rodents of the same species suggest group foraging, which may relate to trafficking of Sin Nombre virus (Calisher et al., 2000). • Long-lived infected individual deer mice may serve as transseasonal res- ervoirs of Sin Nombre virus (Calisher et al., 2001a). • Deer mice have excellent navigational instincts (Calisher et al., 1999a). • There is a positive association of deer mouse movement, available vegeta- tion, and prevalence of infection with Sin Nombre virus (Root et al., 1999). • Mammalian habitat diversity is inversely correlated with prevalence of infection of deer mice with Sin Nombre virus (J. N. Mills et al., unpublished data). • And there is a great deal more we do not know about deer mice and other rodents, about deer mouse genetics, about Sin Nombre virus, and about other viruses (Calisher et al., 1999b, 2001b; Root et al., 2001, 2003, 2004, 2005). These and other papers focusing on Sin Nombre virus and on other hantavi- ruses, in other contexts, by us and by others, have made contributions to the body of scientific knowledge on this subject. Factors That Condition Sin Nombre Virus Transmission and Emergence in Humans The original and principal intents of our investigations were to acquire information regarding deer mouse populations and Sin Nombre virus prevalence and the factors that influence them, in regard to the premise that this information should be directly relevant to prediction and prevention of HPS in the southwest- ern United States. Determining Relative Risk (Incidence of Infection) At all sites, mark-recapture studies allowed us to track individual rodents over time and to determine incidence, seasonality, and prevalence of Sin Nom- bre virus infections in deer mice by age, sex, and location. For example, of 792 deer mice at PCMS, we recaptured 116 males and 162 females, some more than 11 months after they were first captured and two more than a year after they were first captured (Table 2-5). The majority, 514/792 (65 percent), were never recaptured; emigration, starvation, age-related deaths, and predation are among

208 VECTOR-BORNE DISEASES TABLE 2-5  Recaptured Deer Mice (Peromyscus maniculatus), by Sex and Maximum Number of Weeks Between First and Last Capture, Pinyon Canyon Maneuver Site, Southeastern Colorado, January 1995-November 2000 Weeks After First Capture Sex Total 0a 6 7-18 19-30 31-42 43-54 55-66 >66 Mean Female 317 201 29 53 20 10 3 1 0 17.4 Male 475 313 51 55 39 14 2 0 1 17.0 a0 = not recaptured. TABLE 2-6  Incidence of IgG Antibody Reactive with Sin Nombre Virus in Deer Mice (Peromyscus maniculatus) Recaptured and Sampled at Least Twice at Pinyon Canyon Maneuver Site, Southeastern Colorado, January 1995- November 2000 Number Cumulative Mouse Number of New Percentage with Months of Sex at Riska Infections Antibody Observationsb Incidencec Male 149 5 3.4 614 0.81 Female 108 1 0.93 430 0.23 Total 257 6 1044 0.57 aNumber of mice without antibody when first captured. bTotaltime intervals between successive captures when mice were antibody-negative, plus half the interval between the time when mice changed from antibody-negative to antibody-positive. cNew infections per 100 mice per month. the likely explanations for this. As well, we were able to determine the relative risk (incidence of infection) an individual deer mouse experienced at the site. As shown in Table 2-6, the estimated incidence for male deer mice at PCMS was 0.81 and for female deer mice 0.23 (new infections per 100 deer mice per month from January 1995 to November 2000). Generalized Risk Factor Associations Mills (2005) suggested that “prevalence and transmission rates of rodent- borne viruses within host populations vary in time and space and among host- virus systems” and categorized possible regulators of prevalence and transmission as follows: “(1) Environmental regulators such as weather and food supply affect transmission rates through their effect on reproductive success and population densities. (2) Anthropogenic factors, such as disturbance, may lead to ecosystem simplification and decreased diversity. These changes favor opportunistic species,

