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

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

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

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

  • 1. Clinical Manifestations and Pathogenesis ofObligately 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
  • 2. Agents & Vectors of Tick-Borne Obligately Intracellular Bacterial Diseases in the US Agents Ticks DiseasesRickettsia rickettsii Dermacentor variabilis Rocky Mountain spotted fever D. andersoni Rhipicephalus sanguineusR. parkeri Amblyomma maculatum Maculatum spotted feverR. prowazekii ? Amblyomma imitator TyphusR. massiliae Rhipicephalus sanguineus unnamedR. philippi 364D D. occidentalis unnamedR. amblyommii A. americanum unnamedEhrlichia chaffeensis A. americanum Human monocytotropic ehrlichiosisE. ewingii A. americanum Ewingii ehrlichiosisE. muris-like agent Ixodes scapularis unnamedAnaplasma phagocytophilum I. scapularis Human granulocytic anaplasmosis
  • 3. Pathogenic Sequence of Events in Rickettsial InfectionsSpread 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
  • 4. Rickettsia rickettsii inHuman Vascular Endothelium
  • 5. 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)
  • 6. Increased Vascular Permeability in R. conorii-infected Mouse Retina
  • 7. RMSF: Early Rash
  • 8. Petechial Rash
  • 9. Ischemic Necrosis ofDistal Digits 2º Severe Rickettsial Injury to Microcirculation
  • 10. Non-occlusive Hemostatic Plug
  • 11. 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%
  • 12. Rickettsia Infection of Microcirculation
  • 13. RMSF: Non-cardiogenic Pulmonary Edema
  • 14. Cerebral Perivascular Edema in Rickettsial Encephalitis
  • 15. Neurological Manifestations of Rocky Mountain Spotted Fever %Confusion 28Stupor or delirium 21-26Ataxia 5-18Coma 9-10 in nonfatal cases 6 in fatal cases 86Seizures 8CSF pleocytosis 34-38CSF protein concentration increased 30-35Lumbar puncture performed 48-60
  • 16. Gastrointestinal Manifestations of Rocky Mountain Spotted FeverEarly 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 surgicalabdomen or massive g.i. hemorrhage: 14 patientsPotentially lethal g.i. lesions: ruptured appendix gangrenous gallbladderJaundice 8-9%
  • 17. 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
  • 18. Clinical Features of Rickettsia parkeri Rickettsiosis R. parkeri R. parkeri Clinical Rickettsiosis Clinical Characteristic Rickettsiosis (n = 16) % Characteristic (n = 16) %Fever 100 Headache 83Inoculation eschar(s) Lymphadenopathy 25 Any 94 Multiple 17 Nausea or vomiting 8Rash 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
  • 19. Rocky Mountain Spotted Fever United States, 1920 - 2008
  • 20. Confirmed vs. Probable RMSF Cases, 1992-2007 (NNDSS) 2000 100 1800 90 1600 80 Percent of Cases that were 1400 70Number 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
  • 21. 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
  • 22. High Level of Exposure to Lone Star Ticks isAssociated with a High Prevalence of Antibodies to Spotted Fever Group Rickettsiae
  • 23. 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).
  • 24. Dengue Syndrome in Mexico Among 394 suspected cases of dengue fever, 25.1% had antibodies to typhus group rickettsiae
  • 25. Rickettsia prowazekii Isolated from Ticks in Mexico Amblyomma imitator female
  • 26. 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
  • 27. 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
  • 28. Human Anaplasmataceae Infections (human ehrlichioses)Human monocytic ehrlichiosis (HME) - Ehrlichia chaffeensisHuman granulocytic anaplasmosis (HGA) - Anaplasma phagocytophilumEhrlichiosis “Ewingii” - caused by E. ewingii, genetically like E. chaffeensis, phenotypically like human anaplasmosisInfection with E. muris-like agent in upper midwest US and Russia
  • 29. 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
  • 30. Median Percentages of Monocytotropic EhrlichiosisPatients 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
  • 31. Hematologic and Hepatic Enzyme Changes in HMEFishbein DB, Dawson JE, Robinson LE Human ehrlichiosis in the United States, 1985 to 1990 Ann Intern Med 120:736-43
  • 32. Established Clinical Forms ofHuman 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)
  • 33. Compensatory Hemopoietic Hyperplasia
  • 34. Hemophagocytosis
  • 35. Granulomas: A Host Defense
  • 36. Hepatic Cell Death
  • 37. Diffuse Alveolar Damage
  • 38. Meningoencephalitis
  • 39. Overwhelming Ehrlichia chaffeensis in AIDS Patients
  • 40. 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)
  • 41. Ehrlichia chaffeensis Seroprevalence Among Children in the Southeast and South-Central Regions of the United States (Arch Pediatr Adolesc Med. 2002;156:166-170)
  • 42. 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
  • 43. Median Percentages of Anaplasmosis Patients with SpecificSymptoms 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%
  • 44. Median Percentages of Anaplasmosis Patients withSpecific 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%
  • 45. Kinetics of leukocyte and platelet countsand hemoglobin concentrations in HGA
  • 46. 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
  • 47. 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
  • 48. Acknowledgements to ColleaguesWho Have Shared Slides Used in This Presentation J. Stephen Dumler Jennifer McQuiston Aaron Sanchez Sherif Zaki