© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. In the Clinic Lyme Disease

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. Who is at risk for Lyme disease?  People in areas with B. burgdorferi-infected ticks  In U.S., mostly northeastern, upper midwestern regions  Travelers to environments where ticks are present  Areas frequented by the animals that ticks feed on: birds, small mammals, deer  Wooded areas, areas with tall brush or grass  Under leaves, in wood piles

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. What protective clothing can be worn to prevent tick bites?  Long pants and long-sleeved shirts  Light-colored clothes (easier to spot crawling ticks)  Clothing impregnated with or sprayed with permethrin  Tuck pants into socks  Insect repellants containing DEET  Other insect repellants seem to be less effective

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. How should ticks be removed to reduce the chance of infection?  Just brush off ticks that have not attached  If ticks have attached to host:  Grasp tick at point nearest attachment site with flat tweezers or fingers, apply gentle, constant tugging  Mouthparts will release after about a minute  If residual mouthparts are left in skin, leave those alone  Mouthparts will extrude from skin naturally over time  Nightly “tick check” may reduce transmission  Takes h for B. burgdorferi to move from tick to host

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. Should antibiotic therapy be given after a tick bite to prevent infection?  Single-dose doxycycline prophylaxis recommended if:  Ixodes adult or nymph has been attached for ≥36 h  Prophylaxis can be provided ≤72 h of tick removal  Local rate of B. burgdorferi infection in ticks >20%  Doxycycline can be used  Efficacy of prophylaxis unknown in children >8 y (don’t use doxycycline for children ≤8 y)  Alternative: watch for EM, other signs of infection  Initiate treatment if they develop Lyme disease  Outcomes excellent if treated during early EM stage

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. Is it possible to acquire Lyme disease more than once?  Patients treated early in disease can be reinfected  Antibodies are not protective  Antibodies offer only strain-specific protection  Patients with late-stage manifestations unlikely to be reinfected  Have broad antibody responses to multiple antigens  Patients with frequent tick bites may develop immune responses manifested by itching at the bite site

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. Should preexposure antibiotic prophylaxis ever be used? Is there a vaccine?  No studies support preexposure prophylaxis  Human vaccine previously approved in the U.S.  Utilized outer surface protein A of B. burgdorferi as antigen  Withdrawn in 2002 due to low sales  Available for dogs

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. CLINICAL BOTTOM LINE: Prevention...  Tick avoidance is the mainstay of prevention  To decrease transmission: use repellants, insecticides, and change behavior (wear protective clothing)  Spray acaricides to kill ticks around houses  Little evidence that these practices prevent of Lyme disease

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. What symptoms and signs should prompt investigation for Lyme disease?  Risk factor for tick exposure  Living in or frequenting endemic areas  Symptoms consistent with Lyme disease  Fever, fatigue and/or malaise, headache, arthralgia, myalgia, articular articular inflammatory arthritis  Erythema migrans  Carditis  Peripheral neuropathy  Encephalomyelitis  Many people are unaware of having been bitten

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1.  Early localized disease  3-30 days after tick exposure  Characterized by EM at the site of the tick bite  Acute localized disease with systemic symptoms  Early disseminated disease  Days after original EM lesion to a month after tick exposure  Bacteria travel bloodstream to sites distant original EM  Secondary EM, acute carditis, nervous system symptoms, articular arthritis  Late disseminated Lyme disease  Months to years after the original tick exposure  Joint and/or nervous system symptoms  Other systemic symptoms are usually not present

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. What other diseases should be considered in a patient who becomes ill after a tick bite?  Patients may be co-infected with more than one agent  Ticks may be simultaneously infected  B. burgdorferi, Anaplasma phagocytophilum, Babesia microti, Borrelia miyamotoi  Other diseases transmitted by Ixodes ticks  Encephalitis virus (Europe)  Related Powassan virus called deer tick virus (U.S.)  Febrile illnesses without EM  Southern tick-associated rash illness transmitted by Amblyomma americanum ticks

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. What diagnostic tests should be done to confirm Lyme disease and other tick-borne diseases?  Testing is not always warranted  Do not test if patients in endemic areas and potentially exposed to ticks present with EM: treat with antibiotics  Do not test if patients in endemic areas have no history of tick exposure or only nonspecific symptoms  High incidence of false+ results associated with testing  Current testing recommendation is 2-step approach  Initial screening with ELISA  If positive, follow with supplemental Western blot test  Both tests can identify either IgM or IgG antibodies

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1.  Caveats to serologic testing  Sensitivity suboptimal during first 2 weeks of disease  Don’t order IgM testing in patients with >1 month symptoms (associated with more false-positive results)  Absence of positive results not evidence patient did not have disease (early antibiotic treatment abrogates results)  C6 antibody test: newer, first-step ELISA  Sensitivity equal to IgM ELISAs during early stages  Specificity is high but less than that of 2-step testing  More sensitive than 2-step testing for certain strains in early disease and for B. burgdorferi species in Europe  Testing for co-infection is routine in areas where rates are high