VECTOR-BORNE DISEASE DETECTION AND CONTROL 209 which may serve as reservoirs for zoonotic viruses. (3) Genetic factors influence susceptibility of mice to infection or capacity for chronic shedding and may be related to population cycling. (4) Behavioral factors, such as fighting, increase risk of transmission of some viruses and result in different patterns of infection between male and female mice. Communal nesting may result in over-winter transmission in colder climates. (5) Physiologic factors control host response to infection and length of time the host remains infectious.” Whereas these regulators may interact and compound one another, predict- ing risk based on them is far too complex for us to either determine their relative importance or to understand at this time. An excellent beginning to an overall view of these complexities has been made by Glass et al. (2000, 2002) and by Hjelle and Glass (2000). In the former paper the authors reiterated the hypothesis that the 1993 outbreak of HPS was initiated by environmental conditions and amplified rodent populations that were the result of unusual weather the previous 2 years. Glass et al. (2000) tested that premise using rainfall patterns, elevation data, and Landsat Thematic Mapper satellite imagery. Although precipitation at case-patient sites was not higher than it had been in previous years they found an association between environmental conditions (as indicated by elevation and satellite-derived spectral analysis) and HPS risk the following year. Repetition in later years supported those findings and allowed a degree of predictability. Hjelle and Glass (2000) reported results of analyses indicating that increased precipitation resulting from the 1991-1992 El Niño/Southern Oscillation fostered increased rodent population densities and suggested that this indicated a possible increase in transmission of Sin Nombre virus among rodents and from rodents to humans in 1993-1994. Furthermore, they pointed out the strong El Niño/Southern Oscillation of 1997-1998, and that in 1998-1999 the Four Corners states suffered a 5-fold increase in HPS cases over the number of cases expected. These stud- ies are important if we are to understand the basic association between climate, rodent populations, Sin Nombre virus, and HPS, but they cannot provide us with specifics necessary for determining cause and effect. In the 6-year period from 1995 to 2000 we trapped deer mice and other rodents (total number of rodents 2,798; total captures of these rodents 6,155) at the PCMS in southeastern Colorado, tested them for antibody to Sin Nombre virus, and took numerous climatologic measurements. Population dynamics dif- fered for rodents of different species but had some common characteristics. Deer mice had highest relative population abundances in winters, lowest in summers. Nonetheless, there were clear interannual variations, sometimes associated with meteorologic conditions that similarly affected rodents of most of the 18 species captured. The results indicated that “typical” seasonal population dynamics may occur only under “average” conditions. Divergence from average conditions may occur frequently and result in changes in rodent population dynamics. While temperature is not extremely variable focally in the American south- west, precipitation can be. We used mean precipitation and temperature data

210 VECTOR-BORNE DISEASES from three sites near our trapping sites: one where we were trapping (Red Rocks Canyon), one about 24 km from the trapping site, and one 48 km from the trap- ping site; available data were comparable (Figure 2-21). As shown in Figure 2-22, there was an interaction effect between precipitation and temperature. Low rodent population abundances were associated with high precipitation during cold periods and low precipitation during warm periods (Calisher et al., 2005a). Cold, wet fall/winter conditions and hot, dry spring/summer conditions were associ- ated with negative effects on populations of most species, including deer mice. For example, the cold and wet fall of 1997 coincided with an El Niño/Southern Oscillation event with high winter precipitation and abrupt declines in relative abundance of rodents. Of importance to rodent populations is not only the amount of precipitation that occurs, but when it occurs. An abundance of precipitation in September or October, for example, is not the same as a uniformly distributed precipitation occurring in spring. Precipitation affects vegetation and insects, both of which are dietary resources for deer mice, so that the timing of precipitation during the growing season is important. When it occurs outside the growing season it may not contribute to resource availability, but it may negatively impact deer mouse survivorship. Our data also indicate that the timing of rainfall is an important determinant of breeding success and recruitment of juveniles into the population. For example, although juvenile recruitment likely peaked in the autumn (Figure 2-23), the only period during our study when juvenile recruitment appeared to Red Rocks Canyon Rocky Ford Bear Spring Hills 300 250 Precipitation (nm) 200 150 100 50 0 W Sp Su A W Sp Su A W Sp Su A W Sp Su A W Sp Su A W Sp Su A 1995 1996 1997 1998 1999 2000 Season and Year FIGURE 2-21  Quarterly precipitation as recorded at three weather stations in or near the Pinon Canyon Maneuver Site, southeastern Colorado, 1995-2000. SOURCE: Reprinted with permission from Calisher et al. (2005a). 2-21

