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Lyme Disease and Its Epidemiology

Diane E. Griffin, MD, PhDJohns Hopkins University

3

Diane E. Griffin, MD, PhD

Professor and Chair, Department of Molecular Microbiology and ImmunologyResearch interests fall in the area of pathogenesis of viral diseases, with a particular focus on measles and alphavirus encephalitisEditor for Field’s VirologyPresident-elect, American Society for Microbiology

Section A

Background/History

5

First Recognition of Lyme Arthritis in Connecticut, 1976

6

Characteristics of the First 52 Cases Identified

7

Site Affected/total Prevalence per 100 children

Old LymeRoad ARoad B

4/51

4/65

7.8

7.7

East HaddamRoad CRoad D

4/265/33

15.412.1

Total 17/175 9.7

Prevalence of Lyme Arthritis on Four Roads in Connecticut

8

Lyme Arthritis: Associated Symptoms (12 Patients)

MalaiseChills and feverHeadacheStiff neckBackacheMyalgiasNausea and vomitingSore throat

75%75%50%50%33%25%25%8%

Source: Steere, A. C., et al. (1977, June). Ann Intern Med, 86(6), 685–698.

9

Typical Lyme Arthritis

Photo by Dr. Alan Steere, Massachusetts General Hospital, Boston.

10

Typical Skin Lesion: Erythema Migrans (EM)

Source: CDC

11

Secondary Lyme Disease: Cardiac Manifestations

Atrioventricular blockPrimaryWenckebachComplete

90%40%30%

T wave inversion 50%

12

Bell’s Palsy Due to Lyme Disease

Source: CDC

13

Secondary Lyme Disease: Neurologic Manifestations

MeningitisEncephalitisCranial neuropathyRadiculitis

80%40%50%25%

14

Time Course of Various Lyme Disease Clinical Syndromes

15

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.

Case-Control Study

Lyme disease patients and neighbors, 1977

16

Seasonal Incidence of Lyme Disease in the U.S.

17

Disease Transmission

18Source: Steere

et al. (1978). Am J Epidemiol, 108, 312.

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

19

Ticks Found on Each Side of the Connecticut River

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

West East

Section B

Identification of the Etiologic Agent of Lyme Disease and Its Distribution

21

Willy Burgdorfer, PhD

Medical entomologistRocky Mountain LaboratoriesBitterroot Mountains, Montana

22

Where Burgdorfer Studied Ticks in the Summer of 1981

23

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.

24

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

IgM

titer IgG

titer

Isolation of B. burgdorferi from Patients with Lyme Disease

Titers of antibody against spirochetes isolated from three patients

Source: Steere

et al. (1983). N Engl J Med, 308, 733.

25

Distribution of Erythema Migrans Cases in Europe

26

Distribution of Ixodes ricinus in Europericinus

27Source: Berglund et al. (1995). N Engl J Med, 333, 1319.

Manifestation Erythema

migrans

Neurobor-

reliosis Arthritis Acroderma-

titis

Lympho-

cytoma Carditis

Erythema

migrans 1,075 40 10 1 9 1

Neurobor-

reliosis 40 176 8 2 3 1

Arthritis 10 8 65 8 1 0

Acroderma-

titis 1 2 8 34 0 0

Lympho-

cytoma 9 3 1 0 26 0

Carditis 1 1 0 0 0 5

≥

3 mani-

festations 3 5 6 2 2 0

Total no. (%) 1,139 (77) 235 (16) 98 (7) 47 (3) 41 (3) 7 (<1)

Manifestations Differ in Europe and the U.S.Distribution of manifestations of Lyme disease in 1,471 patients

in Southern Sweden*

*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.

28

Borrelia burgdorferi species

B. burgdorferi sensu latoB. burgdorferi sensu strictoB. afzeliiB. garinii

Borrelia burgdorferi Species

29Source: Pachner

et al. (2004, September). Ann Neurol, 56(3), 361–370.

Lyme Neuroborreliosis

Summarized differences in neurologic manifestations of Lyme disease

30

Lyme Disease Incidence in the U.S.

31Source: CDC.

Lyme Disease: Reported Cases by County, U.S., 2001

32

Annual Incidence of Reported Cases, by Age and Sex

Source: CDC.

Section C

Natural Cycle and Reservoir of the Organism

34

Nymph

Male

Female

Ixodes scapularis Ticks

Source: CDC.

35

Abundance of differentstages of Ixodes ticksat different times of year

Abundance of Different Stages by Time of Year

36

White-tailed deer White-footed mouse

Hosts for Ixodes scapularis

Photo by Chili Bob. Some rights reserved.Photo by martytdx. Some rights reserved.

37

Tick Cycle in Relation to B. burgdorferi Transmission

38

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

39Source: Burgdorfer

et al. (1985). Am J Trop Med Hyg, 34(5), 925–930.

Percent Ixodes Ticks Positive for B. burgdorferi, by Location

Shelter Island, New York Up to 100%

Southeast Connecticut 35%

Northern California 1–2%

40

Distribution of Ixodes scapularis and Ixodes pacificus

41

Maintenance of the Natural Cycle: East and WestMaintenance of the natural cycle is different in the eastern & western U.S.

42

National Lyme Disease Risk Map

Source: CDC

43

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

44

Efficacy of OspA Lyme Disease Vaccine in 2 Trials

End of year 1

Sigal et al

Placebo group # subjects (cases)

Vaccine group # subjects (cases)

Measured Vaccine Efficacy (95% CI)

Study and Year

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 al2 doses 1411 (5) 1379 (2) 0 (0-60)3 doses 3770 (26) 3745 (22) 92 (69-97)

Steere et al3 doses (def/prob) 5467 (66/15) 5469 (16/0) 76 (58-86)/

100 (26-100)

Efficacy of OspA Lyme Disease Vaccine in Two Trials

45

Osp

A Osp

C

Borrelia Osp

Expression of outer surface proteins (Osp) on Borrelia in the midgut of unfed ticks

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

46

How the Osp A Lyme Disease Vaccine Protects

47

Lyme Disease Prevention

Distribution of pyrethrin-impregnated cotton balls in habitat of white-footed mice−

Kills ticks overwintering

with mice

48Source: Shapiro et al. (1992). N Engl J Med, 327, 1769.

Lyme Disease Prevention

Treatment Ticks infected Persons with LD

Placebo 23/159 (14%) 2/173 (1.2%)

Amoxicillin 30/185 (16%) 0/192 (0%)

49

Conclusions

Lyme disease is caused by a spirochetal bacteria, Borrelia burgdorferiThe reservoir host in the eastern U.S. is the white-footed mouseBorrelia is maintained in a geographically restricted natural cycle between ticks and mammalsHuman disease is determined by−

Exposure to infected ticks

−

The species of Borrelia causing infection