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June 2013 1 Clinical Manifestations of Lyme Disease Michael T. Melia, MD Assistant Professor of Medicine Division of Infectious Diseases.

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Presentation on theme: "June 2013 1 Clinical Manifestations of Lyme Disease Michael T. Melia, MD Assistant Professor of Medicine Division of Infectious Diseases."— Presentation transcript:

1 June Clinical Manifestations of Lyme Disease Michael T. Melia, MD Assistant Professor of Medicine Division of Infectious Diseases

2 Disclosures Michael T. Melia, M.D. –No financial interests or relationships to disclose June 20132

3 Unapproved/Off-Label Use Ceftriaxone Doxycycline June 20133

4 Objectives By the conclusion of this presentation, the audience will be able to: –Describe the spectrum of erythema migrans eruptions –Discuss the clinical manifestations of early localized, early disseminated, and late Lyme disease –Define post-treatment Lyme disease syndrome –Understand some of the ongoing controversies in the fields of Lyme disease and tick-borne infections June 20134

5 5

6 Common tick vectors June

7 Reported Cases of Lyme Disease, U.S., June 20137www.cdc.gov

8 Reported Cases By County of Residence, 2011 June 20138www.cdc.gov

9 Notifiable Diseases U.S DiseaseReported Cases 1. Chlamydia1,307, Gonorrhea309, Salmonellosis54, Syphilis45, HIV/AIDS35, Lyme disease30, Pertussis27, Giardiasis19, S. pneumoniae16, Varicella15,427 June 20139MMWR 2012;59(53):1-111

10 Notifiable Diseases MD 2010 DiseaseReported Cases 1. Chlamydia26, Gonorrhea7, Lyme disease1, HIV/AIDS1, Salmonellosis1, Meningitis, aseptic Campylobacteriosis Strep pneumoniae, invasive Strep Group B, invasive Mycobacteriosis (non-TB)360 June MMWR 2012;59(53):1-111

11 Natural History of Untreated Lyme Disease June Morrison C et al. J Am Board Fam Med 2009;22:

12 Clinical Manifestations Early Lyme Disease, localized –Days-weeks –Erythema migrans (EM) No symptoms other than rash in 20-30% –Flu-like symptoms (70-80%) Headache = meningitis-like –Flu-like syndrome without rash Uncommon –Many unaware of tick bite June Wormser GP et al. Clin Infect Dis 2006;43:1089–134

13 Case 1 42F gardener Asymptomatic –Growing rash over 5-7d –Husband “worried” June

14 Erythema Migrans: Homogenous Rash Most Common No Central Clearing1d later following abx June

15 Typical Erythema Migrans June

16 Multiple erythema migrans June

17 June

18 Early Localized Lyme: Clinical Manifestations and Diagnosis Erythema migrans –At tick bite site, 7-14d average –>5 cm = secure diagnosis Unsure? Observe for expansion Characteristic rash + epidemiology = Lyme –Clinical diagnosis sufficient: no need for lab testing –Serology insensitive for early disease –Uncertain: Observe and obtain acute + convalescent (4-6 wk) serology June Wormser GP et al. Clin Infect Dis 2006; 43:1089–134

19 Early Lyme Disease Early disseminated Lyme –Weeks-months –Multiple erythema migrans Usually with flu-like symptoms, fever –Neurologic (Bell’s palsy, radiculopathy, meningitis) Rash may occur simultaneously –Musculoskeletal (arthritis, tendonitis, bursitis) –Cardiac (AV block, rare carditis) Objective symptoms PLUS serology or erythema migrans history June Wormser GP et al. Clin Infect Dis 2006; 43:1089–134

20 Case Presentation 53-year-old man awoke drooling on the morning of today’s urgent office visit –4-7 days earlier, he had slight flu-like symptoms and headache that resolved –No rash –Golfer –Resident of Rockingham County June

21 June

22 Diagnosis – Facial Palsy Up to 25% due to B. burgdorferi –Long Island Serology may take 4-6 wks to turn positive –If untreated, recheck if initially negative Lumbar puncture optional 99% recover without antibiotic therapy –Main role of abx: prevent late disease June Halperin JJ et al Neurology 1992; 42:1268. Clark JR et al Laryngoscope 1985;95:1341. Wormser GP et al. Clin Infect Dis 2006; 43:1089–134.

