Apheresis Therapy for Rickettsial- Related Infections & Thrombotic Microangiopathy?

Nick Rose, MD University of Wisconsin Hospital Madison, WI Diseases

• Rocky Mountain spotted fever (RMSF) • Human monocytic ehrlichiosis (HME) • Human granulocytic anaplasmosis (HGA)

Outline 1: Disease Basics

• Microbiology • Clinical manifestations • Lab diagnosis • Treatment • Transfusion-transmitted infection (TTI) risk Outline 2: Relevance to Us

• Pathophysiology – Endothelial damage • Thrombosis risk? – Multifactorial thrombocytopenia – Other cytopenias • Potential mimicker of TTP – Clinical clues

Rickettsia Microbiology

• Gram negative • Obligate intracellular parasites • Arthropod vector • Acute febrile illness

• 3 important genera – Rickettsia – Ehrlichia – Anaplasma RMSF Microbiology

• Rickettsia rickettsii • American dog tick (Dermacentor variabilis) – Rocky Mountain wood tick (Dermacentor andersoni) • Dog & many other small mammals

RMSF Epidemiology

• Peak incidence Apr-Sep • Ages 5-9 & 40-65 • 8/million – Most common rickettsial disease

RMSF Epidemiology

RMSF Clinical

• Endothelial cell is main target • High & persistent fever • Nausea, vomiting, myalgia, anorexia, headache

RMSF Clinical

• Classic rash at presentation in 50-80% adults & >90% in kids – Starts around palms & soles then spreads inward – Reflects endothelial damage/spread – Also occurs viscerally • 5-10% fatality rate

RMSF Lab

• Moderate thrombocytopenia in ~50%, mild hyponatremia, & mildly elevated hepatic transaminase levels • Anemia ~30% • Often confirmed retrospectively – Fourfold rise in titers from sick to convalescent – Skin biopsy IHC – PCR – Culture

RMSF Treatment

• Doxycycline • Treated presumptively on clinical suspicion • Lack of response after 3 days  reconsider dx

• All the above are true for RMSF, HME, & HGA

HME Microbiology

• Ehrlichia chaffeensis • Lone star tick (Amblyomma americanum) • White-tailed deer

HME Epidemiology

• Peak incidence May-Aug • Ages >50 • 3/million

HME Epidemiology

HME Clinical

• Monocytes & macrophages – Other WBCs & endothelial cells also • Fever, headache, malaise, myalgia • Rash sparing palms & soles variably present – 30% adults & 60% kids • 2-3% fatality rate

HME Lab

• Leukopenia • Moderately high AST & ALT • Moderate thrombocytopenia • Anemia ~50% • Infected WBCs on smear in ~5% – Much more common in HGA • Often diagnosed retrospectively – Serology; PCR, culture • Treatment: doxycycline; improve ~1-3 days

HGA Microbiology

• Anaplasma phagocytophilum • Blacklegged tick (Ixodes scapularis) – 10% also infected with babesiosis and/or Lyme – Western blacklegged tick (Ixodes pacificus) • White-footed mouse

HGA Epidemiology

• Peak incidence May-Aug • Ages >50 • 6/million

HGA Epidemiology

HGA Clinical

• Neutrophils – Other WBCs & endothelial cells also • Fever, headache, malaise, myalgia • Rash rare • 0.5% fatality rate

HGA Lab

• Similar to HME – Leukopenia – Moderately high AST & ALT – Moderate thrombocytopenia – Anemia ~50% • Infected WBCs on smear in ~75% • Often diagnosed retrospectively – Serology, PCR, culture • Treatment: doxycycline; improve ~1-3 days

Transfusion-Transmitted Infection (TTI) Risk • RMSF: ~1 • HME: 0 • HGA: ~8 • About 10 total cases overall • Minimal risk • Seropositive rates can be ~15% • Tick bites often go unnoticed • Many experts: screening (lab and/or questionnaire) is not worth the tradeoff Pathophysiology

• Endothelial cell damage • Without lysing • Increased permeability of the microcirculation  edema, hypovolemia, hypoperfusion

Pathophysiology

• Though modified, coagulation & fibrinolytic systems maintain hemostasis • No pathological thrombosis – Even in fulminant cases & in tissues with high disease burden • No significant consumption of clotting factors – DIC is rare: RMSF <10%; even less for HME/HGA

Multifactorial Thrombocytopenia

• Platelet adhesion – To ECs & exposed collagen • Direct infection of platelets – Infected megakaryocytes not seen • Antiplatelet antibodies – During acute phase

Other Cytopenias

• Mechanism of leukopenia is unclear – Probably not direct infection • Leukopenia in HME despite low % WBCs infected – No evidence of marrow suppression in biopsies • Anemia, if present, is of uncertain mechanism – Not clearly hemolytic – RBCs & precursors are not infected – “Anemia of inflammation” iron sequestration?

Potential Mimicker of TTP

• Very little in literature – Almost all pre-ADAMTS13 era • Few case reports of suspected TTP  didn’t respond to TPE  ddx expanded – Oklahoma registry: RMSF for 3 cases • Or, other findings gave a clue – Stony Brook registry: HGA (seen early on smear) Potential Mimicker of TTP

• Couple reports of Rickettsial dx  didn’t quickly respond to doxycycline  “TTP-like illness” in pre-ADAMTS13 era • TPE was added since TTP couldn’t be ruled out; doxycycline was cont’d • Hard to say adjunct TPE helped • No evidence / argument that TPE helps any Rickettsial illness

Clinical Clues

• Epidemiology – Season – Exposure – Prevalence • Clinical & lab – Elevated liver enzymes (HME/HGA > RMSF) – Leukopenia (HME/HGA > RMSF) – Rash (RMSF > HME >> HGA) – Absence of anemia (RMSF > HME/HGA)

Quiz 1

• Which of the following diseases shares a vector with babesiosis and Lyme disease?

A. RMSF (Rocky Mountain spotted fever) B. HME (Human monocytic ehrlichiosis) C. HGA (Human granulocytic anaplasmosis) Quiz 2

• Which of the following would most likely show pathogens on peripheral blood smear?

A. RMSF (Rocky Mountain spotted fever) B. HME (Human monocytic ehrlichiosis) C. HGA (Human granulocytic anaplasmosis) Quiz 3

• What is the treatment for RMSF, HME, & HGA?

A. Azithromycin B. Doxycycline C. Trimethoprim-sulfamethoxazole Quiz 4

• What is the transfusion transmission risk from Rickettsial organisms?

A. About 10 cases have been reported B. About 1 in 3,000,000 C. About 1 in 300,000

Quiz 5

• What cell is the main target in RMSF?

A. Endothelial cell B. Hepatocyte C. Red blood cell

Quiz 6

• While the mechanism of thrombocytopenia in Rickettsial diseases is incompletely understood, which of the following is/are likely to contribute?

A. Antiplatelet autoantibodies B. Direct infection of platelets C. Platelet adhesion

Quiz 7

• Which of the following would be LEAST likely in HME (human monocytic ehrlichiosis)?

A. Elevated liver enzymes B. Fever C. Leukopenia D. Thrombocytopenia E. Thrombosis Pugs Not Bugs