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7/12/2018
Lyme Disease
Update 2018
Amy Prunuske PhD– Medical College of Wisconsin
Department of Microbiology and Immunology
Adam Clements DO – Aspirus
Lyme Disease Cases- 2016
Centers for Disease Control and Prevention
Disclosures/conflicts
Adam Clements DO
I no conflicts of interest or disclosures to disclose
Amy Prunuske PhD
Tick Surveillance with Minnesota Department of Health
Developer- Biomeme RT-PCR test to screen ticks
STEM outreach at University of Wisconsin-Stevens Point
1
7/12/2018
• A 30 YO male presents to
clinic 4 days after cutting
wood in August
• Mildly tender rash
• Fever 102.0 F
• Fatigued
• No respiratory symptoms
• History of Lyme disease
treated in June with
doxycycline
Rash on day 4 post exposure
Measures 7 cm in longest dimension
Select the most appropriate next step
A Treat with topical clotrimazole/betamethasone cream
B Draw a Lyme titer and a tick panel. Give him a prescription for
doxycycline to fill later if titers are positive
C Tell him you have a high suspicion of Lyme and treat with doxycycline
without testing
D Refer to Dr Bowler
2
7/12/2018
What would the serology look like?
A +IgM, -IgG
B +IgM, -IgG
C +IgM, +IgG
D Need more information
Objectives
• Discuss epidemiology of Lyme disease
• Discuss microbiology and life cycle of Borrelia burgdorferi
• Discuss clinical presentation of Lyme disease
• Differentiate between stages and review complications of Lyme
disease
• Discuss diagnostic testing for Lyme and interpretation of serology
• Mention other common tick-borne infections in Wisconsin
• Answer any of your questions (Ask at any time)
3
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Epidemiology
4
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5
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County Total cases in Incidence / Aspirus facilities
2016 100,000
Marathon 101 74 Wausau hospital,
others
Lincoln 41 147 Merrill Clinic
Oneida 58 163 Rhinelander clinic
Portage 62 88 Stevens point
clinic, walk-in, ER
Langlade 15 78 Langlade hospital,
Elco clinic
Wood 47 64 Riverview hospital
Taylor 18 88 Medford hospital
6
7/12/2018
“We know that routine surveillance only gives us part of the picture and that the true number of illnesses is much greater,”
Paul Mead, MD, MPH, chief of epidemiology and surveillance for the CDC’s Lyme disease program. Estimate 300,000
cases/yr
Microbiology
and
Transmission
7
7/12/2018
Which of the following pathogens causes Lyme disease?
A Anaplasma phagocytophilum
B Babesia microti
Borrelia burgdorferi
C Spirochetes transiently enter bloodstream at low levels
Difficult to culture- BSK-H media and takes >6 days
Powassan virus
D
All of these pathogens are transmitted by ticks and co-infections are increasing
Future research: prevalence of co-infections and
characterization of new genospecies of Borrelia
8
7/12/2018
Transmission of Borrelia
burgdorferi to humans is
mediated by nymph and
adult ticks.
Nymphs can be
difficult to detect.
Locally 30% of ticks carry
Borrelia burgdorferi
Tick identification can help characterize disease risk
Ixodes scapularis Amblyomma americanum Dermacentor variabilis
9
7/12/2018
Lyme Stages
•Early localized
•Early disseminated
•Late disseminated
•Post-treatment Lyme disease syndrome
Early localized disease
Erythema migrans
80% of seropositive patients
Usually within 7-14 days of tick exposure.
1/3 will have central clearing,
Confluence, ulceration and necrosis may occur.
Constitutional symptoms
Fatigue 54%
Anorexia 25%
Headache 42%
Neck Stiffness 35%
Myalgias 44%
Arthralgia 44%
Regional lymphadenopathy 23%
Fever 16%
107/12/2018
Early disseminated disease - Skin
-15-20 % of patients with
an EM rash will have
multiple at presentation
-Rash is due to
hematogenous spread, not
from multiple ticks
-Typical symptoms usually
accompany the rash
(similar to one EM rash)
https://emedicine.medscape.com/article/330178-clinical
8-year-old patient from Athens presents to walk-in with a recent
tick bite, normal vitals, erythema migrans, a large unilateral joint
effusion, and restricted range motion.
A Prescribe outpatient Doxycycline for 14-21 days
B Prescribe amoxicillin for 28 days
Admit to the hospital for IV ceftriaxone and surgical washout
C
Order Lyme titer, tap the joint and perform PCR
D
117/12/2018
Early disseminated – Arthritis
• Knee the most likely joint up to
60% of untreated adults and
children will progress to arthritis
• 15-20% of cases present with
arthritis
• Borrelia don’t create toxins or
proteolytic enzymes, joint
damage is caused by
inflammation and host response https://www.aerzteblatt.de/int/archive/article/63240
Septic arthritis vs Lyme arthritis (Children)
Joint fluid
Neutrorphils
127/12/2018
Septic arthritis vs Lyme on MRI (Children)
I had a tick bite last week,
and now my face is droopy
A Treat with doxycycline
B Send immediately to the ER
Treat with doxycycline and steroids
C
Order a lyme titer treat with doxycycline if
D positive
JEMS.com
137/12/2018
Facial Palsy
• Most common neuro manifestation, though others
are significantly under-reported
• pathophysiology of Lyme induced facial palsy is
different than idiopathic/viral facial nerve palsy
• Lyme facial palsy is humorally mediated (antibodies)
• Idiopathic/viral is T cell mediated
• 2 tiered testing assay is very sensitive for Lyme
• Patients taking steroids with antibiotics vs
antibiotics alone had worse long term outcomes
and longer time to symptom resolution
• Treatment for Lyme facial palsy is the same as other
non-severe manifestations
Laryngoscope. 2017 Jun;127(6):1451-1458.
