Rickettsial Diseases Notes

NOTES NOTES RICKETTSIAL DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Vector-borne obligate intracellular bacteria; poor Gram staining, rod-shaped structure ▪ Common tropism for endothelial cells → variable amount of hemorrhage, edema, organ dysfunction SIGNS & SYMPTOMS ▪ Disease-specific; fairly consistent integument manifestations (e.g. rash) DIAGNOSIS LAB RESULTS ▪ Isolation of Rickettsiae ▫ Inoculation of animal/via cell culture ▪ Serology ▫ Enzyme-linked immunosorbent assay (ELISA), western blot, microimmunofluorescent antibody test (detection of bacterial-specific antigens) 514 OSMOSIS.ORG ▪ Immunologic detection in tissue ▫ Isolation in epithelial tissue (from integument involvement) ▫ Requires sophisticated laboratory capability (not common in endemic areas of disease) ▪ Polymerase chain reaction (PCR) ▫ Detection of rickettsial DNA OTHER DIAGNOSTICS ▪ Clinical presentation (disease-specific) TREATMENT MEDICATIONS ▪ Prompt antimicrobial therapy ▫ Doxycycline (preferred)

Chapter 95 Rickettsial Diseases ANAPLASMA osms.it/anaplasma PATHOLOGY & CAUSES ▪ Tick-borne, obligate intracellular bacteria, endemic to wooded areas in North America → self-resolving disease, AKA human granulocytic anaplasmosis (HGA) Vector ▪ Anaplasma phagocytophilum: Ixodes tick ▫ Ixodes scapularis: also transmits Borrelia burgdorferi, Babesia spp. in eastern United States (US) ▫ Ixodes pacificus: main vector in western US ▫ Ixodes ricinus: implicated in European disease Life cycle and transmission ▪ Reservoir hosts: deer, white-footed mice (source of disease, not affected by pathogen) ▪ Vector: Ixodes tick (connects organism from reservoir to target) ▪ Human transmission Pathogenesis ▪ Tick bite → blood circulation → leukocyte infection, membrane attachment → phagocytosis → replication (in early endosome of leukocyte) → dysfunctional vacuolization, immature lysosomal micelles → microcolony (AKA morulae) development → release into extracellular space after cell lysis/exocytosis ▫ P-selectin glycoprotein (identified binding domain for A. phagocytophilum) ▫ Ligand: P-selectin glycoprotein ligand-1 (PSGL-1) required on granulocytes for internalization Disease: HGA ▪ Direct leukocyte cell death ▪ Inflammatory response → perivascular inflammatory infiltrates in multiple organ systems (without organ failure/endothelial damage) RISK FACTORS ▪ Residence in/travel to wooded areas in North America ▫ Especially during peak tick activity (e.g. spring, summer) ▪ Direct contact with slaughtered deer ▪ Occupational exposure (e.g. military) COMPLICATIONS ▪ Co-infection with Borrelia burgdorferi, Babesia spp. ▪ Respiratory insufficiency, renal failure, septic shock ▪ Neurological ▫ Demyelinating polyneuropathy, brachial plexopathy ▪ Serious, fatal opportunistic infections ▫ Herpes simplex esophagitis, invasive aspergillosis, SIGNS & SYMPTOMS ▪ Onset 1–2 weeks after identified tick bite ▪ Fever, malaise, headache ▪ Rash ▫ Typically trunk (sparing hands, feet), maculopapular (more evident in children) ▪ Gastrointestinal (GI) symptoms infrequent ▪ Neurological (rare) ▫ Mental status change, meningismus, clonus DIAGNOSIS LAB RESULTS ▪ Leukopenia ▫ Specific to disease (neutropenia) ▪ ↑ hepatic enzymes, lactate dehydrogenase OSMOSIS.ORG 515

