1. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. * For Best Viewing: Open in Slide Show Mode Click on icon or From the View menu, select the Slide Show option * To help you as you prepare a talk, we have included the relevant text from ITC in the notes pages of each slide

2. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. in the clinic Lyme Disease

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4. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. Who is at risk for Lyme disease?  Anyone exposed to Ixodes ticks infected with Borrelia burgdorferi  Also called “deer ticks” or “blacklegged ticks”  Endemic: Northeastern, upper Midwestern regions; also N. California, N. Europe, parts of E. Asia  Found in areas with animals they feed on  Birds, small mammals: immature larval & nymphal ticks  Deer: adult ticks  In woods, tall brush or grass, leaves, wood piles  Most common vector-borne disease in U.S.

5. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. What protective clothing can be worn to prevent tick bites?  Limit access to exposed skin  Tuck long pants into socks  Wear long-sleeved shirt, hat  Wear light-colored clothes  Easier to spot crawling ticks  Wear clothing impregnated with acaricide permethrin  Alternately, spray permethrin on clothing  Use insect repellants containing DEET  DEET more effective than picaridin or IR3535

6. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. How should ticks be removed to reduce the chance of infection?  Unattached ticks  Can’t transmit disease if unattached: Just brush them off  Attached ticks  With tweezers or fingers: grasp at attachment site & tug gently, constantly  Mouthparts will release, allowing clean removal in 1-2min  If tick decapitated or mouthparts left in skin  don’t worry: will shed from skin naturally  Avoid other removal methods  can lead to injury  Takes 24-48h for B. burgdorferi to move tick to host  Nightly “tick check” reduces disease transmission  Bathing ≤2h of exposure may also reduce transmission

7. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. Should antibiotic therapy be given after a tick bite to prevent infection?  Prophylaxis may be beneficial  Amoxicillin or doxycycline  Risks: medication side effects (nausea, vomiting)  IDSA: use single-dose doxycycline if all criteria met:  Tick is Ixodes adult or nymph  Attached ≥36h  Prophylaxis can be provided within 72h of tick removal  Local rate of B. burgdorferi infection in ticks: >20%

8. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. Is it possible to acquire Lyme disease more than once?  Perhaps: If treated early in course of illness  Antibodies expressed early provide only strain-specific protection  Short-lived immunity possible: EM incidence reduced in first year after Lyme disease episode  Unlikely: If late-stage manifestations occur  Signals broad antibody response to multiple antigens  If frequent tick bites: Immune response may develop  If itching occurs at bite site: B. burgdorferi less likely  Reason unclear: ? result of early recognition and removal or local immune response to the bite

9. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. Is there a vaccine for Lyme disease?  Human vaccine previously approved  Utilized outer surface protein A (OspA) of B. burgdorferi as antigen  Withdrawn from U.S. market in 2002, due to low sales  OspA vaccine remains available for dogs

10. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. CLINICAL BOTTOM LINE: Prevention…  Mainstay of prevention: avoidance  Disease transmission by exposure to infected Ixodes tick  To decrease transmission  Use repellants, insecticides  Perform nightly tick checks  Wear long sleeve tops and pants  Avoid tick habitats  Remove any attached ticks  Using tweezers or fingers, grasp at attachment site and tug gently until mouthparts release

11. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. What symptoms and signs should prompt investigation for Lyme disease?  Fever  Early disease; low predictive value because nonspecific  Fatigue and/or malaise, headache  At any stage of disease; low predictive value bc nonspecific  Headache: ? meningitis  Arthralgia  Early disseminated infection or late disease with joint involvement  Myalgia  Indicative of acute disease but nonspecific  Mono-/ oligoarticular inflammatory arthritis  Disseminated or late disease  Early antibiotic Rx reduces progression to arthritis

12. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1.  Erythema migrans  In endemic areas, highly specific, may be mimicked by tick- associated rash  Acute, localized disease (if multiple lesions indicate acute, disseminated disease) Note: Hx of witnessed tick bite not required  Carditis (acute onset, AV conduction defects)  Acute, disseminated disease  Acute neurologic involvement (cranial neuropathy, meningitis, radiculoneuropathy)  Acute neurologic dissemination  More specific if Hx of EM  Bilateral 7th nerve palsy more specific  Peripheral neuropathy, encephalomyelitis, encephalopathy (rare)  Late neurologic disease, but nonspecific

13. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. What other diseases should be considered in a patient who becomes ill after a tick bite?  Co-infection: B. burgdorferi, A. phagocytophilum, B. microti  Ticks may be simultaneously infected  A. phagocytophilum + B. microti: transmission requires less time for tick attachment than B. burgdorferi  A. phagocytophilum + B. burgdorferi or B. microti: may worsen initial presentation, but not long-term outcomes  Infection with A. phagocytophilum or B. microti  Febrile illness, w/o many other distinguishing symptoms  A. phagocytophilum can cause early leucopenia + hepatitis

14. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1.  Southern tick-associated rash illness (STARI)  Hard to distinguish from Lyme disease w/o identifying tick  Rash similar to EM + fatigue, headache, muscle & joint pain, but no reported cardiac, joint, CNS involvement  Associated with Amblyomma americanum ticks, common in southern U.S. & range expanding to Midwest, NE U.S.  Infection with Ehrlichia  New species found in Wisconsin and Minnesota  Fever, headache, fatigue, muscle aches, rash

15. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1.  Cellulitis  Urticaria  Rocky Mountain spotted fever  Cutaneous fungal infections  Local reaction to tick bites  Febrile viral illnesses  Facial nerve palsy  Viral meningitis  Heart block  Inflammatory arthritis  Peripheral neuropathy  Radiculoneuropathy  Encephalomyelitis Differential diagnosis

16. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. What diagnostic tests should be done to confirm tick-borne diseases?  Don’t test…  Patients in endemic areas with tick exposure and EM (treat with appropriate antibiotics)  Patients in endemic areas w/o tick exposure or with nonspecific symptoms (high incidence false-positives)  When testing appropriate: Use 2-step approach  1. Screen initially with ELISA  2. If positive, use supplemental Western blot test  Both tests can identify either IgM or IgG antibodies  IgM response occurs in 1-2 weeks; IgG in 2-4 weeks  In first 2 weeks: sensitivity suboptimal for IgM or IgG testing with ELISA and Western blot

17. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1.  C6 antibody test: newer, first-step ELISA  Peptide from constant region B. burgdorferi protein (VlsE)  Sensitivity equals IgM ELISA tests w/ improved specificity  But specificity <2-step testing (98.4% vs. 99.5%)  Recommended as a first step in 2-step strategy  Area with high rates B. microti & A. phagocytophilum infection  Test for co-infection  B. microti: use routine blood parasite smear, serologic testing, or PCR testing  PCR may remain positive even once asymptomatic (doesn’t necessarily indicate need for Rx)  A. phagocytophilum: use blood smears (poor sensitivity)  Human granulocytic anaplasmosis (ehrlichiosis): use serologic or PCR testing

18. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. What are the major complications of Lyme disease?  EM: >90% prevalence  Neurologic symptoms: 10%–20% (esp facial palsy)  Cardiac involvement: 4%–10%  Arthritis: ≈10% (less common now: earlier detection)  All major manifestations typically resolve over time  Nerve palsies and radiculopathy may persist  Antibiotic Rx speeds resolution of some symptoms  Rx in early stages generally = minimal sequelae

19. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. Is there a role for antibody screening to detect previous infection in asymptomatic persons?  Don’t screen asymptomatic people in endemic areas  Would yield high # of false-positive results  ? Treat asymptomatic seropositive patients  Expert opinion divided  No studies support routine Rx  Since perhaps >50% untreated patients develop arthritis, some experts recommend treatment  Others believe # of asymptomatic seropositive patients who progress to clinical disease is much less

20. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. CLINICAL BOTTOM LINE: Diagnosis…  In patients with manifestations other than EM: Diagnosis of Lyme disease depends on serologic testing  More reliable for later-stage disease  Lower sensitivity in early disease  Use two-step testing  Increases the specificity but may cause a slight decline in sensitivity  Serologic results + clinical and epidemiologic data (i.e., prior probability of disease): increases/decreases likelihood a patient has Lyme disease

21. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. What antibiotic treatment should be given?  Doxycycline  Best bioavailability and CNS penetration  Active vs. human granulocytic anaplasmosis  Extended regimen for early disseminated disease manifestations (mild carditis, isolated facial nerve palsy)  Amoxicillin (well-tolerated during pregnancy)  Cefuroxime axetil (FDA approved for Lyme disease)  Erythromycin (tolerated in penicillin allergy)  Azithromycin  Ceftriaxone (IV 1x/d for higher degree heart block, meningitis)  Cefotaxime (no risk for biliary tract disease)  Penicillin G (narrow spectrum) Efficacy equal: penicillins, cephalosporins, tetracyclines… but macrolides less efficacious

22. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. When should a patient with suspected or confirmed Lyme disease be admitted to the hospital?  High-degree heart block  To manage condition  Meningitis or arthritis  To establish Dx, determine if Lyme disease is cause  Parenteral therapy  Hospitalization often used to initiate Rx (not required)

23. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. How should cardiac complications of Lyme disease be treated?  AV conduction delays  Range: first-degree to complete heart block  Most cases resolve spontaneously, even w/o Rx  Administer antibiotics as soon as Dx established  If Dx delayed and suspicion high: start antibiotic Rx before serologic testing available  If second- or third-degree heart block  May need temporary pacing device  Patients typically admitted to hospital for IV treatment  Once block resolved, switch to oral to complete Rx course

24. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. How should the neurologic complications of Lyme disease be treated? Facial palsy  Use oral antibiotics: isolated peripheral nerve facial palsy  Use parenteral antibiotics: central facial nerve palsy  No steroids (don’t improve natural Hx Lyme facial palsy) Meningitis and severe radiculoneuritis (with/ without meningitis) and late neurologic complications (encephalomyelitis, radiculitis)  Use parenteral antibiotics for 14–28 days  Meningitis usually mild, self-limited (even without Rx) In Europe, oral doxycyline used for early Lyme disease neurologic complications, including meningitis  Studies show noninferiority to IV penicillin or ceftriaxone

25. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. What is “chronic Lyme disease,” and how should it be treated?  Continuation of symptoms after antibiotic Rx  Is chronic Lyme disease legitimate clinical entity?  Some manifestations of disease can persist  Arthritis, neuropathy, radiculopathy  Mechanism: ? damage from inflammatory response, persistent low-level infection, or autoimmune response  Fatigue commonly persists up to 1 year  Some patients report symptoms similar to fibromyalgia or chronic fatigue syndrome persist for many years  Treatment  Extended antibiotics don’t reduce such symptoms  Arthritis: may respond to anti-inflammatory or immuno- modulatory agents (methotrexate, TNF inhibitors)

26. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. What other tools are available to help clinicians manage Lyme disease?  CDC  Up-to-date information on prevention, Dx, and Rx  State-by-state statistics for transmission: www.CDC.gov/lyme www.CDC.gov/lyme  Info on patient management, including instructions on tick removal, and fact sheets for patients  Lyme Disease Foundation (www.ALDF.com)www.ALDF.com  Connecticut handbook: management of tick exposure risk for homeowners  www.ct.gov/caes/lib/caes/documents/publications/bulletins /b1010.pdf www.ct.gov/caes/lib/caes/documents/publications/bulletins /b1010.pdf

27. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. CLINICAL BOTTOM LINE: Treatment…  Symptoms resolve in most patients  Even without antibiotic therapy  Antibiotic therapy is recommended  Hastens symptom resolution, prevents late sequelae  Oral antibiotics: first-line therapy  Parenteral therapy: if severe cardiac & neurologic symptoms present