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

Agents & Vectors of Tick-Borne Obligately

Intracellular Bacterial Diseases in the US Agents Ticks Diseases

Rickettsia rickettsii Dermacentor variabilis

D. andersoni

Rhipicephalus sanguineus

Rocky Mountain spotted fever

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

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

Rickettsia rickettsii in

Human Vascular Endothelium

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)

Increased Vascular Permeability in

R. conorii-infected Mouse Retina

RMSF: Early Rash

Petechial Rash

Ischemic Necrosis of

Distal Digits 2º Severe

Rickettsial Injury to

Microcirculation

Non-occlusive Hemostatic Plug

Rash in Rocky Mountain Spotted Fever

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%

%

Occurrence 89-91

Onset day 1 14

days 1-3 49

days 5-6 18-20

Rickettsia Infection of Microcirculation

RMSF: Non-cardiogenic Pulmonary Edema

Cerebral Perivascular Edema in

Rickettsial Encephalitis

%

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

Neurological Manifestations of

Rocky Mountain Spotted Fever

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%

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

Clinical Features of Rickettsia parkeri Rickettsiosis

Clinical

Characteristic

R. parkeri

Rickettsiosis

(n = 16) %

Fever 100

Inoculation eschar(s)

Any 94

Multiple 17

Rash

Any type 88

Macules or papules 83

Petechiae 17

Vesicles or pustules 42

On palms or soles 45

Clinical

Characteristic

R. parkeri

Rickettsiosis

(n = 16) %

Headache 83

Lymphadenopathy 25

Nausea or vomiting 8

Diarrhea 0

Coma, delirium, or

seizure

0

Hospitalization 33

Death 0

Rocky Mountain Spotted Fever

United States, 1920 - 2008

0

200

400

600

800

1000

1200

1400

1600

1800

2000

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

Year

Nu

mb

er

of

Cases

0

10

20

30

40

50

60

70

80

90

100

Perc

en

t o

f C

ases t

hat

were

Co

nfi

rmed

Confirmed

Probable

Percent Confirmed

Confirmed vs. Probable RMSF Cases,

1992-2007 (NNDSS)

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

4.0%

CFRConf CFRProb

Case Fatality Rate among Confirmed and Probable Cases

Perc

en

t D

ied

2000-2003

2004-2007

RMSF Case Fatality Rate by Confirmed vs.

Probable Case Status, 2000-2007 (CRFs)

High Level of Exposure to Lone Star Ticks is

Associated with a High Prevalence of Antibodies to

Spotted Fever Group Rickettsiae

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).

Dengue Syndrome in Mexico

Among 394 suspected cases of dengue fever, 25.1% had

antibodies to typhus group rickettsiae

Rickettsia prowazekii Isolated from Ticks

in Mexico

Amblyomma imitator

female

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

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

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

Median Percentages of Monocytotropic Ehrlichiosis Patients

with Specific Symptoms or Signs at Any Time

during the Course of Illness

Symptom or Sign (n = 234-422)

%

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

Median Percentages of Monocytotropic Ehrlichiosis

Patients with Specific Abnormal Laboratory Findings

at any Time during the Course of Illness Laboratory Abnormality

(n = 250-308)

%

Leukopenia 60

Thrombocytopenia 79

Anemia 50

Elevated serum aspartate

transaminase

88

Elevated serum creatinine 24

Fishbein DB, Dawson JE, Robinson LE Human ehrlichiosis in the United States, 1985 to 1990 Ann Intern Med 120:736-43

Hematologic and Hepatic Enzyme Changes in HME

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)

Compensatory Hemopoietic Hyperplasia

Hemophagocytosis

Granulomas: A Host Defense

Hepatic Cell Death

Diffuse Alveolar Damage

Meningoencephalitis

Overwhelming Ehrlichia chaffeensis

in AIDS Patients

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)

Ehrlichia chaffeensis Seroprevalence Among Children in the

Southeast and South-Central Regions of the United States

(Arch Pediatr Adolesc Med. 2002;156:166-170)

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

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%

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%

Kinetics of leukocyte and platelet counts

and hemoglobin concentrations in HGA

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

A. phagocytophilum-Induced

Neutrophil Functional Alterations

ACTIVATION

• Degranulation

• Inflammation

• Mobility

• Production of

– Proteases

– Chemokines

– Chemotactic factors

DEACTIVATION

• Respiratory burst

• Apoptosis

• Endothelial cell adhesion

• Transmigration

• Phagocytosis

• Microbial killing

Acknowledgements to Colleagues

Who Have Shared Slides Used in

This Presentation

J. Stephen Dumler

Jennifer McQuiston

Aaron Sanchez

Sherif Zaki