ASTMH President David H. Walker's keynote presentation from the 2013 Tick-Borne Disease Integrated Pest Management conference.

1. Clinical Manifestations and Pathogenesis of
Obligately Intracellular Bacterial Tick-borne
Diseases in the US
DAVID H. WALKER, M.D.
The Carmage and Martha Walls Distinguished University Chair in
Tropical Diseases
Professor and Chairman, Department of Pathology
Executive Director,
Center for Biodefense and Emerging Infectious Diseases
University of Texas Medical Branch

3. Agents & Vectors of Tick-Borne Obligately
Intracellular Bacterial Diseases in the US
Agents Ticks Diseases
Rickettsia rickettsii Dermacentor variabilis Rocky Mountain spotted fever
D. andersoni
Rhipicephalus sanguineus
R. parkeri Amblyomma maculatum Maculatum spotted fever
R. prowazekii ? Amblyomma imitator Typhus
R. massiliae Rhipicephalus sanguineus unnamed
R. philippi 364D D. occidentalis unnamed
R. amblyommii A. americanum unnamed
Ehrlichia chaffeensis A. americanum Human monocytotropic ehrlichiosis
E. ewingii A. americanum Ewingii ehrlichiosis
E. muris-like agent Ixodes scapularis unnamed
Anaplasma phagocytophilum I. scapularis Human granulocytic anaplasmosis

4. Pathogenic Sequence of Events in
Rickettsial Infections
Spread in the Body
• From portal of entry most likely via
dermal lymphatic vessels to regional
lymph node (e.g., R. slovaca, R. africae,
R. sibirica strain mongolitimonae)
• Hematogenous spread to endothelium
throughout the body
• Cell-to-cell spread of SFG rickettsiae
• No extravascular spread other than
vascular smooth muscle (R. rickettsii)
and occasional perivascular
macrophage

5. Rickettsia rickettsii in
Human Vascular Endothelium

6. Pathophysiology of Rickettsial Diseases
Increased vascular permeability
Edema (life threatening in brain and lungs)
Low blood volume
Hypotension
Decreased perfusion of organs
Organ dysfunction
(e.g., acute renal failure: prerenal azotemia)

7. Increased Vascular Permeability in
R. conorii-infected Mouse Retina

8. RMSF: Early Rash

9. Petechial Rash

10. Ischemic Necrosis of
Distal Digits 2º Severe
Rickettsial Injury to
Microcirculation

11. Non-occlusive Hemostatic Plug

12. Rash in Rocky Mountain Spotted Fever
%
Occurrence 89-91
Onset day 1 14
days 1-3 49
days 5-6 18-20
Involvement of palms and soles: 36-82%
Onset after day 5: 43%
Petechiae in center of
maculopapules: 41-59%
Appearance on or after day 6: 74%
Cutaneous necrosis or peripheral gangrene: 4%

13. Rickettsia Infection of Microcirculation

14. RMSF: Non-cardiogenic Pulmonary Edema

15. Cerebral Perivascular Edema in
Rickettsial Encephalitis

16. Neurological Manifestations of
Rocky Mountain Spotted Fever
%
Confusion 28
Stupor or delirium 21-26
Ataxia 5-18
Coma 9-10
in nonfatal cases 6
in fatal cases 86
Seizures 8
CSF pleocytosis 34-38
CSF protein concentration increased 30-35
Lumbar puncture performed 48-60

17. Gastrointestinal Manifestations of Rocky
Mountain Spotted Fever
Early course
nausea and/or vomiting 38-56%
abdominal pain 30-34%
diarrhea 9-20%
Abdominal tenderness 8-42%
Guaiac positive stools or vomitus 10%
Exploratory laparotomy for acute surgical
abdomen or massive g.i. hemorrhage: 14 patients
Potentially lethal g.i. lesions:
ruptured appendix
gangrenous gallbladder
Jaundice 8-9%

18. Factors in Severity of
Rickettsial Illness
 Older age
 Male gender
 Glucose-6-phosphate dehydrogenase deficiency (and
possibly other causes of hemolysis)
 Diabetes mellitus
 Alcoholism
 Sulfonamide treatment
 Probably other co-morbid conditions (e.g.,
cardiovascular disease)
 IFN-γ SNP genetic polymorphism

