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Clinical Manifestations of Lyme Disease

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

2 Disclosures Michael T. Melia, M.D.
No financial interests or relationships to disclose June 2013

3 Unapproved/Off-Label Use
Ceftriaxone Doxycycline June 2013

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 2013

5 June 2013

6 Common tick vectors June 2013

7 Reported Cases of Lyme Disease, U.S., 2002-2011
June 2013

8 Reported Cases By County of Residence, 2011
June 2013

9 Notifiable Diseases U.S. 2010
Reported Cases 1. Chlamydia 1,307,893 2. Gonorrhea 309,341 3. Salmonellosis 54,424 4. Syphilis 45,834 5. HIV/AIDS 35,741 6. Lyme disease 30,158 7. Pertussis 27,550 8. Giardiasis 19,811 9. S. pneumoniae 16,569 10. Varicella 15,427 Lyme disease ranks sixth among the top ten notifiable diseases in the United States. Tickborne diseases are a major public health concern. Despite effective personal prevention measures such as repellents and regular tick checks, identifying effective prevention measures at the household and community levels has been challenging. June 2013 MMWR 2012;59(53):1-111

10 Notifiable Diseases MD 2010
Reported Cases 1. Chlamydia 26,192 2. Gonorrhea 7,413 3. Lyme disease 1,617 4. HIV/AIDS 1,259 5. Salmonellosis 1,086 6. Meningitis, aseptic 650 7. Campylobacteriosis 532 8. Strep pneumoniae, invasive 526 9. Strep Group B, invasive 430 10. Mycobacteriosis (non-TB) 360 Lyme disease ranks third among the top ten notifiable diseases in Maryland. June 2013 MMWR 2012;59(53):1-111

11 Natural History of Untreated Lyme Disease
June 2013 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 2013 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 2013

14 Erythema Migrans: Homogenous Rash Most Common
No Central Clearing 1d later following abx June 2013

15 Typical Erythema Migrans
June 2013

16 Multiple erythema migrans
20-25% per Wormser’s 2006 NEJM article June 2013

17 June 2013

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 <5cm tick bite hypersenstivity reaction, usually disappears within 48hrs June 2013 Wormser GP et al. Clin Infect Dis 2006; 43:1089–134

19 Wormser GP et al. Clin Infect Dis 2006; 43:1089–134
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 2013 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 2013

21 10-25% of facial palsies secondary to LD in highly endemic regions
June 2013

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 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. June 2013

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 2013 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 2013 Wormser GP et al. Clin Infect Dis 2006; 43:1089–134 24

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 2013 Wormser GP et al. Clin Infect Dis 2006; 43:1089–134 25

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 2013 Wormser GP et al. Clin Infect Dis 2006; 43:1089–134 26

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 2013 27

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 Level I evidence from RCTs June 2013 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 Treatment: Late lyme arthritis
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 2013

32 Why is Lyme Disease Controversial?
Subjective symptoms Serologic testing Syndrome bigotry The internet June 2013

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 Suggest symptoms are due to slow improvement/clearance of inflammatory processes June 2013 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 2013
A. Marques 2011 in Lyme Disease: An Evidence-based Approach, Halperin Ed, 2011

35 Symptoms in General Populations
Fatigue complaints % Arthritis % Serious pain % Fibromyalgia 2% Background problems in average population make difficult interpretation of non-specific subjective symptoms US populations Pain Northern England 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. June 2013

36 Lyme Is Not Unique for Causing Post-infectious Fatigue
Bacterial Coxiella burnetti (Q fever)1 Brucella2 Viral EBV3 Viral hepatitis4 Viral Meningitis5 Parasitic Toxoplasmosis6 Toxin Toxic Shock Syndromes7 Sepsis8 PIF well described in other infections/acute processes 1QJM 1998; 91:105, 2JAMA 1934;103:665, 3Brit J Gen Prac 2002; 52:844, 4J Viral Hepat 1995; 3:133, 5J Neurol Neurosurg Psych 1996; 60:495, 6Prin Prac ID; Chap 7Ann Intern Med 1982;96:865 8Crit Care Med 2000; 28:3599 June 2013

