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Lyme Disease and Its Epidemiology Diane E. Griffin, MD, PhD Johns Hopkins University
Diane E. Griffin, MD, PhD Professor and Chair, Department of Molecular Microbiology and Immunology Research interests fall in the area of pathogenesis of viral diseases, with a particular focus on measles and alphavirus encephalitis Editor for Field s Virology President-elect, American Society for Microbiology 3
Section A Background/History
First Recognition of Lyme Arthritis in Connecticut, 1976 5
Characteristics of the First 52 Cases Identified 6
Prevalence of Lyme Arthritis on Four Roads in Connecticut Old Lyme Road A Road B Site East Haddam Road C Road D Affected/total 4/51 4/65 4/26 5/33 Prevalence per 100 children 7.8 7.7 15.4 12.1 Total 17/175 9.7 7
Lyme Arthritis: Associated Symptoms (12 Patients) Malaise Chills and fever Headache Stiff neck Backache Myalgias Nausea and vomiting Sore throat 75% 75% 50% 50% 33% 25% 25% 8% Source: Steere, A. C., et al. (1977, June). Ann Intern Med, 86(6), 685 698. 8
Typical Lyme Arthritis Photo by Dr. Alan Steere, Massachusetts General Hospital, Boston. 9
Typical Skin Lesion: Erythema Migrans (EM) Source: CDC 10
Secondary Lyme Disease: Cardiac Manifestations Atrioventricular block Primary Wenckebach Complete 90% 40% 30% T wave inversion 50% 11
Bell s Palsy Due to Lyme Disease Source: CDC 12
Secondary Lyme Disease: Neurologic Manifestations Meningitis Encephalitis Cranial neuropathy Radiculitis 80% 40% 50% 25% 13
Time Course of Various Lyme Disease Clinical Syndromes 14
Case-Control Study Lyme disease patients and neighbors, 1977 Patients Neighbors P Male 53 44 Rural environment 47 45 Woods activities 77 61 Pets 86 81 Pet cats 63 39 <0.01 Ticks on pets 70 27 <0.0001 Farm animals 26 11 <0.05 Tick bites 44 26 <0.05 Mosquito bites 72 70 Source: Steere, A. C., Broderick, T. F., and Malawista, S. E. (1978, October). Am J Epidemiol, 108(4), 312 321. 15
Seasonal Incidence of Lyme Disease in the U.S. 16
Disease Transmission 17
Lyme Disease: Attack Rates on Each Side of River, 1977 Rate per 1,000 residents East side of Connecticut River 2.8 West side of Connecticut River 0.1 Source: Steere et al. (1978). Am J Epidemiol, 108, 312. 18
Ticks Found on Each Side of the Connecticut River West East l. scapularis D. variabilis l. scapularis D. variabilis Humans 8 37 33 20 Dogs 2 78 27 95 Cats 12 17 3 5 White-footed mice 29 26 498 143 Voles 0 5 3 2 Chipmunks 3 0 2 0 Raccoons 0 10 3 69 Skunks 0 0 1 6 Dragging 0 0 8 43 Total 54 173 578 373 19
Section B Identification of the Etiologic Agent of Lyme Disease and Its Distribution
Willy Burgdorfer, PhD Medical entomologist Rocky Mountain Laboratories Bitterroot Mountains, Montana 21
Where Burgdorfer Studied Ticks in the Summer of 1981 22
Spirochetes Seen in the Midgut of Deer Ticks Spirochetes seen in the midgut of deer ticks collected on Shelter Island From Burgdorfer W, et al. Lyme disease-a tick-borne spirochetosis? Science, 1982;216:1317. Reprinted with permission from AAAS. All rights reserved. 23
Isolation of B. burgdorferi from Patients with Lyme Disease Titers of antibody against spirochetes isolated from three patients IgM titer IgG titer Source Days sick Culture 2 weeks Culture 2 weeks Blood 2 16 64 16 512 Skin 25 64 32 32 128 Spinal fluid 70 32 32 512 1024 Source: Steere et al. (1983). N Engl J Med, 308, 733. 24
Distribution of Erythema Migrans Cases in Europe 25
Distribution of Ixodes ricinus in Europe ricinus 26
Manifestations Differ in Europe and the U.S. Distribution of manifestations of Lyme disease in 1,471 patients in Southern Sweden* Manifestation Erythema migrans Erythema migrans Arthritis 1,075 40 10 1 9 1 40 176 8 2 3 1 Carditis Arthritis 10 8 65 8 1 0 Neuroborreliosis Acrodermatitis Lymphocytoma Neuroborreliosis Acrodermatitis Lymphocytoma 1 2 8 34 0 0 9 3 1 0 26 0 Carditis 1 1 0 0 0 5 3 manifestations 3 5 6 2 2 0 Total no. (%) 1,139 (77) 235 (16) 98 (7) 47 (3) 41 (3) 7 (<1) *The numbers of cases with only one manifestation of disease are indicated in boldface type. Six patients had three or more manifestations, and their data are presented on a separate line. Source: Berglund et al. (1995). N Engl J Med, 333, 1319. 27
