Lyme Disease: When to Test & Treat

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1 Lyme Disease: When to Test & Treat DJ Signs, MD, MSc, FACP Lyme (not Limes) Disease The most common vector-borne ID in temperate N hemisphere (US, Europe) Tick-borne, zoonotic bacterial infection Vector- Black legged ticks Ixodes scapularis - NE US, South US, North MW But is recently seen to be spreading Ixodes pacificus -Western US Causes: Borrelia burgdorferi sensu lato (NE, South, North MW) Borrelia mayonii (N Dakota, Minnesota, Wisconsin) Black Legged Deer Tick Nymphs (size of poppy seed) feed May to early June; Adults (size of a sesame seed) feed in Fall & early Spring 1

2 Feeding Black Legged Deer Tick (more than half full!) All full Question Which criteria is not necessary to prescribe doxycycline 200 mg x 1 for a tick bite 1. It was a black legged nymphal or adult tick 2. >20% of ticks in that area are infected with B. burgdorferi 3. The tick fed for >24 H 4. The bite occurred w/i 72H of presentation 5. The patient demands it Signs & Symptoms: B borgdorferi Localized Early Stage 3-30 d post tick bite Erythema Migrans (EM)-red expanding rash ~7d post tick bite in 70-90% of cases target like, expands up to 12 inches warm, rarely itchy or painful NONSPECIFIC Systemic symptoms of fatigue, chills, fever, HA, myalgias, arthralgias, lymphadenopathy 1/3 of patients never develop disseminated disease 2

3 Erythema Migrans Early Focal Lyme Early Disseminated Lyme Question Do you need to get a Lyme Antibody Test on a patient with a classic Erythema Migrans before you prescribe antibiotics? Early Disseminated Lyme Disease Days to weeks post tick bite (~ 3 wks.) ¼ of patients w/lyme present to doctor at this stage Wide spread EM lesions Neurologic Symptoms (5-20%) Bell s Palsy or other Cranial Neuropathies Aseptic Meningitis Radiculoneuritis: Shooting pains A-V nodal block (~4% of patients) Migratory musculoskeletal pain (most common) 3

4 Late Disseminated Lyme Disease Occurs Months to years after tick bite 60% have intermittent arthritis, severe joint pain with swelling Up to 5% may develop chronic neurological complaints: shooting pains numbness or tingling in hands/feet short term memory problems When to Test The patient has: 1. Compatible Clinical Illness of Disseminated Phase Symptoms 2. Risk of the disease hx of tick bite in an endemic area Do NOT test those with Erythema Migrans just treat them! How to Test Cautiously and Wisely 4

5 Testing for Lyme Disease Recommendations of the Center for Disease Control (CDC): 2-tiered serologic test in patients with a compatible clinical illness Do not perform a Wester Blot without an ELISA Testing the Tick Make sure it is a black-legged tick and not a dog tick Cost ELISA: $ 68 to $285 WB: $ million LD tests were conducted by participating laboratories in 2008, at an estimated cost for laboratory services of $492 million Hinkley,A, et al Lyme Disease Testing by Large Commercial Laboratories in the US. CID (5):676 5

6 Interpreting the Tests ELISA Becomes positive 2-8 wks post infection and remains + Lyme IgM antibody Becomes positive 2-4 wks, peaks at 8 wks, declines after 6 mos Lyme IgG Antibody Becomes positive at 6-8 wks. post infection, peaks at 4-6 mos and remains positive DESPITE THERAPY Tests not approved for Lyme Disease Capture assays for antigens in urine Culture, immunofluorescence staining, or cell sorting of cell walldeficient or cystic forms of B. burgdorferi Lymphocyte transformation tests Quantitative CD57 lymphocyte assays Reverse Western blots In-house criteria for interpretation of immunoblots Measurements of antibodies in joint fluid (synovial fluid) IgM or IgG tests without a previous ELISA/EIA/IFA Cross Reactive Ab w/other Spirochetal Diseases Serum antibodies that Xreact to B burgdorferi by Elisa or IFA tests B. hermsii (Tick Born Relapsing Fever) B. recurrentis (Louse Born Relapsing Fever) Treponemes (Syphilis, Yaws, Pinta,Treponema denticola bacteria found in the mouth that can cause gum disease and/or infection after dental procedures) Leptospires Cross-Reactivity in Serological Tests for Lyme (1987) 156 (1):

7 Other causes of False Positive ELISA Screening Test for Lyme Disease Anaplasmosis (formerly known as granulocytic Ehrlichiosis) Leptospirosis Some autoimmune disorders (e.g., lupus) Bacterial endocarditis Infection with Helicobacter pylori Epstein Barr virus oppa1 PCR NEW w/ Exciting Potential in Lyme Testing Not yet ready for prime time A PCR test targeting a Substrate Binding Protein (OppA) of Borelia species Able to detect new B. mayonii species So what about Chronic Lyme Disease? Largely undefined term that is applied by a small minority of practicing clinicians to patients with a wide variety of symptoms. Moreover, the diagnosis is not contingent upon laboratory evidence of B burgdorferi infection Lantos,P.,Auwaerter, P., Wormser,G (CID)2014(58)663 Symptoms: fatigue, diffuse pain, cognitive dysfunction 7