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. What are the major complications of Lyme disease, how often do they occur, and how should they be diagnosed?  Major manifestations usually resolve over time  EM, facial palsy, heart block, arthritis  Recovery typically complete except for nerve palsies and radiculopathy  Antibiotic therapy speeds resolution of some symptoms (arthritis, cardiac conduction delay), not all (facial palsy)  Treatment in early stages of disease generally results in excellent outcomes with minimal sequelae  Serologic testing used to assess probability of Lyme disease as cause of these symptoms (exception: EM)

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. Differential diagnoses for for the major manifestations of Lyme disease  Cellulitis  Urticaria  Rocky mountain spotted fever  Cutaneous fungal infections  Local reaction to tick bites  Southern tick-associated rash illness  Febrile viral illnesses  Facial nerve palsy  Viral meningitis  Heart block  Inflammatory arthritis  Peripheral neuropathy  Radiculoneuropathy  Encephalomyelitis

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. What is the role of a spinal tap in the evaluation of Lyme disease?  Studies of CSF can help establish neuroborreliosis  PCR: Very low sensitivity (0%-20%); don’t use routinely  Lyme CSF:serum antibody index  Sensitive and specific but often performed or ordered incorrectly  Standard ELISAs can’t be used  CSF evaluation can r/o other causes of disease in suspected Lyme disease with meningitis symptoms  In acute Lyme disease, CSF evaluation can guide choice of antibiotics

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. Is there any role for antibody screening to detect previous infection in asymptomatic persons?  Routine serologic screening of asymptomatic persons living in endemic areas is not recommended  High number of false-positive results if used on population with low prior probability of disease  No studies support routine treatment of asymptomatic seropositive patients  Expert opinion is divided

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. CLINICAL BOTTOM LINE: Diagnosis...  With manifestations other than EM, diagnosis depends on serologic testing  Serologic testing more reliable for later-stage disease  Lower sensitivity in early disease  2-step testing increases specificity, may decrease sensitivity  Use serologic results in conjunction with clinical and epidemiologic data to make diagnosis

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. What antibiotic treatment should be given? For how long?  Efficacy equal: penicillins, tetracyclines, some 2 nd and 3 rd generation cephalosporins  Macrolides may be less efficacious  Doxycycline has best bioavailability, CNS penetration  Minocycline also good oral bioavailability, CNS penetration but associated with vestibular side effects  Consider stage of disease and organs involved  Determines oral vs parenteral therapy  Determines treatment duration

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1.  Localized disease: oral antibiotics (i.e., doxycycline 100 mg orally twice daily for days)  Early disseminated disease (mild carditis, isolated facial nerve palsy): extend oral regimen to days  Higher degree heart block or meningitis: parenteral therapy with ceftriaxone 2 g IV once daily  Severe neurologic disease: full course of parenteral therapy  Late-stage arthritis: oral antibiotics for 28 days; consider second course (oral or parenteral) if arthritis continues  Pregnant women: don’t use doxycycline  Children: use adjusted dosages and don’t use doxycycline if younger than 8 y old

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. When should a patient with suspected or confirmed Lyme disease be admitted to the hospital?  Hospitalize patients with high-degree heart block  Required for management  Consider hospitalizing patients with meningitis, arthritis  To establish diagnosis, determine Lyme disease as cause  Consider hospitalizing patients when initiating parenteral therapy

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. How should cardiac complications of Lyme disease be treated?  Atrioventricular conduction delays range from first- degree to complete heart block  Administer antibiotics as soon as diagnosis established  Prior to confirmatory serologic testing if suspicion is high  Treat second- and third-degree heart block in hospital  Use IV antibiotics  Once heart block has resolved, switch to oral antibiotics  Temporary pacing device may be needed

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. How should the neurologic complications of Lyme disease be treated?  Treat isolated peripheral nerve facial palsy with oral antibiotics  Most patients with unilateral Lyme facial palsy recover fully  Some with bilateral facial palsy have residual deficits  For patients with involvement of other cranial nerves, parenteral antibiotics recommended

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. What is "chronic Lyme disease," and how should it be treated?  Continuation of symptoms after antibiotic therapy  Fatigue, myalgia, arthralgia, memory loss, headache  Long-term fibromyalgia- or chronic fatigue-like symptoms  Highly controversial whether legitimate clinical entity  Symptoms may occur at same rate as in general population  Current recommendation for management of chronic disease: supportive care only

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1.  “Chronic Lyme disease” distinguished from well-accepted Lyme disease sequelae  Little disagreement some manifestations persist after antibiotic therapy  Arthritis, neuropathy, radiculopathy  Can be documented objectively through medical testing  Persistent arthritis after antibiotic therapy often responds to anti-inflammatory or immunomodulatory agents  Possible mechanisms for persistent manifestations  Preexisting damage from inflammatory response to infection  Persistent low-level infection  Autoimmune response

© Copyright Annals of Internal Medicine, 2016 Ann Int Med. 164 (5): ITC5-1. CLINICAL BOTTOM LINE: Treatment...  Lyme disease symptoms resolve in most patients  Even without antibiotic therapy  Antibiotic therapy recommended  To hasten resolution of symptoms  To prevent late sequelae  First-line therapy for Lyme disease: oral antibiotics  Initiate parenteral therapy if severe cardiac or neurologic symptoms are present  Can likely switch to oral antibiotics as patient improves