Clinical Manifestations of Lyme Disease

Download Report

Transcript Clinical Manifestations of Lyme Disease

Clinical Manifestations of Lyme Disease

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

Disclosures

• Michael T. Melia, M.D.

– No financial interests or relationships to disclose June 2013 2

Unapproved/Off-Label Use

• Ceftriaxone • Doxycycline June 2013 3

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 4

June 2013 5

Common tick vectors

June 2013 http://facstaff.cbu.edu/~seisen/IxodesSpp.htm

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

June 2013 www.cdc.gov

Reported Cases By County of Residence, 2011

June 2013 www.cdc.gov

Notifiable Diseases U.S. 2010

June 2013

Disease

1. Chlamydia 2. Gonorrhea 3. Salmonellosis 4. Syphilis 5. HIV/AIDS

6. Lyme disease

7. Pertussis 8. Giardiasis 9.

S. pneumoniae

10. Varicella MMWR 2012;59(53):1-111

Reported Cases

1,307,893 309,341 54,424 45,834 35,741

30,158

27,550 19,811 16,569 15,427 9

Notifiable Diseases MD 2010

Disease

1. Chlamydia 2. Gonorrhea

3. Lyme disease

4. HIV/AIDS 5. Salmonellosis 6. Meningitis, aseptic 7. Campylobacteriosis 8.

Strep pneumoniae

, invasive 9.

Strep

Group B, invasive 10. Mycobacteriosis (non-TB) June 2013 MMWR 2012;59(53):1-111

Reported Cases

26,192 7,413

1,617

1,259 1,086 650 532 526 430 360 10

Natural History of Untreated Lyme Disease

June 2013 Morrison C et al. J Am Board Fam Med 2009;22:219-222 11

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 12

Case 1

• 42F gardener • Asymptomatic – Growing rash over 5-7d – Husband “worried” June 2013 13

Erythema Migrans: Homogenous Rash Most Common

No Central Clearing 1d later following abx

June 2013 14

Typical Erythema Migrans

June 2013 15

Multiple erythema migrans

June 2013 16

June 2013 17

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 2013 Wormser GP et al. Clin Infect Dis 2006; 43:1089 –134 18

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 19

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 20

June 2013 21

Diagnosis – Facial Palsy

June 2013 • 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.

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 23

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 • >2000-25,000 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

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

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

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

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 2013 Wormser GP et al. Clin Infect Dis 2006;43:1089-1134 28

Recommended antimicrobial regimens for treatment of patients with Lyme disease.

Wormser G P et al. Clin Infect Dis. 2006;43:1089-1134

Recommended therapy for patients with Lyme disease.

Wormser G P et al. Clin Infect Dis. 2006;43:1089-1134

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 2013 31

Why is Lyme Disease Controversial?

1. Subjective symptoms 2. Serologic testing 3. Syndrome bigotry 4. The internet June 2013 32

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 2013 Wormser et al. Ann Intern Med 2003; 138: 697. Nowakowski et al. Am J Med 2003; 115:91.

Symptoms 6-24 mos post abx

June 2013 A. Marques 2011 in Lyme Disease: An Evidence-based Approach, Halperin Ed, 2011 34

Symptoms in General Populations

• Fatigue complaints • Arthritis • Serious pain • Fibromyalgia 20-30% 21.5% 3.72-12.1% 2% • Background problems in average population make difficult interpretation of non-specific subjective symptoms June 2013 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.

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 257 1995 7 Ann Intern Med 1982;96:865 8 Crit Care Med 2000; 28:3599 June 2013 36

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 2013 Steere AS, et al. JAMA 1993;269:1812 37

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

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

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 40

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 2013 Clin Infect Dis. 2001 Sep 15;33(6):780-5 41

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 2013 MMWR 1995;44:590 42

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 2003. 138:697. 3 Wien Klin Wochenschr 2005; 117:393. June 2013 43

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 2013 Klempner M, et al. NEJM 2001; 345:85 44

Overall Outcomes d180 SF-36

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Antibiotic

June 2013

Improved Unchanged Worse

No significant statistical difference

Placebo

*No evidence of persistent infection

B. burgdorferi

by Cx or PCR in blood, CSF (700 samples in 129 patients) Klempner M, et al. NEJM 2001; 345:85 45

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 2013 Kaplan RF, et al. Neurology 2003; 60:1916 46

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

0 4 1.

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 47

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 – Chronic Lyme disease June 2013 48

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 2013 Wormser GP, et al. Clin Infect Dis 2006;43:1089-134 49

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 50

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 June 2013

•

I. scapularis

does not transmit: –

E. chaffeensis

– – –

Bartonella spp.

Mycoplasma spp.

Rickettsia spp.

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

Coinfection Prevalence

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

Lyme Information: Internet

June 2013 Cooper JD, Feder HM Jr. ,Pediatr Infect Dis J. 2004;12:1105 53

June 2013 54

Reliable Resources

• • • •

American Lyme Disease Foundation

: http://www.aldf.com/ – Patient and physician information – Help with physician referral to evidence-based physicians

Centers for Disease Control:

www.cdc.gov/lyme/ – Helpful clinical information, photos, statistics – Excellent FAQ section Feder HM Jr, et al.

N Engl J Med

2007;357:1422-30.

– 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;43:1089-1134.

– IDSA Guideline June 2013 55