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A Brief History of Lyme Disease
& A Review of the U.S. Clinical Trials
Columbia Lyme & Tick-Borne Diseases Research Center
Brian A Fallon, MD

2. Note of Changes after the Talk
 On Slide 6: Removed a sentence about
antibiotics and replaced it with:
“Dr. Alan Barbour developed a culture and a
serologic test for Lyme”
 On Slide 8: Corrected the date for the 3rd
clinical trial (replaced 2007 with 2008)
 Added an addendum of 3 slides at the end:
slides 44-46

3. Faculty/Presenter Disclosure
 Faculty: Brian A. Fallon, MD
 Relationships with commercial interests:
 Grants/research support: Oxford Immunotec, Inc
 Speakers Bureau/Honoraria: none
 Consulting Fees: none
 Mitigation of Bias:
 I will not be referring in my talk to any product developed by
Oxford Immunotec, Inc.

4. Outline of Talk
 History of Lyme Disease
 Columbia Lyme Encephalopathy Study
 Other U.S. Clinical Trials
 Recent Netherlands Study
 Considerations for New Guidelines

5. 5TBG Briefing on Lyme Disease_15 11 ...
•Two key early pioneers
•Historical Eras (a personal view)
•1976-1990 Discovery & Openness
•1990- 2008 Narrow Definitions & Retrenchment
•2008- Renewed discovery & exploration

6. 6TBG Briefing on Lyme Disease_15 11 ...
Dr. Willy Burgdorfer
• It was long suspected that a virus in ticks
caused Lyme disease.
• A Swiss “Tick Surgeon” (medical
entomologist) in 1982 discovered that it
wasn’t a virus after all. While looking in
the mid-gut of ticks from Long Island, he
found spirochetes & linked them to Lyme
disease.
• Due to this discovery:
• the spirochete was named after him
“Borrelia burgdorferi”
• Dr. Alan Barbour developed a culture
and a serologic test for Lyme
• The European ECM and neurologic
variants confirmed as Lyme disease
“Chance favors the prepared mind”

7. 7TBG Briefing on Lyme Disease_15 11 ...
Dr. Allen Steere
• Described the early cases of Lyme
disease, linking the EM rash and arthritis
cases in children.
• Researched the role of autoimmunity
• Identified Genetic risk (HLA DR4)
• Identified an autoantigen (ECGF)
• Reported: not all cases meet the CDC
surveillance criteria (~20% do not)
• Reported: antibiotics may not always
lead to cure
• refractory Lyme arthritis
• Intracranial pressure blindness
• Reported: brain blood flow deficits in
Lyme (SPECT) are reversible

8. 8TBG Briefing on Lyme Disease_15 11 ...
A brief history of Lyme disease…
3000 BCE 1980 1990 2000 2010 2015
Lyme, CT
“Lyme:
The NEW
great
imitator”
Lyme Clinical
Trials
2001, 2003, 2008
CDC 2-
Tier
Criteria
Cluster of
unexplained
childhood arthritis
Spirochete
found in tickIce Man:
Lyme DNA
>300,000 new dx/yr
Bb
genome
sequenced
CDC 2-
Tier
Criteria
Systems
Biology –
“-Omics”
Persistence
of Bb in
Animal
Models
Columbia Lyme & Tick-Borne Diseases Research Center

9. Five Randomized Placebo-
controlled Studies
 Two Symptom-Specific Studies
 Columbia – Persistent Cognitive Impairment after Lyme
(2008)
 Stonybrook – Persistent Fatigue after Lyme (2003)
 Two Heterogenous Symptom Studies
 New England Med Center - Persistent post-Lyme
Symptoms (2001) – seropositive & seronegative studies
 One Heterogeneous Symptom Study of
patients with possible Past Lyme
 Netherlands Study (2016)

10. Columbia Study of Post-Treatment
Lyme Encephalopathy Study (NINDS)
GOALS:
 To assess brain structure (MRI) & function (PET)
 Metabolism by FDG PET
 Blood flow by O-15 PET (before & after hypercapnea)
 To assess improvement in response to 10 week of
IV ceftriaxone vs IV placebo
 Primary Measures – cognition/memory
 Secondary Measures– fatigue, pain, physical functioning