8 Chronic Lyme Disease A negative test is a negative test Think about what you will do with a FALSE POSITIVE test before you order a test Predictive Value of a Positive Lyme Test in a Low Prevalence Area Lantos, PM, etc CID 2015;61(9): Retrospective EMR review ( ) at Duke Results: Of appropriately obtained tests (patients with compatible clinical history) Low percent of positive tests, 2% of 297) Found a low predictive value of positive tests (10%) High rate of false positive tests (80%) Risk of Disease: Lyme Disease In Ohio Number of Black legged deer ticks are rising in Ohio Esp., in Coschocton, Holmes and Knox Counties Number of Lyme Disease cases Low incidence, but rising 0.2/100,000 in 2010 to 0.8/100, 000 in

9 Risk of Transmission: Prevalence of Infection in Ticks Prevalence of B Burgdorferi in I scapularis nymphs NE US % Ohio - 6% Risk of Transmission: Duration of Tick Feeding Duration of Tick Attachment: Time Matters classic rodent study: Ticks transmitted B. burgdorferi to 1 /14 exposed for 24 h (7%) 5 /14 exposed for 48 h (36%) 13 /14 exposed for >/= 72h (93%) Post Lyme Disease Syndrome Symptoms >6 mos post documented infection Cause unknown Study: levels of 23 cytokines and chemokines, representative of innate and adaptive immune found: IL-23 level elevations noted w/plds Strl,K. CID 2014;58 (3):372 9

10 Post Lyme Disease Syndrome No response to prolonged IV antibiotic therapy in 4 controlled treatment trials Recent Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease. Berendt, A et al. NEJM:2016; 374: wks IV Ceftriaxone plus either placebo, 12 wks Doxycycline or 12 wks clarithromycin Conclusions In patients with persistent symptoms attributed to Lyme disease, longerterm antibiotic treatment did not have additional beneficial effects on health-related quality of life beyond those with shorter-term treatment. Signs and Symptoms: B mayonii Fever, HA, Neck pain and Rash Rash- can be a diffuse macular rash Nausea +/- vomiting Neurologic effects: confused speech, profound lethargy, and or dizziness unusually high rate of spirochaetaemia (180X B borgdorferi) Not in Ohio yet but remember this bug if your patient was recently in N.Dakota, Minnesota, or Wisconsin Treatment IDSA 2006 Guidelines Early Lyme Disease (EM) Doxycyline 100 mg po q12 hrs for d Amoxocillin 500 mg TID for d Cefuroxime 500 mg BID for d Lyme Arthritis- as above but for 28 d Lyme Meningitis or early neurologic Lyme Disease: Ceftriaxone 2g q d IV x 14 d Cefotaxime 2g q8 hrs PCN G 3-4 mil q 4 hrs Doxycycline 100 to 200 mg q 12 hrs for d 10

11 Summary Test patients who have a compatible clinical illness in the disseminated phase who have known risk factors for disease Order ELISA with reflex Western Blot Never order Western Blot if the ELISA is negative Beware of non-cdc approved Lyme Tests The VAST MAJORITY of patients with a chronic fatigue like illness in Ohio do NOT have Chronic Lyme Disease Patients w/post Lyme Disease Syndrome do NOT benefit from prolonged antibiotic treatment References Hu,Lynden. Lyme Disease. Ann Intern Med. 2012;157(3): Pritt, BS, et al. Identification of a novel pathogenic Borrelia species causing Lyme borreliosis with unusually high spirochaetaemia: a descriptive study Lancet ID.2016, (10):1016. Wormser GP,et al. CID 2011,(10):1086 Wormser, GP et al IDSA Guidelines: Lyme Disease. CID. IDSA (2006) 43 (9): Wormser GP, Single tier testing with the C6 peptide ELISA kit compared with two tier testing for Lyme disease. Diagn Microbio ID 2013; Magnarelli, et al. JID (1987)156(1): Lantos, PM et al Poor positive predictive value of Lyme Disease serologic testing in an area of low disease Incidence. CID (9) Lantos,PM, et al A systematic review of B burgdorferi morphologic variants does not support a role in Chronic Lyme Disease. CID 2014;58(5): Piesman, J et al.duration of tick attachment and Borrelia burgdorferi transmission.j clin Micro 1987;25(3): 557Regulators of Expression of the Oligopeptide Permease A Proteins of Borrelia burgdorferi Medronal, M. Regulators of Expression of the Oligopeptide Permease A Proteins of Borrelia burgdorferi J.Bacteriology 2007:189 (7):2653 Mark S. Klempner, M.D., Linden T. Hu, et al. Two Controlled Trials of Antibiotic Treatment in Patients with Persistent Symptoms and a History of Lyme Disease. N Engl J Med 2001; References (pg 2) Berendt, A et al. Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease. NEJM:2016; 374: Strl,K. Elevated Levels of IL-23 in a Subset of Patients With Post Lyme Disease Symptoms Following Erythema Migrans CID 2014;58 (3):372 For IDSA Guideline- go to 11

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