▪ Serology: indirect IFA ▫ Detection of IgG/IgM antibodies of Anaplasma species ▫ If negative on acute serum testing, repeat with convalescent serum (confirms diagnosis if ↑ fourfold in IgG antibody titer) ▪ Whole blood PCR ▫ Detects epank1 primers on genogroup A. phagocytophilum ▪ Wright stain: morulae of Anaplasma in leukocyte ▫ A. phagocytophila: peripheral blood neutrophils; 25–75% (highest among morulae-producing bacteria) OTHER DIAGNOSTICS ▪ History ▫ Tick bite in endemic area TREATMENT MEDICATIONS ▪ Prompt antibacterial management ▫ Doxycycline (if pregnant, rifampin); chloramphenicol OTHER INTERVENTIONS ▪ Prevention ▫ Avoid tick habitats ▫ Careful inspection after outside activity in wooded areas (esp. in spring, summer); rapid discovery, tick removal < 24–48 hours post bite → effective prophylaxis ▫ Skin application of insect repellants ▫ Proper clothing for outside work/play (light-colored, long pants tucked into socks, long-sleeved shirts) 516 OSMOSIS.ORG Figure 95.1 Mites of the genus Ixodes act as vectors for many rickettsial diseases.

Chapter 95 Rickettsial Diseases COXIELLA BURNETII (Q FEVER) osms.it/coxiella-burnetii PATHOLOGY & CAUSES ▪ Coxiella burnetii: primarily zoonotic pathogen → febrile illness (after contact with animal amniotic fluid/placental contents) Taxonomy ▪ Order: Legionellales ▪ Family: Coxiellaceae Morphology ▪ Short, pleomorphic rod ▫ Strict intracellular bacterium Life cycle ▪ Source of human infections ▫ Farm animals (e.g. cattle, goats, sheep) ▫ Wild animals (e.g. birds, rabbits, reptiles) ▫ Arthropods (e.g. ticks) ▪ Main reservoir ▫ Ticks Transmission ▪ Inhalation of spores/bacteria ▫ Animal feces, milk, products of conception ▪ Ingestion of contaminated milk ▪ Percutaneous ▫ Crushing of ticks near skin breaks ▪ Vertical spread (transplacental) Pathogenesis ▪ Host cell ▫ Macrophage ▪ Antigenic variation (AKA phase variation) important in virulence ▫ Lipopolysaccharide capsule modifications underly antigenic variation RISK FACTORS ▪ Occupation involving animal contact (e.g. veterinarian, farmer) ▪ ↑ age ▪ Unpasteurized milk consumption COMPLICATIONS ▪ Q fever pneumonia, chronic hepatitis, osteomyelitis ▪ Infective endocarditis ▫ Pre-existing heart/valve disease predisposes to endocarditis development ▫ May have secondary, septic embolic manifestation SIGNS & SYMPTOMS ▪ Q fever (sudden onset) ▫ Fever, headache (often frontal), general malaise, cough, anorexia, myalgia ▪ Pneumonia ▫ Cough, pleural effusion ▪ Hepatitis ▫ Hepatomegaly DIAGNOSIS LAB RESULTS ▪ ↑ serum hepatic enzymes, leukopenia/ leukocytosis, thrombocytopenia ▪ Immunofluorescent antibody assays: detect IgM/IgG antibodies; differentiate between acute, chronic infection ▫ IgM: detectable 4 days after symptom onset ▫ IgG: detectable 9–14 days after symptom onset ▫ Concentration of serum samples can assist in diagnosis (esp. if vague clinical presentation) OSMOSIS.ORG 517