doi: 10.1002/lary.26273. Epub 2016 Sep 6.
Lyme meningitis
Rare, even in endemic areas it represents .1-1% of all confirmed lyme cases
Treatment is typically IV Ceftriaxone
2 tiered testing and PCR are both very sensitive and both recommended
147/12/2018
35 Year old male DNR warden presents to ED in July with fever 100.8 one
episode of syncope. Other symptoms include knee swelling, left shoulder
pain, malaise, and headache. Normal exam including neuro.
A Treat presumptively with doxycycline and arrange close follow-up
B Order labs, EKG, admit to Dr Clements
Treat with amoxicillin
C
Arthrocentesis of the knee, cell count, gram stain, lyme PCR, treat
D based on the results
Cardiac Lyme
Direct invasion of heart tissues
Can involve any layer of the
heart.Pericarditis, myocarditis and
endocarditis have all been
reported
Myocarditis most common
Less than 10% of Lyme cases
involve the heart
157/12/2018
Third degree heart block
Male: female ratio 5:1
Median time from symptom onset to third degree block is
14 days
Median time to resolution is 6 days with treatment
Only rarely is permanent pacing required,7/12/2018
A 35 YO is seen in the walk-in clinic with a 5 month history of fatigue,
intermittent arthralgia, proximal myalgias, headache, and subjective fevers.
Her temperature is 99.6°. Exam unremarkable. Laboratory studies show:
CBC- WNL, ESR 24, comprehensive panel WNL, Lyme WB IgM (+) IgG WB (-).
The most appropriate therapeutic intervention is:
A. Start ceftriaxone for late Lyme disease.
B. Start doxycycline for late Lyme disease.
C. Provide reassurance and symptomatic care.
D. Page Dr Bowler, STAT
The patient is given a four week course of doxycycline 100 mg b.i.d by a
different provider. She returns to you two months later with the same
symptoms. Her symptoms improved on doxycycline, but then returned again
after.
Repeat lyme serology WB IgM (+) IgG (-)
A.Give four weeks of ceftriaxone for chronic Lyme disease.
B.Provide reassurance and symptomatic care.
C.Give another four week course of doxycycline for chronic Lyme disease.
D.Refer for ID consult.
177/12/2018
Only muscle pain
and difficulty
formulating ideas
was statistically
more common in
the patients with
Lyme.
These symptoms
are unexplained
Stop-LD
trial
Extra month of ceftriaxone
in patients with symptoms
persisting > 6 months
Appears to be a benefit in
fatigue
Groups not well matched,
not well powered
No benefit in cognitive
function
Significant adverse effects
Authors recommended
against long term
antibiotics
187/12/2018
NEJM July 2001
Patients with poor QOL scores
Ceftriaxone for 30 days, followed by doxy for 60 days
Minerva Med - Amox vs placebo in patients with low QOL scores
Authors calculated 90 patients in
each group would need to complete
the study to achieve adequate power
Only about half the patients finished
the study
This study is one of the more
commonly cited articles people use to
justify prolonged antibiotics in lyme
patients
Both groups improved
quite a bit
Looks like the amoxicillin
helped!?!
197/12/2018
Post-treatment lyme disease syndrome
• Up to 30% of patients will report some persistent symptoms after completing
treatment. Muscle pain and cognitive slowing are most common
• Quality of life is clearly lower, symptoms are real
• This is frequently referred to as “chronic lyme” but there is limited evidence
that Borrelia persist in patients
• No long term benefit of antibiotics when compared to placebo
• Antibiotics can cause unnecessary harm
Diagnostic testing
Everyone currently sleeping please wake up!
Ordering and interpreting diagnostic tests is the most challenging part of treating
Lyme disease
207/12/2018
Why not just test everyone?
Prices at AWH $405 in lab costs alone for one
positive screen. $131 for each
Lyme antibody screen: $131 negative screen not including the
Lyme western blot: $274 cost of the tick panel which is
often ordered when Lyme is
Doxycycline: $30-60 suspected.