VECTOR-BORNE DISEASE DETECTION AND CONTROL 211 5 Mean Maximum Temperature (°C) 14 4 A. * 12 10 3 * 8 2 * 6 4 1 2 0 0 -1 -2 -3 * Peromyscus maniculatus Trap Success (%) -4 * Mean maximum temperature deviation P. maniculatus trap success 3.5 14 B. Deviation from 50-yr Mean 3 * Mean Minimum Temperature (°C) 12 2.5 * 10 2 8 1.5 6 1 4 0.5 2 0 0 - 0.5 -1 -1.5 Mean maximum temperature deviation P. maniculatus trap success -2 16 150 C. * 14 125 12 * 10 100 Preciptation (mm) 75 8 * 6 50 * 4 25 * 2 0 0 2 -25 -4 -50 -6 Mean maximum temperature deviation P. maniculatus trap success -75 -8 W Sp Su A W Sp Su A W Sp Su A W Sp Su A W Sp Su A W Sp Su A 1995 1996 1997 1998 1999 2000 Season and Year FIGURE 2-22  Deviations from the 50-year mean (1951-2000) for quarterly (A) mean maximum and (B) mean minimum temperatures and quarterly precipitation at Rocky Ford, Colorado, weather station. Asterisks indicate deviations that are at least two stan- dard deviations from the 50-year mean. The line shows quarterly trap success (number of 2-22 individuals captured per 100 trap nights) for deer mice. SOURCE: Reprinted with permission from Calisher et al. (2005a). be zero was the wet, cold El Niño autumn of 1997 (Figures 2-22 and 2-23). Con- versely, the highest juvenile recruitment was observed in the unusually wet sum- mer of 1999. Because rainfall in the American southwest can be remarkably focal, and because we did not monitor for diseases or predation, we cannot determine with certainty exactly what caused these population declines and surges but the

300 16 212 Precipitation Trap success 14 250 A. 12 200 10 150 8 6 100 Precipitation (mm) 4 50 2 Individuals per 100 Trap Nights 0 0 100 B. Breeding Juvenile 80 60 Percent 40 20 0 W Sp Su A W Sp Su A W Sp Su A W Sp Su A W Sp Su A W Sp Su A 1995 1996 1997 1998 1999 2000 Season and Year FIGURE 2-23  (A) Quarterly trap success for deer mice and total quarterly precipitation; (B) percent of adults in reproductive condition and percent of captures consisting of juveniles, at two mark-recapture sites in southeastern Colorado, 1995-2000. 2-23 Landscape view SOURCE: Reprinted with permission from Calisher et al. (2005a).

VECTOR-BORNE DISEASE DETECTION AND CONTROL 213 weather patterns we have monitored suggest that they have an essential effect on relative abundance of rodent populations. Consequently, we caution that predict- ing rodent populations based on data from one site cannot be made with accuracy based on data from another, even nearby, site. Nonetheless, at the PCMS we found that precipitation during cold periods or lack of precipitation during warm periods each was associated with declines of populations of deer mice. What Data Are Necessary and Sufficient to Establish Predictive Models? Central to determining predictive models for Sin Nombre virus and HPS are observations suggesting delayed density-dependency. Niklasson et al. (1995), Mills et al. (1999), Yates et al. (2002), and Madhav et al. (2007) have hypoth- esized that prevalence of antibody to hantaviruses in host rodents was delayed density-dependent. That is, increasing and peaking host populations consist pre- dominantly of uninfected juveniles that are likely not to have antibody (i.e., not infected). In the case of Sin Nombre virus, antibody prevalence will rise most quickly in declining populations in which reproduction has ended and the juvenile dilution effect (the consequence of there being more seronegative juveniles in the population) also has ended. Because the rate of intraspecific encounters and, therefore, virus transmission events are likely to be positively correlated with population density, the prevalence of antibody in those declining or low-density populations may be proportional to the peak population density from the previ- ous reproductive season (i.e., prior to the decline). We have demonstrated clearly that deer mouse population abundances vary among sites and are positively and statistically correlated with prevalence of infection, an association that others, who have done shorter-term studies, failed to demonstrate (Calisher et al., 2007). Accordingly, high rodent population densities may not be directly predictive of an immediate rise in antibody prevalence, indicative of an increasing incidence of infection, but rather may be a longer-term predictor of such an increase. Com- mon sense suggests that reducing contact with infected rodents is a critical first step in the prevention of human disease caused by Sin Nombre virus and other rodent-borne viruses. For example, having 10 deer mice in a residence, with 1 of them infected (10 percent), is not as great a risk as having 100 deer mice in that residence, with 10 of them infected (10 percent). Temporizing efforts, such as rodent exclusion, are important but beg the question of prevention in the long term (Glass et al., 1997). Until we have determined the fundamental relationships between meteorological events and plant productivity and quality, the dynamics of persistence and shedding of virus in Sin Nombre virus-infected deer mice, the effects of diet on urinary, fecal, and salivary pH, and the effects caused by changes in diet due to the aforementioned meteorological events, we will not be able to fully appreciate the complex sequence of events in the trophic cascade leading from precipitation to HPS. Figures 2-24 and 2-25 summarize the asso- ciations between meteorological events of 1991-1993 and 1997-1998, rodent