▪ PCR ▫ Blood/serum detection possible before IgM serology peak ▪ Immunohistochemistry ▪ Culture OTHER DIAGNOSTICS ▪ History ▫ Animal contact, occupation ▫ Trimethoprim-sulfamethoxazole: pregnant individuals; treat even if asymptomatic ▪ Chronic infection: prolonged therapy ▫ 18 months doxycycline, hydroxychloroquine (monitor serologic response across therapeutic intervention; biannual ophthalmic examinations required) OTHER INTERVENTIONS TREATMENT MEDICATIONS ▪ Prompt antimicrobial treatment ▫ Doxycycline: effectiveness of antibacterial agent, severity of complications warrants use despite side effects; shorter therapy for children (14 day course) ▪ Management ▫ Individuals with pre-existing valvulopathy/cardiomyopathy; echocardiogram ▪ Prevention ▫ Whole cell vaccine; recommended for individuals working with farm animals (e.g. farmers, slaughterhouse workers) EHRLICHIA osms.it/ehrlichia PATHOLOGY & CAUSES ▪ Tick-borne, obligate intracellular bacteria with leukocytic tropism, associated with febrile disease with rare, serious neurologic complication ▫ AKA human monocytic ehrlichiosis (HME) ▪ Characteristics ▫ Small (0.5–1.5 micrometer) gramnegative cocci, (1.8 megabases) genome TYPES ▪ Ehrlichia ewingii ▫ Southeastern, central United States ▪ Ehrlichia chaffeensis ▫ Northeastern, midwestern United States ▪ Ehrlichia sennetsu ▫ Western Japan 518 OSMOSIS.ORG Vector ▪ Amblyomma americanum (AKA lone star tick) ▫ Ehrlichia ewingii, Ehrlichia chaffeensis Life cycle ▪ Tick bite → blood circulation → leukocyte infection, membrane attachment → phagocytosis → replication (in early endosome of leukocyte) → dysfunctional vacuolization, immature lysosomal micelles → microcolony (AKA morulae) development → release into extracellular space after cell lysis/exocytosis Pathogenesis ▪ Direct leukocyte cell death ▪ Inflammatory response → perivascular inflammatory infiltrates in multiple organ system without organ failure/endothelial damage Disease: Sennetsu fever

Chapter 95 Rickettsial Diseases RISK FACTORS ▪ Residence in/travel to western Japan ▪ Occupational exposure (e.g. military) COMPLICATIONS ▪ Co-infection with Babesia spp./B. burgdorferi ▪ Encephalitis, seizure ▫ Associated most with E. chaffeensis ▫ May result in persistent neurologic deficit (rare; seen especially in children) ▪ Heart failure, respiratory insufficiency, renal failure, shock SIGNS & SYMPTOMS ▪ Sennetsu fever ▫ Abrupt-onset fever, chills, headache, malaise, sore throat, myalgias, arthralgias ▪ Atypical rash ▫ Maculopapular with occasional petechiae; located on trunk (sparing hands, feet) ▪ Generalized lymphadenopathy ▫ Most associated with E. sennetsu; includes hepatosplenomegaly ▪ GI ▫ Associated with E. chaffeensis ▫ Anorexia, diarrhea, nausea, vomiting ▪ Leukopenia, thrombocytopenia, anemia, hyponatremia ▪ Hepatic transaminitis: most common in E. chaffeensis infection ▪ Cerebrospinal fluid (CSF) analysis: pleocytosis (mononuclear cells with morulae), ↑ protein OTHER DIAGNOSTICS ▪ History ▫ Tick bite in endemic area TREATMENT MEDICATIONS ▪ Prompt antibacterial management: poxycycline, chloramphenicol OTHER INTERVENTIONS Prevention ▪ Avoidance of tick habitats ▪ Careful inspection after outside activity (esp. in spring, summer) ▫ Rapid discovery, removal < 24–48 hours after bite → effective prophylaxis ▪ Proper skin application of insect repellants DIAGNOSIS LAB RESULTS ▪ Serology: indirect IFA ▫ Detection of IgG/IgM antibodies (Ehrlichia species) ▫ If negative on acute serum testing, repeat with convalescent serum (confirms diagnosis if fourfold increase in IgG antibody titer) ▪ Whole blood PCR: detects 16S rRNA gene ▪ Wright stain: morulae (Ehrlichia) in leukocyte ▫ E. ewingii: in peripheral blood granulocyte ▫ E. chaffeensis: in peripheral blood monocyte OSMOSIS.ORG 519