11. These patients met highly conservative criteria
for Post-treatment Lyme Syndrome
 Age 18-65
 Lyme patients:
 Historically well-documented Lyme disease based on
CDC surveillance clinical and laboratory criteria
 Prior treatment with at least 3 weeks of IV ceftriaxone
 Memory deficit (-1SD) confirmed by cognitive testing
 Current positive IgG Western blot at our reference
lab
 Healthy Controls: age-, sex-, education-
matched

12. Columbia University Study of Chronic Lyme Encephalopathy
(Fallon et al, Neurology, 2008)
Baseline Week 12 – Primary Outcome Week 24 - Sustainability
PET/MRI
Neuropsych tests
Self-report
Neuro & Rheum exam
LP
Blood work
Start
10 wks IV Placebo
or IV CFTX
PET/MRI
Neuropsych
Self-report
Rheum Exam
Blood Work
Completed
10 wks of IV
Ceftriaxone/Placebo
PET/MRI
Neuropsych
Self-report
Rheum Exam
Blood work
No treatment
from week 11-24
End of
Double-Blind

13. Final Study Entry Sample Size
 Total: 55
 37 Lyme patients: 23 IV ceftriaxone/ 14 IV placebo
 18 Healthy controls: 18
– All were seronegative for Bb infection
– All had no history of Lyme or Lyme-like illness
 Of 3700 evaluated, only 1% were enrolled
 Why? Conservative criteria requiring:
– cognitive impairment
– current +IgG WB
– at least 3 wks of IV Abx

14. The 37 enrolled patients had received many
courses of prior antibiotic treatment
 Mean age 45.1 yrs, 59% female
 Delay bet symptoms and treatment: 1.2 yrs
 Amount of Prior Treatment: Considerable.
 Mean amount of prior IV: 2.3 months
 Mean amount of prior oral: 7.7 months
This is a particularly chronic sample –
less likely to benefit from re-treatment

15. Baseline Clinical
 Cognitive: mild-moderate deficits
 Verbal Memory, Working memory, Verbal Fluency
 Psychiatric: depression & anxiety only mild
 Systemic Symptoms are debilitating:
 PAIN – comparable to post-surgical pain
 FATIGUE – comparable to M.S. patients
 PHYSICAL DISABILITY – comparable to congestive
heart failure patients

16. Baseline CSF Laboratory Results
 CSF (n=33):
 Few Routine abnormalities:
– WBC (2), Protein (4), Oligoclonal bands (none)
 CSF Bb Antibodies:
– 66.7% ELISA positive & 84.8% IgG WB positive
– 0% IgM WB positive
– 12% WCS Intrathecal Ab Index positive
 PCR Positive: None using OspA based PCR
 Culture Positive: 1 sample (false positive)
(Fallon et al, Neurology, 2008)

17. Significant Change in Cognition over time for 3 groups (p=.04):
10 wks of IV Drug vs Placebo vs healthy controls-
Response then Relapse when off antibiotics
Week
z-score
0 12 24
-0.7
0.0
0.7
CognitiveIndex (z-scores)
Control
Plac ebo
Drug
ControlsHealthy
Controls
Drug vs Placebo p=.053
Week 0 Week 12 Week 24
PRIMARY OUTCOME – COGNITIVE CHANGE
(Fallon et al, Neurology, 2008)

18. Baseline Severity is key to detecting a treatment
effect. Treatment response is sustained
FATIGUE PAIN
PHYSICAL
FUNCTIONING
SECONDARY OUTCOMES
Fallon et al, Open Neurology 2012

19. Are there objective biomarkers
that differentiate
the Lyme patients from controls?

20. Global Cerebral Blood Flow: is there a difference
in vasodilation capacity bet pts and controls? Yes
 The patient group showed a
diminished ability to enhance
blood flow compared to
controls
8.2% increase in patients
vs 28.1% increase in controls, p<.02
 This finding suggests vascular
compromise in the patients
Resting Flow
After CO2
Fallon et al, JAMA Psychiatry 2009
0
10
20
30
Patients Controls
%
increase
in Brain
BlooFlow