214 VECTOR-BORNE DISEASES population abundances, and HPS in New Mexico (Parmenter et al., 1993) and between the 1997-1998 El Niño and rodent population densities in New Mexico and Colorado (Yates et al., 2002; Mills and Calisher, unpublished data). Complicating our understanding of this moving target is climate change. Should mean temperatures and precipitation patterns continue to deviate upward from the current norms, increases in rodent population densities, the geographic distribution of rodents, and the prevalence of the viruses they harbor are likely to increase significantly, to the detriment of humans (Anyamba et al., 2006b). What is needed is a great deal more effort and funding invested in basic studies of the biology of both virus and vertebrate host—on their interactions, on the relative interactions of environmental variables, and on the variables that account for meaningful deviations from the norm. Conclusions The data accumulated during these and associated longitudinal studies of hantaviruses, specifically Sin Nombre virus, suggest that longitudinal studies may be the only current means available to identify predictors of risk for rodent acquisition of this virus and for subsequent transmission to humans. We know that rodent populations fluctuate, sometimes considerably, but we do not know all the variables that impact those fluctuations. We know that virus (antibody) prevalence fluctuates, sometimes from 0 to 40 or 50 percent, but we do not know all the variables that impact those fluctuations. Nonetheless, these data suggest that the “trophic cascade” hypothesis is an innovative and acceptable one to test further. A simple and obviously correct hypothesis is not yet within our grasp but we seem to be intriguingly close. It has long been accepted that certain ecologic and/or environmental con- ditions are associated with emergent transmission of agents causing zoonotic diseases. Recent development of predictive models for plague in the American southwest (Enscore et al., 2002; Eisen et al., 2007) are an example. In addition, Linthicum et al. (1999) offered a predictive model for Rift Valley fever in Kenya, and Anyamba et al. (2006b) predicted Rift Valley fever and malaria in East Africa, dengue fever and respiratory illnesses in specific areas of Asia, malaria in South America, cholera in Bangladesh and coastal India, southwestern United States for increased risk for HPS and plague, southern California for increased West Nile virus transmission, and northeast Brazil for increased dengue fever and respira- tory illness. The recent extensive epizoodemic of Rift Valley fever, recognized in Kenya in December 2006, spread to Sudan, Tanzania, Somalia, and Burundi by May 2007 (ProMED-Mail, 2007). This disease outbreak alone indicates the utility of such predictive models. It is possible that the trophic cascade hypothesis is a conceptual umbrella, and that using key elements of the predictive modeling systems mentioned earlier, and of other systems, might be useful in establishing models of other emerging

The 1991-1993 El Niño Peromyscus spp. rodent abundance begins to increase in Peromyscus spp. rodent central New Mexico abundance increases abruptly at some central New Mexico sites El Ni ño begins Second Rodent densities consecutive warm, decline to normal Warm, wet winter wet winter levels by fall 9/91 11/91 1/92 3/92 5/92 7/92 9/92 11/92 1/93 3/93 5/93 7/93 9/93 11/93 Initial HPS cases detected near the Arizona-New Mexico-Colorado border Main HPS outbreak ends by August, with 29 cases in Four Corners states FIGURE 2-24  The 1991-1993 El Niño and some of its consequences in the southwestern United States. 2-24 215 Landscape view

216 The 1997-1998 El Niño Deer mouse abundance increases 20-fold at some northwestern New SNV antibody Mexico sites prevalence begins to increase in deer 1 0-fold increase in mice in abundance of SNV - northwestern New antibody positive deer Mexico mice at some sites in New Mexico El Ni ño begins The 1997-1998 SNV antibody prevalence El Niño ends increases rapidly in deer mice 4/97 6/97 8/97 10/97 12/97 2/98 4/98 6/98 8/98 10/98 12/98 2/99 4/99 6/99 8/99 33 HPS cases reported (5.5-fold increase over the number of cases expected) FIGURE 2-25  The 1997-1998 El Niño and some of its consequences in the southwestern United States. 2-25 Landscape view the original bracket, which was made of straight lines,