23 Early Disseminated Lyme Disease: Neurologic Manifestations CN palsies Radiculoneuritis Mononeuritis multiplex Meningitis Encephalomyelitis (rare) Optic Neuritis –children >> adults Possible associations –Hearing loss Usually afebrile CSF –<10% PMNs –May be confused with viral meningitis Most seropositive at presentation Other tests: –Helpful: CSF index, intrathecal Ab production –Not helpful: PCR June Wormser GP et al. Clin Infect Dis 2006; 43:1089–134

24 Clinical Manifestations of Late Infection(Months-to-Years Later) Arthritis –Usually large weight bearing joint –Almost 100% have knee involvement Others: hip, ankle, TMJ –100% seropositive IgG including WB –Synovial fluid > ,000 WBC May have positive PCR if not previously treated ~10% antibiotic refractory June Wormser GP et al. Clin Infect Dis 2006; 43:1089–134

25 Neurologic Manifestations of Late Infection Less common now compared with initial reports from 1970’s-1980’s Encephalopathy –Objective cognitive findings –CSF may be normal –Non-infectious? –Rare: 7 pts dx in 5 yrs by IDSA panel members Encephalomyelitis –MRI abnormalities –Rare in US: 1 pt dx in 5 yrs by IDSA panel members June Wormser GP et al. Clin Infect Dis 2006; 43:1089–134

26 More Neurologic Manifestations of Late Infection Peripheral Neuropathy –CSF normal –Stocking/glove paresthesia –Sensory findings –Intermittent radicular pain –Rare (9 patients in 5 years by IDSA Lyme panel members) All late Neuroborreliosis: expect positive serology and CSF antibodies June Wormser GP et al. Clin Infect Dis 2006; 43:1089–134

27 Neurologic Manifestations of Late Infection Caveats –MRI reports often include Lyme disease in the differential diagnosis Treat as unlikely unless proven otherwise Consider other diagnosis if Lyme serology negative –Intrathecal antibody production may persist for years despite antibiotic therapy June

28 Lyme disease: Antibiotics Antibiotic-responsive illness –10-21d for early infection: oral doxycycline/amoxicillin –14-28d for late infection: orals or ceftriaxone IV –Rare second courses of treatment needed Late manifestations from untreated infection Subjective symptoms may persist after abx –More common in women –Increased with longer duration of untreated infection –No convincing evidence of persistent infection after abx June Wormser GP et al. Clin Infect Dis 2006;43:

29 Recommended antimicrobial regimens for treatment of patients with Lyme disease. Wormser G P et al. Clin Infect Dis. 2006;43: © 2006 Infectious Diseases Society of America

30 Recommended therapy for patients with Lyme disease. Wormser G P et al. Clin Infect Dis. 2006;43: © 2006 Infectious Diseases Society of America

31 Lyme Disease Issues Diagnosis –Unlike most bacterial infections, diagnosis is clinical Bacteria hard to detect by culture, PCR, microscopy Serological tests = laboratory diagnostic standard –Up to 60-70% early Lyme (EM) seronegative –EM is only characteristic finding Absent or unrecognized in 10-30%? Treatment: Late lyme arthritis –~10% have persistent arthritis unresponsive to abx Fatigue after early Lyme Disease –25% at 3 months; ≥5% (?) after 1 year June

32 Why is Lyme Disease Controversial? 1.Subjective symptoms 2.Serologic testing 3.Syndrome bigotry 4.The internet June

33 Lyme Disease: Expectations Subjective symptoms post-treatment –Prospective studies (treated erythema migrans) 24% with mild symptoms at 3 months –Fatigue, aches, neurocognitive symptoms 5-17% with symptoms at 6-12 months Culture confirmed LD (n = 96) –81 f/u (mean 5.6 yrs): 10% with symptoms –4% with symptoms at every visit June Wormser et al. Ann Intern Med 2003; 138: 697. Nowakowski et al. Am J Med 2003; 115:91.

