Kenneth L. Woods, DO, MPH

Chair, Department of Medicine

Medical Director, Infectious Disease

Chair, Infection Control/Prevention Committee

Chair, Antibiotic Stewardship Subcommittee

Trinity Health System

Steubenville, Ohio

Email: kwoods@trinityhealth.com

Disclosures

Nothing to disclose.

Objectives

Discuss Lyme Disease and practical implications in

Primary Care.

Review diagnostic testing for Lyme Disease.

Discuss the management of Lyme Disease and

prevention/prophylaxis strategies.

Lyme Disease - Background

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History:

First recognized in 1976, in Lyme, CT.

Recognized as spirochete from tick vector in 1982.

Spirochete bacterium Borrelia burgdorferi.

Ixodies scapularis (Blacklegged or deer tick) vector.

Horizontal vector with white footed mouse, white tailed

deer, chipmunks, squirrels. (humans are end host)

Most common vector borne disease in US.

Most common tick-borne disease in N. America & Europe.

6th most common reportable disease in US.

>40,000 cases / yr in US.

Lyme Disease

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Ixodies scapularis (Blacklegged or deer tick).

Very small

Borrelia burgdorferi harbors in tick’s salivary gland.

Lyme Disease

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CDC 2016 incidence map

Lyme Disease

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Lyme Disease - seasonality

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*CDC through 2016

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Spirochete Borrelia burgdorferi.

Motile, corkscrew-shaped bacterium

Up to 11 flagella

Small linear chromosome

Grows best at 33 C, on Barbour-Stoenner-Kelly medium,

but rarely grown (poor sensitivity).

Giemsa or Wright stain.

Can stain weakly Gram negative.

Larger than most spirochetes.

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Spirochete Borrelia burgdorferi.

Pathogenesis / Virulence factors:

Osp (outer surface protein) A-F.

Helps adapt to and survive different environment

between arthropod to mammal.

Decorin binding proteins that allow to bind to collagen

especially in heart, nervous system, and

joints/synovium.

Depends on host for nutritional requirements.

Incubation period 3-32 days.

Multiplies locally at site of inoculation.

Lyme Disease

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Spirochete Borrelia burgdorferi

Dissemination takes days to weeks, but has been

recovered from bld, CSF, synovial fluid, myocardium,

retina, muscle, bone, spleen, liver, brain…

Affected tissues often show lymphocyte infiltration,

vasculitis, or hypervascular occlusion.

Can inactivate complement cascade.

Extensive antigenic variation/changes to minimize

immune recognition

IgG can take months to develop.

Increase in mononuclear cells in peripheral blood, IFN-γ

Host defense mostly via B-cell response, complement

fixation, and opsonization.

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Lyme Disease – Stages

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Three main stages:

1. Early/Localized:

Avg ~7 days after tick bite.

Erythema migrans rash in ~70-80%.

○ Most patients do not recall tick bite.

○ Mostly groin, thigh, axilla.

○ Starts without the center clear ring

○ Rash can be pruritic (rarely) or hot or even painful.

○ Rare to see EM on head/face – more common to be

linear streaking in the head/face region.

○ Can be multiple lesions.

Headache and joint aches common.

Lyme Disease

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Erythema migrans

• Usually appears 7-14 days after tick attachment

(usually takes attachment >32h).

• Rare to be <5 cm diameter.

• Rare to occur <48 h from tick bite, and more likely

hypersensitivity reaction if occurs rapidly.

Lyme Disease – Stages

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2. Disseminated/late infection:

Days to weeks after tick bite.

EM rash similar to early disease, but less prominent,

smaller, and lack indurated or clear center, can be

multiple skin lesions, malar rash, or urticaria.

Often this stage is where the malaise, myalgia, fatigue,

fevers, chills, conjunctivitis, lymphadenopathy develop.

Musculoskeletal pain (60%), headache/neck stiffness,

hepatitis, splenomegally, cough, testicular swelling,

hematuria, proteinuria.

Rare to get Lyme arthritis (<<10%) but mostly unilateral

knee.

Lyme Disease – Stages

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2. Disseminated infection/Neuroborreliosis:

10-15% of untreated pts progress to neurological sx

(meningitis/encephalitis, cranial neuritis (esp CN-VII),

tingling or neuropathies, short term memory fx

CN-VII palsy does not equate to Neuroborreliosis.

Focal neuro sx/sx.

CSF shows lymphocytic pleocytosis.

Lyme Disease - Stages

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2. Disseminated-Cardiac involvement/myocarditis:

○ 5-10% of untreated pts progress to cardiac sx with

classic finding of varying degree AV block and

myocarditis. (avg time 2 mo.).

○ ~54% have at least intermittent 3rd degree block.

○ 3:1 Male:female dominance.

○ Pathology shows perivascular interstitial infiltration as

well as AV node infiltration.

