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
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Clinical Manifestation and Pathogenesis of Obligately Intracellular Bacterial Tick-borne Diseases in the US
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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