34 Symptoms 6-24 mos post abx June 2013A. Marques 2011 in Lyme Disease: An Evidence-based Approach, Halperin Ed,

35 Symptoms in General Populations Fatigue complaints 20-30% Arthritis 21.5% Serious pain % Fibromyalgia 2% Background problems in average population make difficult interpretation of non-specific subjective symptoms June Ann Int Med 1995; 123:81. Ann Intern Med 2001; 124:838. MMWR 2005;54:484. J Rheumatol 1993;20:710. Arthritis Rheum, 1995;38:19.

36 Lyme Is Not Unique for Causing Post-infectious Fatigue Bacterial –Coxiella burnetti (Q fever) 1 –Brucella 2 Viral –EBV 3 –Viral hepatitis 4 –Viral Meningitis 5 Parasitic –Toxoplasmosis 6 Toxin –Toxic Shock Syndromes 7 Sepsis 8 1 QJM 1998; 91:105, 2 JAMA 1934;103:665, 3 Brit J Gen Prac 2002; 52:844, 4 J Viral Hepat 1995; 3:133, 5 J Neurol Neurosurg Psych 1996; 60:495, 6 Prin Prac ID; Chap Ann Intern Med 1982;96:865 8 Crit Care Med 2000; 28:3599 June

37 788 “Lyme” Patients Presenting to a Lyme Center Active Lyme disease: 23% Prior Lyme disease: 20% Not Lyme disease: 57% Implication: Serology has poor- predictive value in patients without objective signs and symptoms June 2013Steere AS, et al. JAMA 1993;269:181237

38 Lyme Serology: Two-Tier Testing First: ELISA/EIA/IFA Screen (Total AB) Second: Western blots (immunoblots) –IgM: Need 2/3 bands: 23,39,41 kDa Caution: Use only for illness < 1 month –Positive IgM WB alone = frequent false (+) Lyme diagnosis –Cross reactive with other bacterial and non-bacterial antigens June MMWR 1995;44:590

39 Lyme Serology Western blot –IgG: Need 5 of 10 potential bands 18,23,28,30,39,41,45,58,66 or 93 kDa –More reliable test –Usually positive by wk 4-6 of infection –Only use this test for sx > 6 wks. June MMWR 1995;44:590

40 Lyme testing: False Positives Non-specific sx Westchester NY –50/182 false (+) IgM immunoblot –78% unnecessary antibiotics June Seriburi V et al. Clin Microbiol Infect 2012; 18: 1236–1240

41 Lyme Serologies Immunological test –Host response to infection –Does NOT detect actual bacteria Tests do NOT distinguish between active or inactive disease –40-60% seropositive 25 years after initial infection –No reason to follow titers routinely June Clin Infect Dis Sep 15;33(6):780-5

42 Common Clinical Scenarios with Improper Use of Serology 1)EIA only, no Western Blot (WB) 2)WB only (without EIA/IFA) –>50% population reactive to 1 or more antigens 3)Using the IgM WB alone for symptoms >1 mo –Usually false positive 4)Serology at time of erythema migrans 5)Treating tests that “stay positive” 6)Testing samples by WB other than serum June MMWR 1995;44:590

43 Longer-term Antibiotic Courses Do Not Influence Outcomes Evidence: Prospective trials, shorter term outcomes – longer therapy without benefit –Early Lyme disease 1 (n=108: PCN, TCN, erythromycin) –Erythema migrans 2 (n=180: 10d doxy +/- CTX v 20d doxycycline) –Late Lyme disease 3 (n=143: 14d vs. 28d CTX) 1 Ann Intern Med 1983;99:22. 2 Ann Intern Med : Wien Klin Wochenschr 2005; 117:393. June