PCR has poor sensitivity
Tick ID: $66 on peripheral blood
Tick Panel PCR: $364
IgG from a previous infection will Misdiagnosis
persist for prolonged periods in
cured patients
Early in the disease course ELISA
screening has low sensitivity
217/12/2018
Testing at Aspirus - 2017
Lyme IgG & IgM Antibody Lyme IgG & IgM Western
(Screen) Blot (Confirmation)2
Total Orders 5865 Total Orders 636
Negative 5528 IgG Positive 201
Positive 382 IgM Positive 219
Equivocal 36 2. Many orders are reflexed from Positive or
Equivocal IgG/IgM screen. Results may be
2017 - 5528/5865 = 94% negative positive for IgG and/or IgM
2016 - 2962/3228 = 92% negative
1.4 million dollars spent on
2015 - 3340/3688 = 91% negative screening tests in the last 3 years
Lyme PCR testing at Aspirus
Lyme PCR Source of PCR Samples
Total Orders 34 Peripheral blood 14% sensitive
123
Positive 4 39 CSF 73% sensitive
Inhibited3 3 50 Joint fluid 83% sensitive
3. Interference in the sample that
prevented testing
227/12/2018
Antibody response following infection
5 day to 2 week
lag time to IGM
production
depending on
the patient
In patients with previous infection knowing if and when they were treated is IgG Titers may be elevated
important. If treated early they may not have made antibodies. If treated for years, persistence of
late they should have IgG but likely stopped making IgM so a new IgM signal antibodies doesn’t indicate
may be diagnostic of a new infection chronic or repeat infection
Sick patient
Low pretest Intermediate pretest High pretest
probability probability probability
Don’t test (unless/until Screen
Don’t test
pretest probability Start with a sensitive
changes) (Treat)
test - Elisa
Confirm Pretest probability > Test
Low specificity of screening tests
sensitivity.
False positives > True positives Use a specific test –
False negatives > True negatives
Western blot
237/12/2018
When and
who to test
should be
based on
pretest
probability
The Journal Of Family Practice VOL 54, NO 12 / DECEMBER 2005 Thomas Bayes (1701–1761)
Testing patients Sensitivity after
with an EM rash several weeks
isn’t sensitive due improves but still isn’t
to lack of very high. Repeat
seroconversion testing may be
necessary if Infection
is suspected
Specificity is high across all
populations. If you have a positive
test you can be confident they are
seropositive. Be careful
interpreting seropositivity in
patients in endemic areas or with
known previous infection
AAFP June 1, 2012 Volume 85, Number 11
247/12/2018
False positive western blots - as high as 27.5%
Control
sample
uninfected
Patient
False positive western blots can occur due to infections including Epstein Barr which
is common and causes many similar symptoms. Over reading of faint or misaligned
bands can also cause a negative test to be read as positive. CMI December 2012 Volume 18, Issue 12, Pages
1236–1240
Sensitivity
and
specificity
of PCR by
specimen
source
Aguero-Rosenfeld Et Al. Clinical Microbiology Reviews, July 2005, p. 484–509
257/12/2018
Treatment
267/12/2018
Outpatient or oral treatment regimens
Babesia coverage
Drug Dose Duration Anaplasma coverage clindamycin plus quinine or
atovaquone plus azithromycin
Doxycycline 200mg/day 14-21 days YES NO
Do not use in children 4mg/kg/day (10 is adequate7/12/2018
Prevention
(no bite, no infection)
Which of the following does NOT repel ticks?
A Citronella candle
B Permethrin treated shirt
C 20% DEET
Grapefruit essential oil
D
287/12/2018
Prevention strategies
• Decrease questing habitat: remove leaf litter,
keep grass short, wood chips
• Cover skin with light colors, full-body tick checks,
remove with tweezers, shower, and place clothes
in dryer at high heat for 1 hr
• Repellants: Permethrin and 20% DEET
• Lyme vaccine: not available since 2002 and
immunity wanes over time
Closing thoughts from Dr Bowler
•Lyme serology is frequently negative at the time of initial presentation, and should not dissuade from treating for Lyme
disease in the right clinical setting (even in the absence of ECM). In the absence of ECM, a repeat (“convalescent”) serology
two weeks later will be positive if the syndrome is due to Lyme disease.
•ECM is virtually pathognomonic for acute Lyme disease, and serologic testing is generally not necessary.
•Prompt treatment of early Lyme disease is nearly always (95%) curative, and prevents chronic sequelae.
•Chronic somatic symptoms that arise after delayed treatment of Lyme disease are immunologic in nature, and repeated
courses of antibiotics should not be given.
•Once positive, Lyme serology (EIA and IgG WB) will remain positive for years (indefinitely ?), and does not indicate chronic
infection.
•In the presence of chronic symptoms of greater than one months duration, an IgM WB should not be obtained, or if it is, the
results disregarded.
–A negative IgG WB excludes Lyme disease as the cause chronic symptoms.
•In serologically or clinically (ECM) confirmed Lyme disease, a positive IgM WB can persist for > 12 months and does not, in and
of itself, indicate persistent, or new Lyme infection.
•Be alert to the possibility of co-infection with Anaplasma or Babesia.
–The “footprint” of Anaplasma is: leukopenia, thrombocytopenia, and elevated liver function tests.
–Non-response to doxycycline could suggest Babesiosis (dx = peripheral smear or PCR).
The disease is “Lyme”, not “Lymes”!!
297/12/2018
Questions?
Comments?
Concerns?
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