RICKETTSIA RICKETTSII (ROCKY MOUNTAIN SPOTTED FEVER) osms.it/rickettsia-rickettsii PATHOLOGY & CAUSES ▪ Tick-borne, obligate intracellular, Gramnegative bacteria endemic to parts of North America → potentially lethal febrile disease ▪ Characteristics ▫ Weakly gram-negative, nonmotile coccobacillus; 0.7–2.0 micrometers: cannot be visualized by traditional staining methods/direct fluorescent antibody techniques ▫ Bacterial contents: ribosome; single, circular chromosome; microcapsule surrounding cell wall (may be important in pathogenicity) Vectors ▪ Dermacentor variabilis (American dog tick) ▫ Eastern, South-central US ▪ Dermacentor andersoni (Rocky Mountain wood tick) ▫ West of Mississippi River ▪ Rhipicephalus sanguineus (common brown dog tick) ▫ Southwestern US ▪ Virulence of strain depends on tick’s feeding status ▫ ↑ feeds → ↑ incubation at high temperatures → ↑ extracellular slime → ↑ virulence (AKA reactivation phenomenon) Life cycle ▪ Tick bite (requires 6–10 hours of feeding) → proliferates by binary fission ▪ Grows in nucleus, cytoplasm of host cells Pathogenesis ▪ Tropism for endothelial cells, downstream systemic effects as sequelae ▪ Endothelial cell entry: rickettsial outer membrane proteins (rOmps) interact with 520 OSMOSIS.ORG ▪ ▪ ▪ ▪ ▪ ▪ lipopolysaccharides, surface-exposed proteins (SEPs) for entry ▫ rOmps bind Ku70 (membrane protein) → activate Ku70 → recruit ubiquitin ligase → ubiquitination of Ku70 → act upon cAMP receptors protein kinase A, Epac (exchange protein) → rearrangement of host cell actin filaments → rickettsial endocytosis Bacterial spread: R. rickettsii express phospholipase D, tlyC → lyse phagosomal membrane → entry into cytosol → polymerization of host cell monomeric actin filaments → invagination of host cell membranes → passage into neighboring cells Further bacterial spread ▫ Filopodia (from host cell membranes) assist in intercellular movement ▫ Bloodstream, lymphatic spread assist in more distant infection sites Small blood vessel injury (not entirely elucidated) ▫ Associated with phospholipase A activity, protease activity, free radicalinduced lipid peroxidation ▫ Cell necrosis (from other infected cells) → CD8+ T-cell response → endothelial cell injury → immune, phagocytic cellular response → lymphohistiocytic vasculitis Sequelae of small vessel injury: ↑ fluid in interstitial space → exposes brain, lung parenchyma to devastating pathophysiologic consequences Ability to spread cell-to-cell without causing obvious damage ▫ Rarely accumulate in large numbers inside cells Speeds of 4.8m/min ▫ Achieves speed via rapid recruitment, polymerization of host cell actin filaments