19. Clinical Features of Rickettsia parkeri Rickettsiosis
R. parkeri R. parkeri
Clinical Rickettsiosis Clinical
Characteristic Rickettsiosis
(n = 16) % Characteristic
(n = 16) %
Fever 100 Headache 83
Inoculation eschar(s)
Lymphadenopathy 25
Any 94
Multiple 17 Nausea or vomiting 8
Rash Diarrhea 0
Any type 88
Coma, delirium, or 0
Macules or papules 83
seizure
Petechiae 17
Hospitalization 33
Vesicles or pustules 42
On palms or soles 45 Death 0

20. Rocky Mountain Spotted Fever
United States, 1920 - 2008

21. Confirmed vs. Probable RMSF Cases,
1992-2007 (NNDSS)
2000 100
1800 90
1600 80
Percent of Cases that were
1400 70
Number of Cases
Confirmed
1200 60 Confirmed
1000 50 Probable
800 40 Percent Confirmed
600 30
400 20
200 10
0 0
92
93
94
95
96
97
98
99
00
01
02
03
04
05
06
07
19
19
19
19
19
19
19
19
20
20
20
20
20
20
20
20
Year

22. RMSF Case Fatality Rate by Confirmed vs.
Probable Case Status, 2000-2007 (CRFs)
4.0%
3.5%
3.0%
Percent Died
2.5%
2000-2003
2.0%
2004-2007
1.5%
1.0%
0.5%
0.0%
CFRConf CFRProb
Case Fatality Rate among Confirmed and Probable Cases

23. High Level of Exposure to Lone Star Ticks is
Associated with a High Prevalence of Antibodies to
Spotted Fever Group Rickettsiae

24. Evidence for Human Infection
with Rickettsia amblyommii
• In a study of soldiers undergoing training in an
environment with heavy exposure to R. amblyommii -
infected lone star ticks, numerous seroconversions to
SFG rickettsiae occurred.
• 56% of seroconversions were asymptomatic.
• Significantly more seroconverters than
nonseroconverters reported fever, chills, headache,
myalgia, rash, arthralgia, dyspnea, and confusion (odds
ratio > 2).

25. Dengue Syndrome in Mexico
Among 394 suspected cases of dengue fever, 25.1% had
antibodies to typhus group rickettsiae

26. Rickettsia prowazekii Isolated from Ticks
in Mexico
Amblyomma imitator
female

27. Case Report of
Rickettsia prowazekii Infection
 50 year old man from New Mexico
 Vacationed at Padre Island in May- early June 1999
 10 days later: fever, headache
 June 20: admitted to hospital with fever, stiff neck,
photophobia, abdominal pain
 CSF: 30 cells/μl (60% lymphocytes, 40% PMNs)
protein 58 mg/dl

28. Case Report of
Rickettsia prowazekii Infection
 3 days later CSF: 46 cells/μl (73% PMNs),
protein 73 mg/dl
 Typhus group Rickettsia IgG-IFA; 1:256 → 1:512
 Doxycycline → defervesence
 2 CSF samples 17kDa gene PCR:
Rickettsia prowazekii DNA
Massung et al, Clinical Infectious Diseases 32:979-82, 2001

29. Human Anaplasmataceae Infections
(human ehrlichioses)
Human monocytic ehrlichiosis (HME) -
Ehrlichia chaffeensis
Human granulocytic anaplasmosis (HGA) -
Anaplasma phagocytophilum
Ehrlichiosis “Ewingii” - caused by E.
ewingii, genetically like E. chaffeensis,
phenotypically like human anaplasmosis
Infection with E. muris-like agent in upper
midwest US and Russia

30. Median Percentages of Monocytotropic Ehrlichiosis Patients
with Specific Symptoms or Signs at Any Time
during the Course of Illness
(n = 234-422)
Symptom or Sign
%
Fever 96
Myalgia 68
Headache 72
Malaise 77
Nausea 57
Vomiting 47
Diarrhea 25
Cough 28
Arthralgias 41
Rash 26
Stiff Neck 21
Confusion 20

31. Median Percentages of Monocytotropic Ehrlichiosis
Patients with Specific Abnormal Laboratory Findings
at any Time during the Course of Illness
(n = 250-308)
Laboratory Abnormality
%
Leukopenia 60
Thrombocytopenia 79
Anemia 50
Elevated serum aspartate 88
transaminase
Elevated serum creatinine 24