21. FDG Imaging: are there regional metabolic
differences between patients & controls? Yes.
 Patients demonstrate
large clusters of
decreased metabolism,
primarily in the
temporal and parietal
areas
 These areas of
decreased metabolism
were also areas of
decreased blood flow
Fallon et al, JAMA Psychiatry 2009

22. Which variables were not associated with
response to re-treatment with Antibiotics?
 Presence of positive titers for other infections
(Anaplasma, Babesia, Bartonella)
 Positive Lyme IgM Western blot
 Magnitude of NK CD 57
 Positive ANA, CRP, or ESR
 CSF abnormalities: protein, WBC, ELISA, IgG WB
Amount of prior IV or oral Abx was not associated with
responsiveness to IV Ceftriaxone treatment

23. Greater severity was associated with greater
likelihood of improvement with Antibiotics
 Worse Cognitive impairment
 Worse Pain, Fatigue, Physical Functioning
 Greater # of joints in pain on rheum exam
 Greater # of abnormal areas on neuro exam

24. Strengths & Limitations of the
NINDS Lyme Encephalopathy Study
 Strengths:
 Rigorously Defined Patients
 Quantitative methods for assessment
 Excellent Study Retention
 Age-, Gender-, and Educ.-matched controls
 Weaknesses:
 Small sample size – severely underpowered
to show treatment differences
 Cognition was not the most severe problem

25. Questions & Recommendation
Would a less treatment refractory sample have done
better?
What alternative & safer non-antibiotic therapies may
enhance patient response? These are urgently
needed.
What was the mechanism? Antimicrobial? Glutamate?
Clinical Research Trials should focus on more
homogenous populations recruited for severity level
– fatigue, pain, physical dysfunction.

26. Other Randomized NIH-funded
Placebo Controlled
U.S. Studies of PTLDS
STOP-LD Study (Krupp, Neurology 2003)
Klempner et al. (New England J Med 2001)

27. STOP-LD Study (Krupp et al, Neurology 2003)
 55 patients with persistent fatigue after
treated LD who had had at least 3 weeks
of antibiotic treatment previously
 Fatigue severity for all enrollees had to be
at least “moderate” on the Fatigue
Severity Scale

28. STOP-LD Study Design
 Three primary outcome measures
(Fatigue, Reaction time, CSF OspA) but
only on one – Fatigue – were patients
uniformly impaired.
 Random assignment to 1 month of IV
ceftriaxone or placebo followed by 5
months of no treatment.
 Primary end-point: 6 months

29. Stop-LD Primary Outcomes
 No improvement in reaction
times, but “deficits were
relatively mild which may
have contributed to a lack of
a treatment effect”
 No reduction in OspA antigen
but “only 16% had this
marker at baseline… it was
not a useful measure of
outcome”
% of Responders on Fatigue
64%
18.5%
P<.001
Significant improvement on the
primary outcome of Fatigue
STOP-LD Study (Krupp, Neurology 2003)

30. IgG WB+ emerged as a biomarker
of treatment response: 80% vs 13%
IgG WB+ Patients did
better (p<.01)
0
10
20
30
40
50
60
70
80
IgG WB + IgG Wb -
Drug
Placebo
13%
Prior IV therapy did not confer
significantly worse outcome.
0
10
20
30
40
50
60
70
80
No prior
IV
Had Prior
IV
Drug
Placebo
(STOP-Lyme Study, Stonybrook, Krupp, Neurology 2003)
80%

31. Comparing Two PTLDS Studies –
% responders on fatigue at 6 months
0
20
40
60
80
100
Krupp:%Pts Improved on Fatigue Scale
IV antibiotic IV placebo
0
20
40
60
80
100
Fallon:%Improved on Fatigue Scale
IV antibiotic IV placebo
StonyBrook: 1 month IV CFTX Columbia: 10 weeks IV CFTX