Chapter 95 Rickettsial Diseases RISK FACTORS ▪ Residence in/travel to endemic areas (esp. in spring, summer) ▪ ↑ age (peak: 40–64) ▪ Individuals who are biologically male ▪ Glucose-6-phosphate dehydrogenase (G6PD) deficiency COMPLICATIONS ▪ Skin necrosis at sites of terminal arterial supply (e.g. fingers, toes, nose, ears, genitals) ▪ Interstitial pneumonitis, myocarditis, encephalitis SIGNS & SYMPTOMS ▪ Early infection ▫ Fever, headache, malaise, myalgias, arthralgias, nausea (without vomiting), edema (esp. in children) ▪ Rash development (hallmark of infection) ▫ Blanching, erythematous rash ▫ Macules (1–4mm) → petechiae ▫ Ankles, wrist → truncal spread → palms, soles rash (characteristic of late-stage disease) ▪ Confusion, conjunctival erythema, seizures, focal neurologic deficit ▪ Fundoscopic examination ▫ Retinal vein engorgement, arterial occlusion, flame hemorrhage DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Interstitial infiltrates Echocardiogram ▪ Minimal myocardial dysfunction with normal capillary wedge pressure ▪ Consistent with noncardiogenic nature of pulmonary edema (commonly present) ▪ Advanced disease ▫ Hyponatremia (sign of central nervous system involvement); transaminitis; ↑ bilirubin; azotemia (due to hypovolemia); ↑ prothrombin, partial thromboplastin times ▪ CSF ▫ Pleocytosis (monocytic, polymorphonuclear predominance possible), ↑ protein OTHER DIAGNOSTICS ▪ History ▫ Residence in/travel to endemic area; recollection of tick bite (only 30% of individuals recollect bite) TREATMENT MEDICATIONS ▪ Early treatment: prompt, empiric antimicrobial therapy with doxycycline (first-line), chloramphenicol (second-line) ▫ Even if mild symptoms (due to potential lethality of bacterial strain); recommended for pregnant individuals, children ▫ Goal: initiate < five days after symptom onset ▫ Duration: until three days after resolution of febrile illness; minimum seven days ▪ Antiemetics, antimotility agents (individuals intolerant of doxycycline) OTHER INTERVENTIONS ▪ Hemodynamic monitoring in ICU setting; respiratory support; renal replacement therapy, blood transfusions ▪ Prevention ▫ Vigilant detection, early removal of ticks, proper clothing LAB RESULTS ▪ Thrombocytopenia (worsens with progression of disease) OSMOSIS.ORG 521

RICKETTSIA TYPHI (MURINE TYPHUS) osms.it/rickettsia-typhi PATHOLOGY & CAUSES ▪ Rat-borne zoonotic disease transmitted to humans via flea; flu-like illness; minority of individuals require ICU-level care ▫ AKA murine, endemic, flea-borne typhus Transmission ▪ Zoonotic reservoir: Rattus typhi ▪ Vector: Xenopsylla cheopis (AKA Oriental rat flea) Life cycle ▪ Flea feeds on infected rodent → lifetime infection → fecal bacterial shedding → human contact with flea feces through breaks in skin barrier/inhalation → human disease ▫ Further human infection occurs via body lice passed human-to-human ▪ Replicates in high titers in yolk sacs of embryonated chicken eggs Pathogenesis (not well elucidated) ▪ Perivascular infiltration with lymphocytes, macrophages, plasma, mast cells (on biopsy) ▪ Vasculitis (rare) ▫ Accompanied by mural/intimal thrombi; heart, lungs, kidneys, central nervous system (CNS) ▪ Disease ▫ Mild, flu-like illness RISK FACTORS ▪ Warmer climates, seaports, major commercial areas COMPLICATIONS ▪ Shock, sepsis, myocarditis, renal/respiratory failure, severe hemolysis (associated with 522 OSMOSIS.ORG G6PD deficiency) ▪ Neurological ▫ Meningitis, meningoencephalitis, facial paralysis, hearing loss, ocular abnormalities SIGNS & SYMPTOMS ▪ Fever (8–16 days after exposure), chills, headache (commonly frontal), myalgia, rash (concurrent with fever; maculopapular, less commonly petechial; spares face, palms, soles), nausea, vomiting DIAGNOSIS LAB RESULTS ▪ ↑ erythrocyte sedimentation rate (ESR) ▪ Left shifted leukocyte count (absolute neutropenia/lymphopenia possible) ▪ Abnormal hepatic enzymes ▪ Electrolytes ▫ Hyponatremia, hypokalemia, ↑ serum creatinine TREATMENT MEDICATIONS ▪ Prompt doxycycline antimicrobial therapy ▪ Ciprofloxacin (viable alternative) OTHER INTERVENTIONS Prevention ▪ Rodent, flea eradication ▪ Rat-proofing homes, food service areas ▪ Protective clothing for occupational exposure to rats