TICK-BORNE ILLNESSES Disease Lyme Disease Causative agent Borrelia burgdorferi Vector Ixodes Differentiating Erythema migrans symptoms Diagnosis Serology Treatment of Tetracyclines choice
Mark Tuttle 2013
Babesiosis Babesia microti + others Ixodes Hemolysis
Anaplasmosis Anaplasma phagocytophilum Ixodes Leukopenia, ↓ plt, ↑ LFTs Smear, PCR PCR, smear, serology Atovaquone/azithro Tetracyclines
Ehrlichiosis Ehrlichia chaffeensis
RMSF Rickettsia rickettsii Amblyomma, Ixodes p. Dermacentor Leukopenia, ↓ plt, Rash on ↑ LFTs, severe palms/soles PCR, smear, serology Skin bx, serology Tetracyclines Tetracyclines
PREVENTION ● ● ● ●
DEET (N,N-diethyl-m-toluamide) Self inspect Ticks require 4-24 hour attachment to transmit Ehrlichia and Anaplasma and 36-72 hours to transmit Lyme Removal: tweezers as close to skin as possible, pull straight. Do not attempt to remove retained material.
POST-EXPOSURE PROPHYLAXIS: 200mg doxycycline x1. Not generally recommended unless ALL below criteria met. ● ● ● ● ●
Attached tick identified as an adult or nymphal I xodes scapularis tick (deer tick) Tick is estimated to have been attached for ≥36 hours (by degree of engorgement or time of exposure) Prophylaxis is begun within 72 hours of tick removal Local rate of infection of ticks with B. burgdorferi is ≥20 percent (these rates of infection have been shown to occur in parts of New England, parts of the mid-Atlantic States, and parts of Minnesota and Wisconsin) Doxycycline is not contraindicated (the patient is not <8 years of age, pregnant, or lactating)
GENERAL TREATMENT PRINCIPLES: Most disease agents are susceptible to doxycycline. If no response to therapy in 48 hours, consider Babesiosis or Borrelia miyamotoi
LYME DISEASE: BORRELIOSIS
Background: First isolated in 1981 in Lyme, Connecticut by Willy Burgdorfer. Epidemiology: Northeast, Midwest US. 0.5/1000 in CT. Highest in children 5-10 yrs. In Europe, mostly Scandinavian. Biology ● Causative agent: Borrelia burgdorferi ● Vector: Ixodes scapularis, Ixodes pacificus (West US, Europe, Asia). T ick needs to be attached 48-72 hours. ● Reservoir: White-footed mouse (Peromyscus leucopus), other small mammals Clinical Manifestations ● Early localized: No systemic symptoms. Serology negative during this period. ○ Erythema migrans (3-30 days after exposure) (90%): Papule -> spreading erythema w/central clearing ■ Variable: central clearing (37% early, 80% later), uniform color (27%), vesicular (7%) ■ Southern tick-associated rash illness (STARI) (Master’s disease) causes similar rash, from Lone Star Tick Amblyomma americanum tick in SW US. Susceptible to doxycycline. ■ Differential: insect bites, nummular eczema, granuloma annulare, ringworm, and cellulitis ● Early disseminated: Starts weeks-months after exposure, lasts 14-21 days ○ Multiple erythema migrans ○ Fever, myalgia, arthralgia (not arthritis), headache, fatigue ○ Isolated cranial nerve (Bell’s) palsy (5-10%): 80% affect CN VII. Steroids unclear. 90%+ recover. ○ Meningitis: Headache, neck stiffness, photophobia, CSF pleocytosis, protein, oligoclonal bands ○ Carditis (4-10% of untreated patients): Can affect all layers of heart, but most commonly conduction. ■ 3:1 male:female predominance
TICK-BORNE ILLNESSES
Mark Tuttle 2013