○ Cardiac MRI associated with epicardial contrast

enhancement (as opposed to subendothelial

enhancement with ACS/ischemic heart dis).

Lyme Disease - Stages

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3. Late/persistent:

~60% of all patients.

Sx include myalgia/arthralgia/joint swelling, esp large

joints with knee #1.

Intermittent sx that usually resolved by 1-2 yrs.

Lyme Disease – Stages

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Post Lyme syndrome – controversial.

Also called PTLDS (Post-treatment Lyme Disease

Syndrome).

Previously “chronic Lyme disease”.

Sx’s lasting >6 months.

>25% of patients will have sx’s >3 months after treatment.

Most common sx: HA/joint aches, fatigue, neuro-congnitive

disturbances.

Several studies looking at tissue/DNA/PCR/Culture without

evidence of active infection after abx (all were positive

before Abx treatment).

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Transplacental transmission has been reported although

very rare (2 cases).

Co-infection is not uncommon, Anaplasma

phagocytophilum (Ehrlichiosis), Babesia microti (RBC

parasite).

Possibly as high as 40% in some areas are

coinfected.

Clues to co-infection are high leukocytosis or

leukopenia, thrombocytopenia, anemia, fever >48h

after treatment.

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Diagnosis

Lyme Disease - Diagnosis

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Early dx largely based on clinical basis.

Serology not recommended if EM rash.

Lyme Disease - Diagnosis

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2-step lab testing algorithm (most labs automated).

1. EIA (enzyme immunoassay) for Lyme Ab.

○ IgM peaks 2-4 wks, normalizes 6-8 wks (?).

○ IgG peaks 4-6 months.

○ False + with Syphilis, RA, SLE, EBV, SBE reported.

2. +ELISA is followed by Western Blot.

○ WB IgM bands (2 for dx): 23, 39, 41 kDa.

○ WB IgG bands (5 for dx): 18, 23, 28, 30, 39, 41, 45,

58, 66, 93 kDa.

If neg EIA, no WB is needed.

Lyme Disease - Diagnosis

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Lyme Disease - Diagnosis

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PCR is available.

○ Poor sensitivity for serum PCR or early/localized

disease.

○ Good sensitivity for organ level/invasive disease.

CSF, myocardial tissue, synovial fluid (superior to

culture).

Lyme Disease – Neuroborreliosis Dx

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Should not rely on clinical sx/sx alone; guidelines

recommend if clinical suspicion perform CSF analysis

and only consider Neuroborreliosis dx if CSF supports.

Most common indication for LP is severe/prolonged

headache w/ positive Lyme serology/compatible sx.

CN-VII palsy does not equate to Neuroborreliosis.

Lyme CSF DNA by PCR (good sens/spec).

Lyme CSF Ab production (less sensitive unless very late

into course of disease where DNA rarely detected).

CSF: elev protein, >100 WBC, norm glucose.

Almost all CNS Lyme cases have positive serology.

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Treatment

Lyme Disease - Treatment

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IDSA and CDC Guidelines recommend treating based on

clinical findings if early disease.

Early disease (adults & children >8 y.o.):

Doxycycline 100 mg PO bid x 14d (BEST)

(10-21d acceptable)

Amoxicillin 500 mg PO tid x14-21d

Cefuroxime (Ceftin) 500 mg PO bid x14-21d

Early disease children <8 yo:

Amoxicillin 50 mg/kg/d divided TID x14-21d

Cefuroxime (Ceftin) 30 mg/kg/d divided BID x14-21d

Doxycycline Precautions

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Given that Lyme disease is mostly seen in summer/sunny

months, MUST caution patients on PHOTOSENSITIVITY.

Relatively contraindicated if pregnant, breast feeding, or

age <8 y.o.

Higher rates of GI upset, minimized by taking with food.

Esophageal irritation reported, minimized with 6-8 oz H20

and remain upright x30 min after dose.

Lyme Disease – Treatment Pearls

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~15% get Jarisch-Herxheimer-like reaction 1st 24h of Rx.

A lot of data on short courses of Doxycycline are equal

effectiveness so 21d no longer recommended w/o

neuro/cardiac/Lyme arthritis.

Longer durations have no benefit to reduce symptoms

but have increased adverse effects, mortality and other

complications.

Ceftriaxone not superior to PO’s but is effective.

CTX x1, then 10d doxy = 400% inc diarrhea. (IV not

better!)

Lyme Disease – Treatment Pearls

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Azithromycin/clarithromycin less effective so avoid. Maybe

4th line options.

First generation cephalosporins, FQ’s, bactrim are all

ineffective.

Persistent/severe joint sx “can consider" additional 2 wks

of PO ATB’s, but not exclusively recommended.

No repeat ATB’s recommended if recurrent symptoms.

Recommend no treatment for seropositive patients that

are asymptomatic.

IgM/IgG can remain positive for years.

Lyme Disease – PLEASE trial

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Persistent Lyme-Empiric Abx Study of Europe 2014.