32. Hematologic and Hepatic Enzyme Changes in HME
Fishbein DB, Dawson JE, Robinson LE Human ehrlichiosis in the United States, 1985 to 1990 Ann Intern Med 120:736-43

33. Established Clinical Forms of
Human Monocytic Ehrlichiosis
• Rocky Mountain spotted fever or toxic shock
syndrome-like multisystem disease
• Aseptic meningitis with multisystem disease
• ARDS with multisystem disease
• Overwhelming ehrlichial infection of severely
immunocompromised patients
• Asymptomatic presence of antibodies reactive
with E. chaffeensis ( ? stimulated by a less
pathogenic agent, such as E. ewingii)

34. Compensatory Hemopoietic Hyperplasia

35. Hemophagocytosis

36. Granulomas: A Host Defense

37. Hepatic Cell Death

38. Diffuse Alveolar Damage

39. Meningoencephalitis

40. Overwhelming Ehrlichia chaffeensis
in AIDS Patients

41. Fatal Toxic Shock-like Ehrlichiosis
 Severe hepatic apoptosis and necrosis
mediated by CD8 T lymphocytes
 Loss of antigen-specific IFN-γ producing
CD4+ lymphocytes associated with apoptosis
 Overproduction of TNF-α by CD8 T cells and
IL-10 by nonadherent spleen cells
 A weak Th1 response (low IL-12)

42. Ehrlichia chaffeensis Seroprevalence Among Children in the
Southeast and South-Central Regions of the United States
(Arch Pediatr Adolesc Med. 2002;156:166-170)

43. Epidemiology and Ecology
HGA – Anaplasma phagocytophilum
─ risk for disease increased with age, male gender
─ Incidence: Connecticut - 51 cases per 100,000 pop.
Northwestern Wisconsin - 58 cases per 100,000 pop.
─ Seroprevalence: Northwestern Wisconsin, up to
15% of tick- exposed Sweden, 15-20%
─ upper Midwest and northeast US, northern
California, Europe
─ transmitted by Ixodes spp. nymphs and adults
─ reservoir white-footed mice
(Peromyscus leucopus), deer

44. Median Percentages of Anaplasmosis Patients with Specific
Symptoms or Signs at Any Time during the Course of Illness
Symptom or Sign Granulocytotropic
Anaplasmosis
(n= 24-531)
Fever 100%
Myalgia 78%
Headache 89%
Malaise 97%
Nausea 44%
Vomiting 20%
Diarrhea 17%
Cough 20%
Arthralgias 56%
Rash 3%
Stiff neck 22%
Confusion 17%

45. Median Percentages of Anaplasmosis Patients with
Specific Abnormal Laboratory Findings at any Time
during the Course of Illness
Laboratory Abnormality Granulocytotropic
Anaplasmosis
(n= 59-344)
Leukopenia 55%
Thrombocytopenia 75%
Anemia 28%
Elevated serum aspartate 83%
transaminase
Elevated serum creatinine 15%

46. Kinetics of leukocyte and platelet counts
and hemoglobin concentrations in HGA

47. HGA Complications
• Septic or toxic shock-like syndrome
• Coagulopathy
• Atypical pneumonitis/Acute respiratory distress syndrome (ARDS)
• Acute abdominal syndrome
• Rhabdomyolysis
• Myocarditis
• Acute renal failure
• Hemorrhage
• Brachial plexopathy
• Demyelinating polyneuropathy
• Cranial nerve palsies
• Opportunistic infections
• Death ─ 0.5% case fatality rate

48. A. phagocytophilum-Induced
Neutrophil Functional Alterations
ACTIVATION DEACTIVATION
• Degranulation • Respiratory burst
• Inflammation • Apoptosis
• Mobility • Endothelial cell adhesion
• Production of • Transmigration
– Proteases • Phagocytosis
– Chemokines
• Microbial killing
– Chemotactic factors

49. Acknowledgements to Colleagues
Who Have Shared Slides Used in
This Presentation
J. Stephen Dumler
Jennifer McQuiston
Aaron Sanchez
Sherif Zaki