Hospitalize if: PR >0.3, 2nd/3rd degree heart block, symptomatic (palpitations, syncope, CHF) Common: AV conduction delay, Wenckebach, complete heart block ● Likely directly affects AV node: no response to atropine, prolonged A-H interval (EP) ● Usually transient, and unlikely to require pacemaker (94% recover completely) ■ Uncommon: pericarditis, endocarditis, myocarditis, pericardial effusion, myocardial infarction, coronary aneurysm, QT-prolongation, tachyarrhythmia, CHF ■ Symptoms: palpitations (69%), syncope, dyspnea, chest pain ■ Unlikely to cause valvular disease (unlike syphilitic disease) Borrelial lymphocytoma: Inflammatory infiltrate typically in ear lobe or breast Meningoradiculoneuritis (Garin-Bujadoux-Bannwarth): radiculopathy (more common in Europe) ■ ■
○ ○ ● Late: ○ Arthritis (most common): mono/ologoarticular. Usually large joints. ○ Encephalitis ○ Acrodermatitis chronica atrophicans: Chronic sclerosing dermatitis (common in Europe, rare in US) Lab diagnosis ● PCR: Not sufficiently accurate to be clinically useful under nonexperimental conditions ● Serology: ELISA and reflex Western blot. Not positive during early localized stage. Transmission: Unclear if placental transmission occurs, but infected mothers have worse outcomes Treatment ● IV: For meningitis, encephalitis, failed oral, carditis (outpatient acceptable PR < 0.3 sec) ○ Ceftriaxone ● Early localized/disseminated: Without above manifestations ○ Doxycycline 100mg BID (drug of choice since co-treats HGA [but not babesiosis]) ○ Amoxacillin 500mg TID ○ Cefuroxime 500mg BID ● Late (arthritis): Doxycycline OR amoxicillin, NSAIDs ● Duration of therapy: 14-21 days for simple, uncomplicated cases. 30 days for lyme carditis or serious disease. ● May develop Jarisch-Herxheimer reaction as spirochetes are lysed and worsen for 24-48 hours after treatment, but this should resolve. ● Second-line oral agent: cefuroxime for those who can’t tolerate doxycycline and are allergic to penicilin ● Third-line oral agent: azithromycin ● Avoid doxycycline in children < 8 because of risk of tooth discoloration ● Patients on doxycycline can get dermatitis in sun-exposed areas
BABESIOSIS Background ● Named after Viktor Babes, Hungarian pathologist who first described febrile myoglobinuria in cattle in 1888. ○ Texan scientists found out it was transmitted from ticks, the first ever arthropod → vertebrate illness Biology ● A parasite, of the family Apicomplexa (same as malaria, toxo, crypto), named for complex organelles which allow host invasion, located at the apex of cells. ● Obligate intracellular parasite ● Reproduce asexually in mammalian RBCs and sexually in arthropod gut, migrate to arthropod salivary glands ● Some undergo successive divisions resulting in four abutting nuclei, or a Maltese cross Vectors ● Babesia microti (NE) (most common),B. duncani (west), divergens (south) ● Tick vector: Ixodes scapularis (same as Lyme and Anaplasmosis) ● Reservoir: white-footed mouse (Peromyscus leucopus) in NE USA. Also domestic dogs. ● Rarely, can be from blood transfusion. Even more rarely, mother → fetus transmission Clinical manifestations: asymptomatic, moderate viral-like illness (most common), severe (immunocompromised) ● Asymptomatic ● Moderate viral-like illness: Malaise and fatigue followed by intermittent fever
TICK-BORNE ILLNESSES
Mark Tuttle 2013