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 Multiple other studies June 2013 Steere AS, et al. JAMA 1993;269:1812

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 2013 MMWR 1995;44:590 38

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 2013 MMWR 1995;44:590 39

40 Lyme testing: False Positives
Non-specific sx Westchester NY 50/182 false (+) IgM immunoblot 78% unnecessary antibiotics June 2013 Seriburi V et al. Clin Microbiol Infect 2012; 18: 1236–1240

41 Clin Infect Dis. 2001 Sep 15;33(6):780-5
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 Docs repeatedly test and treat serology June 2013 Clin Infect Dis Sep 15;33(6):780-5 41

42 Common Clinical Scenarios with Improper Use of Serology
EIA only, no Western Blot (WB) WB only (without EIA/IFA) >50% population reactive to 1 or more antigens Using the IgM WB alone for symptoms >1 mo Usually false positive Serology at time of erythema migrans Treating tests that “stay positive” Testing samples by WB other than serum antigens due to cross reactivity to other bacterial/nonbacterial Ags June 2013 MMWR 1995;44:590 42

43 Longer-term Antibiotic Courses Do Not Influence Outcomes
Evidence: Prospective trials, shorter term outcomes – longer therapy without benefit Early Lyme disease (n=108: PCN, TCN, erythromycin) Erythema migrans (n=180: 10d doxy +/- CTX v 20d doxycycline) Late Lyme disease (n=143: 14d vs. 28d CTX) 1Ann Intern Med 1983;99:22. 2Ann Intern Med :697. 3Wien Klin Wochenschr 2005; 117:393. June 2013 43

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 Study stopped early at 107 of planned 260 patients, because data monitoring board concluded there would be an unlikely significant difference in study outcome with full planned enrollment June 2013 Klempner M, et al. NEJM 2001; 345:85

45 Overall Outcomes d180 SF-36 No significant statistical difference
ITT v. placebo without significant difference in outcomes with prolonged treatment. No evidence of persistent infection by Cx or PCR in blood, CSF (700 samples in 129 patients) *No evidence of persistent infection B. burgdorferi by Cx or PCR in blood, CSF (700 samples in 129 patients) June 2013 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 Companion Study June 2013 Kaplan RF, et al. Neurology 2003; 60:1916 46

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 4 Klempner M, et al. NEJM 2001; 345:85 Krupp, LB, et al. Neurology 2003;60:1923 Oksi J et al, Eur J Clin Microbiol Infec Dis 2007; 26:571 Fallon BA, et al. Neurology 2008; 70:992 June 2013

48 Lyme Terminology Favored (IDSA & others) Not Favored
Late Lyme disease Objective findings Neuroborreliosis Late arthritis Post-Lyme Disease Syndrome Subjective symptoms Fatigue Musculoskeletal sx Neurocognitive sx Not Favored Chronic Lyme disease Problems interpreting prior studies June 2013

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) Helpful as a description for audience and considered for future study, but difficulties with past studies. June 2013 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 2013

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 2013 Swanson SJ et al. Clin Microbiol Rev 2006;19(4):708.

52 Coinfection Prevalence
June 2013 Swanson SJ et al. Clin Microbiol Rev 2006;19(4):708.

53 Lyme Information: Internet
We used 15 search engines to find general information about Lyme disease. We found 251 Lyme disease websites, which we reviewed. Of these 251 websites, 19 gave general Lyme disease information and were analyzed. We evaluated the accuracy of information concerning 8 Lyme disease topics. RESULTS: Ten of the 19 websites gave accurate information and 9 of the 19 websites provided inaccurate information. There were 8 websites with the word "Lyme" in the domain name, and 7 of the 8 sites gave inaccurate information. There were 2 ".gov" websites, and both gave accurate information. June 2013 Cooper JD, Feder HM Jr. ,Pediatr Infect Dis J. 2004;12:1105

54 June 2013

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 2013


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