Borrelia burgdorferi Species Borrelia burgdorferi species B. burgdorferi sensu lato B. burgdorferi sensu stricto B. afzelii B. garinii 28
Lyme Neuroborreliosis Summarized differences in neurologic manifestations of Lyme disease Source: Pachner et al. (2004, September). Ann Neurol, 56(3), 361 370. 29
Lyme Disease Incidence in the U.S. 30
Lyme Disease: Reported Cases by County, U.S., 2001 Source: CDC. 31
Annual Incidence of Reported Cases, by Age and Sex Source: CDC. 32
Section C Natural Cycle and Reservoir of the Organism
Ixodes scapularis Ticks Female Nymph Male Source: CDC. 34
Abundance of Different Stages by Time of Year Abundance of different stages of Ixodes ticks at different times of year 35
Hosts for Ixodes scapularis White-tailed deer White-footed mouse Photo by martytdx. Some rights reserved. Photo by Chili Bob. Some rights reserved. 36
Tick Cycle in Relation to B. burgdorferi Transmission 37
Changes in North American Wildlife Populations Species 1935* 1985 Bison 12,800 65,000 California Condor 60 6, North American Elk 225,000 500,000 Pronghorn Antelope 40,000 750,000 Trumpeter Swan 73 10,000 White-tailed Deer 5 million 14.7 million Whooping Crane 29 138 Wild Turkey 31,250 2.5 million *Estimates by US Fish and Wildlife Service 38
Percent Ixodes Ticks Positive for B. burgdorferi, by Location Shelter Island, New York Up to 100% Southeast Connecticut 35% Northern California 1 2% Source: Burgdorfer et al. (1985). Am J Trop Med Hyg, 34(5), 925 930. 39
Distribution of Ixodes scapularis and Ixodes pacificus 40
Maintenance of the Natural Cycle: East and West Maintenance of the natural cycle is different in the eastern & western U.S. 41
National Lyme Disease Risk Map Source: CDC 42
Effect of Duration of Attachment Transmission of B. burgdorferi by nymphal ticks effect of duration of attachment Hours of attachment No. of infected ticks fed Mice infected/total 36 14.4 ± 3.5 1/14 42 16.4 ± 4.7 3/12 48 13.0 ± 3.7 6/8 Conclusion: Ticks must remain attached for about 48 hours to transmit infection 43
Efficacy of OspA Lyme Disease Vaccine in Two Trials Efficacy of OspA Lyme Disease Vaccine in 2 Trials Study and Year Placebo group # subjects (cases) Vaccine group # subjects (cases) Measured Vaccine Efficacy (95% CI) End of year 1 Sigal et al 5149 (37) 5156 (12) 68 (36-85) Steere et al Definite/probable 5467 (43/13) 5469 (22/2) 49 (15-69)/ 83 (32-97) End of year 2 Sigal et al 2 doses 1411 (5) 1379 (2) 0 (0-60) 3 doses 3770 (26) 3745 (22) 92 (69-97) Steere et al 3 doses (def/prob) 5467 (66/15) 5469 (16/0) 76 (58-86)/ 100 (26-100) 44
Borrelia Osp Expression of outer surface proteins (Osp) on Borrelia in the midgut of unfed ticks Osp A Osp C Figure Source: Schwan TG, et al. Induction of an outer surface protein on Borrelia burgdorferi during tick feeding. PNAS 1995;92:2909-13. Copyright (1995) National Academy of Sciences, U.S.A 45
How the Osp A Lyme Disease Vaccine Protects 46
Lyme Disease Prevention Distribution of pyrethrin-impregnated cotton balls in habitat of white-footed mice Kills ticks overwintering with mice 47
Lyme Disease Prevention Treatment Ticks infected Persons with LD Placebo 23/159 (14%) 2/173 (1.2%) Amoxicillin 30/185 (16%) 0/192 (0%) Source: Shapiro et al. (1992). N Engl J Med, 327, 1769. 48
Conclusions Lyme disease is caused by a spirochetal bacteria, Borrelia burgdorferi The reservoir host in the eastern U.S. is the white-footed mouse Borrelia is maintained in a geographically restricted natural cycle between ticks and mammals Human disease is determined by Exposure to infected ticks The species of Borrelia causing infection 49