Causative organism: Usually Babesia microti Common symptoms: Chills, sweats, headache, arthralgia, myalgia, anorexia, cough Uncommon symptoms: Sore throat, abdominal pain, nausea, vomiting, weight loss, conjunctival injection, photophobia, emotional lability, depression, hyperesthesia. ○ Physical exam: pharyngeal erythema, jaundice, retinopathy (splinter hemorrhages), splenomegaly ■ Rash uncommon. If present, should suspect intercurrent Lyme ○ Lab findings: hemolytic anemia, hyperbilirubinemia, thrombocytopenia, hemoglobinuria ■ Leukopenia uncommon. If present, should suspect intercurrent Anaplasmosis ○ Duration: Weeks to months if untreated. Can become asymptomatic and persist for years. ● Severe: Occurs in immunocompromised, asplenic patients ○ 20% mortality rate despite therapy ○ Causative organism: Usually Babesia divergens (frequently causes severe) and Babesia duncani ○ Complications: respiratory failure (21%), DIC (18%), CHF, liver failure, AKI, splenic infarction Pathogenesis ● Red blood cell modification: The only cells infected by Babesia. Hemolysis as parasites are released. ● Immune response: IFN-y and TNF-a required for killing. B-cells/Igs not involved in immunity. Lab Diagnosis ● Blood smear: Giemsa or Wright stains see ring form. Tetrads (Maltese cross) pathogoomonic but rare ● PCR: 95% sensitive, 100% specific but expensive. May detect B. duncanii, but not B. divergens ● Serology: 1:1024 titer indicates active disease. Treatment ● Mild-moderate disease ○ Atovaquone 750mg BID and azithromycin (500mg x1 then 250mg QD) x 7-10 days ○ Clindamycin 600mg q8h and quinine 650mg q8h for 7 to 10 days ■ Often get tinnitus, gastroenteritis, limiting this regimen. ○ Should begin to improve in 48 hours, may not fully resolve for 3 months ● Severe disease ○ IV Clindamycin 600mg q8h and quinine 650mg q8h for 7 to 10 days ○ Exchange transfusion ○ If B. divergens, should empirically treat for severe disease, including exchange transfusion ○ ○ ○
ANAPLASMOSIS: Human granylocytic anaplasmosis (HGA)
Background ● From Greek an, which means 'without', and plasma, 'anything formed or molded' ● First described in the early 1930s as Rickettsia phagocytophila infecting sheep ● Renamed to Anaplasma phagocytophilum in 1990s after closer metabolic/phylogenetic analysis Biology: Caused by Anaplasma phagocytophilum. Of Rickettsiales genus. Closely related genus is Erlichia ● Has bilaminar cell wall that looks like Gram negative bacteria, but lacks peptidoglycan ● Metabolism: Cannot perform glycolysis. Relies on glutamine for carbon. ● Life cycle: Live in neutrophils and grow in vacuoles called morulae (latin for mulberry) (light microscopy) ● Vector: Ixodes scapularis (east) and Ixodes pacificus (west). ● Reservoir: White-tailed deer (Odocoileus virginianus) is the preferred blood meal Transmission: Tick bite, blood exposure (possible), never reported via blood transfusion, vertical transmission Clinical manifestations: Nonspecific febrile illness ● Onset: 1-2 weeks after tick exposure. 75% report tick bite or exposure to ticks. ● Common: Fever, shaking chills, myalgia, headache. ● Uncommon: Arthralgias, rash. If present, consider an alternative diagnosis. ● Rare (immunocompromosed): rhabdo, pancreatitis, brachial plexopathy, demyelinating polyneuropathy ● 50% require hospitalization and 17% require admission to ICU ● 0.2%-1% mortality rate ● Labs: Leukopenia, left-shift, thrombocytopenia, transaminemia (50-90% of pts), CSF usually unremarkable Lab Diagnosis: Reportable illness. Must be reported to CDC.