Randomized, double-blind, placebo-controlled trial.

N=280 patients.

Followed through 26-wk post treatment.

Compared short vs. long duration abx (2 wk vs. 12 wk).

PLEASE trial (Persistent Lyme-Empiric Abx Study of Europe. BMC Infec Dis 2014, 14(543).

Berende A, et.al. Randomized Trial of Longer-Term Therapy for Symptoms Attributed to

Lyme Disease. NEJM. 2016, Vol 374(13): 1209-1220.

Lyme Disease – PLEASE trial

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No differences in:

Quality of life scores (RAND-36).

Patient reported sx’s.

Neuropsychological assessment.

Objective fatigue measures/activity monitoring.

68% of patients reported at least 1 possible adverse drug

event.

Diarrhea 32.5% (note 1 episode of diarrhea counted).

Nausea 15.7%.

Rash 11%; Photosensitivity 6.8%.

Mucosal yeast infection 7.1%.

PLEASE trial (Persistent Lyme-Empiric Abx Study of Europe. BMC Infec Dis 2014, 14(543).

Berende A, et.al. Randomized Trial of Longer-Term Therapy for Symptoms Attributed to

Lyme Disease. NEJM. 2016, Vol 374(13): 1209-1220.

Lyme Disease – Treatment

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Neuroborreliosis/CNS Lyme disease:

Ceftriaxone 2 gm IV daily for 14 days (historically)

(*newer evidence* or until clinical improvement, then

can consider complete 21d course with PO doxy).

PCN-G 24M units/day IV x14 days (normal renal fx).

Doxycycline 100-200 mg PO bid may be equivocal to IV

Ceftriaxone. IV Doxy should not be needed.

Steroids do not appear to add any benefit (CNS or CN-

VII palsy related Lyme disease)

Lyme Disease – Treatment

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Lyme Myocarditis:

Temporary pacer often required, average duration

needed is 3 days – 6 wks.

Ceftriaxone 2gm IV daily or PCN-G 24m units/day IV x

14 days or until clinical improvement in heart block.

(very little data to support; no RCT’s)

Followed by Doxycycline 100 mg PO BID to finish 14-21

days total abx course.

Cardiac involvement usually reverses quickly with

treatment (3-7 days). However, 9+ deaths reported.

Lyme Disease – Treatment

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Lyme arthritis:

Should be treated for up to 28 days w/ PO’s (same as early).

(Not arthralgia, but septic Lyme arthritis).

IV Abx compared to PO showed no different in outcome

other than increase adverse effects and cost.

Avoid intra-articular steroid injections (worsens

outcome).

NSAIDs recommended.

No recommendation on systemic steroids.

Related joint pain may persist for years (>5 yrs has

been reported)

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Prevention

&

Prophylaxis

Lyme Disease – Prevention

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Most useful prevention is avoiding exposure.

Decreased tick habitat.

Protective clothing (tight fitting, tucked shirts, pants tucked

into socks, etc.).

DEET based insect repellant.

Daily “tick checks”

Early and complete tick removal. If tick mouth parts not

fully removed from skin, topical disinfectant application

only.

Human Lyme disease vaccine 1999-2002 (not avail).

Lyme Disease – Prophylaxis

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Routine abx prophylaxis or serology testing in absence of

disease (signs/symptoms) is not recommended.

No universal recommendation for post-tick bite

prophylactic ATB’s.

Can consider if: (must have ALL)

1. High endemic area with tick infection rate >20%,

2. Known I. scapularis tick attachment >36h.

3. Doxycyline not contraindicated, AND

4. Abx started within 72 hrs.

If all 4 of the above Doxycycline 200 mg PO x1 (for

adults/children age >8 y.o 4mg/kg max 200 mg).

No other abx recommended (only doxy).

Testing of ticks is NOT recommended (research only)

Berende A, et.al. Randomized Trial of Longer-Term Therapy for Symptoms

Attributed to Lyme Disease. NEJM. 2016, Vol 374(13): 1209-1220.

CDC Website (Accessed 10/2018): https://www.cdc.gov/lyme/index.html

Mandell’s Principles and Practice of Infectious Diseases. 8th ed. 2015.

Marks C et.al. Antibiotic Treatment for Chronic Lyme Disase-Say No to the

DRESS. JAMA 2016. Dec 1;176(12): 1745-1746

NIH Website (Accessed 10/2018): https://www.niaid.nih.gov/diseases-

conditions/lyme-disease

PLEASE trial (Persistent Lyme-Empiric Abx Study of Europe. BMC Infec Dis

2014, 14(543).

Wormser G, et.al. The Clinical Assessment, Treatment, Prevention of Lyme

Disease, HGA, and Babesiosis: Clinical Practice Guidelines by IDSA. CID

2016:43, 1089-1134.

References:

E-mail: kwoods@trinityhealth.com