44 Persistent Symptoms – Controlled Trial Antibiotic Treatment v. Placebo Two studies of patients with clinical Lyme Disease –78 pts seropositive (IgG antibodies); 51 seronegative Entry criteria –Well-documented Lyme disease –Prior antibiotic treatment –Persistent musculoskeletal pain, neurocognitive symptoms (>70%), dysesthesia, fatigue (90%) –Average duration of symptoms: 4 years Ceftriaxone 2 gm IV q24h x 30d, then doxycycline 200 mg x 60d vs. matched placebos Primary outcome: SF-36 scale measuring health- related quality of life at day 180 June Klempner M, et al. NEJM 2001; 345:85

45 Overall Outcomes d180 SF-36 *No evidence of persistent infection B. burgdorferi by Cx or PCR in blood, CSF (700 samples in 129 patients) No significant statistical difference June Klempner M, et al. NEJM 2001; 345:85

46 Cognitive Function: Lyme disease Companion study, n=129 Used cognitive objective testing, mood scores >70% gave cognitive dysfunction as complaint at study entry –Patients had normal baseline neuropsych testing –Suggests symptom report ≠ objective evidence No significant differences between groups June Kaplan RF, et al. Neurology 2003; 60:1916

47 RCT Scorecard: Long-term Antibiotics and persistent symptoms after Lyme disease treatment Long-term abx v. placebo Subjective sx OR Encephalopathy after initial treatment Antibiotics, Durable & Significant Effect Antibiotics without efficacy Klempner M, et al. NEJM 2001; 345:85 2.Krupp, LB, et al. Neurology 2003;60: Oksi J et al, Eur J Clin Microbiol Infec Dis 2007; 26:571 4.Fallon BA, et al. Neurology 2008; 70:992 June

48 Lyme Terminology Favored (IDSA & others) –Late Lyme disease Objective findings –Neuroborreliosis –Late arthritis –Post-Lyme Disease Syndrome Subjective symptoms –Fatigue –Musculoskeletal sx –Neurocognitive sx Not Favored –Chronic Lyme disease June

49 Post-Lyme Disease Syndrome Definition Lyme disease defined by CDC criteria Concluded appropriate antibiotic course 6 months after diagnosis or treatment –Fatigue –Widespread musculoskeletal pain –Cognitive problems –Substantial reduction in functional status Exclusions: –Co-infection –Prior CFS/fibromyalgia or undiagnosed similar problems –Other medical explanation –Active infectious Lyme disease (e.g., neuroborreliosis, persistent Lyme arthritis) June Wormser GP, et al. Clin Infect Dis 2006;43:

50 Case Presentation #2  41F resident of Maryland’s Eastern Shore  Ovoid rash R upper thigh late June with fever, headache, myalgia – resolved in 2-3 days  July 4: Onset of L facial palsy, otherwise well  Lyme serology negative  Doxycyline given, improved within 48h  Now worried about “co-infections” June

51 Science: How likely > 1 microbe? Depends on geography –Nymph I. scapularis ticks 2-5% –Adults 1-28% Usually B. burgdorferi + other –A. phagocytophilum –B. microti I. scapularis does not transmit: –E. chaffeensis –Bartonella spp. –Mycoplasma spp. –Rickettsia spp. June Swanson SJ et al. Clin Microbiol Rev 2006;19(4):708.

52 June Coinfection Prevalence Swanson SJ et al. Clin Microbiol Rev 2006;19(4):708.

53 Lyme Information: Internet June Cooper JD, Feder HM Jr.,Pediatr Infect Dis J. 2004;12:1105

54 June

55 Reliable Resources American Lyme Disease Foundation: –Patient and physician information –Help with physician referral to evidence-based physicians Centers for Disease Control: –Helpful clinical information, photos, statistics –Excellent FAQ section Feder HM Jr, et al. N Engl J Med 2007;357: –A critical appraisal of “chronic Lyme disease” –Reviews data and critiques the use of this term and diagnosis –Helpful physician advice –Appendix available electronically Wormser GP, et al. Clin Infect Dis 2006;43: –IDSA Guideline June


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