TICK-BORNE ILLNESSES
Mark Tuttle 2013
● Serology: Test of choice, but false negative in up to 80% of infected patients in first week of illness4 ● PCR (67-90% sensitive4) where available (not at BIDMC) ● Blood smear with Giemsa stain: 20-80% have morulae Differential diagnosis ● Viral: enteroviris, EBV, HHV-6, parvovirus B19, viral hepatitis, West Nile ● Bacterial: Disseminated gonococcus, endocarditis, meningococcemia, Mycoplasma, GAS, syphillis, typhoid ● Inflammatory: ITP, Kawasaki, TTP, toxic hematophagocytic activation syndrome Treatment: All suspected and confirmed cases should be treated ● Uniformly susceptible to tetracyclines ○ Doxycycline 100mg PO BID (drug of choice) ○ Rifampin 300mg PO BID ● Clinical improvement in 24-48 hours or suspect alternative diagnosis ● Duration: 7-14 days or three days after fever subsides. Treat 14 days if suspect Lyme coinfection Immunity: Only one patient has ever been reported to have recurrent infection
EHRLICHIOSIS: Human monocytic ehrlichiosis (HME)
Background: Ehrlichiosis first described in South Africa in 1800s. E. chaffeensis named for Fort Chaffee, Arkansas where it was first isolated. Epidemiology: Common in Mississippi, Oklahoma, Tennessee, Arkansas, Maryland. Biology: Caused by Ehrlichia chaffeensis ● Like anaplasmosis, but has morulae in monocytes, not granulocytes ● Vector: Lone Star tick (Amblyomma americanum), but also ixodes pacificus ● Reservoir: White-tailed deer (Odocoileus virginianus) Clinical Manifestations ● Similar, but more severe disease than Anaplasmosis, 42% require hospitalization, 3% mortality rate ● Common: Fever (97%), headache (80%), myalgia (57%), arthralgia (41%), N/V, abdominal pain ○ Possible association with sulfonamide antibiotics making infection worse ● Uncommon: Rash (10%-30%) spares palms/soles/face, aseptic meningitis, hemorrhage, liver failure, interstitial pneumonia, ARDS ● Labs: Leukopenia, thrombocytopenia, transaminemia (83%) Lab diagnosis: ● Test of choice: PCR (60-85% sensitive, 60-80% specific) ● Smear with Giemsa stain ● Serology: Ideally collected 3-6 weeks after infection (but antibodies absent at disease onset) Transmission Treatment ● Drug of choice: doxycycline 100mg BID x 10-14 days or 3-5 days after defervescence ● Alternative: Rifampin (children, pregnant women)
ROCKY MOUNTAIN SPOTTED FEVER: Rickettsia rickettsii
Background: Initially known as “black measles”, first recognized in 1906 by Howard Ricketts in Montana. Epidemiology: Predominantly in NE, S USA. 2.2/1,000,000 annual incidence Biology ● Causative organism: Rickettsia rickettsii ● Vector: Dermacentor variabilis, the American dog tick ● Reservoir: Dogs Pathophysiology: Invades endothelial cells, causes vasculitis (rash) Clinical Manifestations: Incubation period of 2 to 14 days with a median of 7 days ● Common: High fever (virtually all), headaches, arthralgias, myalgias, conjunctival injection, nonproductive cough, nausea, and vomiting. ○ Rash: After symptomatic for 3-5 days. Starts on wrists/ankles spreads to palms/soles. Not pruritic. ● Uncommon: meningitis, meningoencephalitis, retinal vasculitis, focal neurological signs, renal failure, pulmonary
TICK-BORNE ILLNESSES
Mark Tuttle 2013
edema, pleural effusion, hepatic dysfunction with jaundice, splenomegaly, and myocarditis ● Death in 7-15 days without treatment ● May be worsened with concurrent use of sulfonamide antibiotics ● Labs: Thrombocytopena (50%), hyponatremia Lab diagnosis: Very difficult. Must be based on clinical suspicion since serology is negative early in disease. ● Skin biopsy: direct immunofluorescence (70% sensitive, 100% specific) ● Serology: Should be positive after 7-10 days. Should be obtained in all patients 14-21 days after onset. Transmission: tick bite, removing ticks from a dog Treatment: Fever should subside in 48 hours after treatment ● Drug of choice: Doxycycline 100mg BID x 7 days. Recommended even in children ● Chloramphenicol, only if life-threatening allergy. 50-75 mg kg1 d 1 , divided in 4 doses SOURCES 1. Human Babesiosis. Infect Dis Clin N Am. 22 (2008) 469–488 2. Human Granulocytic Anaplasmosis. Infect Dis Clin N Am. 22 (2008) 433–448 3. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clin Infect Dis. (2006) 43 (9): 1089-1134. 4. Ismail, N., Bloch, K. C., & McBride, J. W. (2010). Human ehrlichiosis and anaplasmosis. Clinics in laboratory medicine, 30(1), 261-292. 5. Lyme Disease. Clin Lab Med 30 (2010) 311–328 6. Lyme Carditis. Infect Dis Clin N Am 22 (2008) 275–288 7. Erythema Migrans. Infect Dis Clin N Am 22 (2008) 235–260 8. Rocky Mountain spotted fever. Lin L - Dis Mon - 01-JUN-2012; 58(6): 361-9