VECTOR-BORNE DISEASE DETECTION AND CONTROL 217 and recurrent zoonoses, vector-borne and non-vector-borne, such as for arena- viruses. The important point is that, although particular zoonotic diseases have particular etiologic agents, the controlling conditions for each may have enough similarities to provide us with predictors of risk for acquisition and, therefore, with bases for prevention and control measures. Acknowledgments The authors thank the numerous people, not mentioned specifically, who assisted us in the field, helped with logistics, advised, consented, and otherwise made this work possible. In particular we thank K. M. Canestorp, U.S. Fish and Wildlife Service, Colorado Fish and Wildlife Assistance Office, Lakewood, Colorado, who provided background information about the PCMS and antici- pated rodent habitats; Dan Sharp, U.S. Fish and Wildlife Service, Colorado Fish and Wildlife Assistance Office, Lakewood, Colorado, for his persistence in sur- veying the flora; and employees of the Directorate of Environmental Compliance and Management, Ft. Carson, for allowing us to use the Pinon Canyon Maneuver Site to conduct these studies. We are extremely grateful to N. Doeskin, Depart- ment of Atmospheric Sciences, Colorado State University, Fort Collins, and J. Kuzmiak, U.S. Geological Survey, Pueblo, Colorado, who generously provided climatologic data. T. Ksiazek and others at the U.S. Centers for Disease Control and Prevention, Atlanta, Georgia, provided enthusiastic support and reagents with which to do the serologic tests. Funding for this work was provided by the U.S. Centers for Disease Control and Prevention, Atlanta, Georgia, under cooperative agreement No. U50/ccu809862-03, for which we are grateful. Ms. Brooke Roeper, Colorado State University, provided the templates from which we devised Figures 2-24 and 2-25. REFERENCES Abd el-Rahim, I. H., U. Abd el-Hakim, and M. Hussein. 1999. An epizootic of Rift ���������������� Valley fever in Egypt in 1997. Revue Scientifique et Technique 18(3):741-748. Ai-leen, G. T., and R. J. Song. 2000. The use of GIS in ovitrap monitoring for dengue control in Singapore. Dengue Bulletin 24:110-116. Akita, G. Y., M. Ianconescu, N. J. MacLachlan, B. I. Osburn, and R. T. Green. 1994. Bluetongue dis- ease in dogs associated with contaminated vaccine. The Veterinary Record 134(11):283-284. Al Hazmi, M., E. A. Ayoola, M. Abdurahman, S. Banzal, J. Ashraf, A. El Bushra, A. Hazmi, M. Abdullah, H. Abbo, A. Elamin, E. Al Sammani, M. Gadour, C. Menon, M. Hamza, I. Rahim, M. Hafez, M. Jambavalikar, H. Arishi, and A. Aqeel. 2003. Epidemic Rift Valley fever in Saudi Arabia: a clinical study of severe illness in humans. Clinical Infectious Diseases 36(3):245-252. Alexander, N., A. E. Lenhart, C. M. E. Romero-Vivas, P. Barbazan, A. C. Morrison, R. Barrera, ��������� J. I. Arredondo-Jime Nez, and D. A. Focks. 2006. Sample sizes for identifying the key types ������������������������������������������������� of container occupied by dengue-vector pupae: the use of entropy in analyses of compositional data. Annals of Tropical Medicine and Parasitology 100(Suppl 1):5-16.

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Vector-borne infectious diseases, such as malaria, dengue fever, yellow fever, and plague, cause a significant fraction of the global infectious disease burden; indeed, nearly half of the world's population is infected with at least one type of vector-borne pathogen (CIESIN, 2007; WHO, 2004a). Vector-borne plant and animal diseases, including several newly recognized pathogens, reduce agricultural productivity and disrupt ecosystems throughout the world. These diseases profoundly restrict socioeconomic status and development in countries with the highest rates of infection, many of which are located in the tropics and subtropics.

Although this workshop summary provides an account of the individual presentations, it also reflects an important aspect of the Forum philosophy. The workshop functions as a dialogue among representatives from different sectors and allows them to present their beliefs about which areas may merit further attention. These proceedings summarize only the statements of participants in the workshop and are not intended to be an exhaustive exploration of the subject matter or a representation of consensus evaluation. Vector-Borne Diseases : Understanding the Environmental, Human Health, and Ecological Connections, Workshop Summary (Forum on Microbial Threats) summarizes this workshop.
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