32. Prominent International Treatment Guidelines
for PTLDS disagree with the prior summaries
 Infectious Disease Society of America:
“antibiotic therapy has not proven to
be useful”
 British Infection Association:
“Studies of prolonged antimicrobial
treatments of patients with Post
Lyme Syndrome have not shown
sustained benefit”

33. More Disagreement
 European Federation of Neurological
Societies:
“American trials have demonstrated that
additional prolonged antimicrobial
treatment is ineffective in Post Lyme
Disease Syndrome”

34. So why are these valuable
findings being ignored?
Effect Size: Moderate to Large
Fallon, Open Neurology, 2012

35. Klempner Study of PTLDS
 129 seronegative & seropositive patients
 Enrolled based on report of functional
impairment – but no severity cutoff or
severity measure was used for enrollment.
 Randomly assigned to:
 30 days of IV CFTX + 60 days of oral doxy
 30 days of IV placebo + 60 days of oral placebo
Klempner et al, NEJM, 2001

36. Results at 6 months
Klempner et al, NEJM, 2001
 Primary Outcome:
 No difference in functional outcome as
assessed by the SF-36 measure between
drug and placebo
 Secondary outcomes:
 No difference in change for cognition or
depression.

37. Comments on this negative study
 Strength of this study: sample size
 Limitations of this study:
 Heterogeneity of patient sample
– Not enrolled based on “severity cutoff”
 Statistical analysis did not adjust for
differences in baseline severity on
functional impairment

38. Randomized Trial of Longer-Term Therapy for
Symptoms Attributed to Lyme Disease
Berende et al, New England Journal of Medicine, April 2016
 280 patients with symptoms from Netherlands
 Only 1/3 had objective clinical markers of past LD
 2/3 had possible past LD
 non-specific symptoms with a positive IgM or IgG
 False Positives? Remote Infection but not current?
 11% had never before been treated for Lyme
 All received 2 weeks of IV ceftriaxone plus
 Group 1: 12 weeks of oral placebo pills, or
 Group 2: 12 weeks of oral doxycycline, or
 Group 3: 12 weeks of oral clarithyromycin and
hydroxychloroquine (“Biaxin & Plaquenil”)

39. Results of Netherlands Trial
 All groups improved significantly in physical
functioning
 However – because there was no placebo during
the first 2 weeks, this study cannot state whether or
not “repeated” antibiotic therapy was helpful.
 No benefit was seen for extended antibiotic
therapy beyond the first 2 weeks of IV CFTX.
 This was determined by the physical component
summary score of the SF-36

40. Primary Criticism of this trial with
considerable design limitations
 The sample was far too heterogeneous
 Patients were not enrolled based on severity of
impairment in physical functioning
 Some Patients may not have had past Lyme:
 1/3 were known to have definite prior Lyme disease
 2/3 had no objective clinical evidence of past Lyme
 Therefore, this study can only conclude that
extended antibiotic therapy didn’t improve physical
functional status -- using these antibiotics -- for
people who may - or may not - have had prior LD

41. “Efficacy” vs. “Clinically Recommended”
 Krupp Fatigue Study:
 results showed efficacy but IV treatment
was not recommended due to risks
associated with IV antibiotics
 Fallon Encephalopathy Study:
 results showed non-sustained benefit on
the primary outcome measure of cognition
– so IV treatment was not recommended
for sustained improvement in cognition

42. Conclusions
 Guideline committees should state that
retreatment with IV ceftriaxone has been
shown to reduce PTLS – Fatigue in one
U.S. trials with similar results from a
second U.S. trial
 Treatments with fewer side effects are
needed.
 Other treatments are needed for those
who are no longer benefiting from
antibiotics

43. Thank you for your attention
www.columbia-lyme.org
Columbia Lyme & Tick-Borne
Diseases Research Center

44. Methods:
Blood samples were collected from 2 groups:
a) previously treated symptomatic patients with a history of Lyme disease
b) healthy individuals who had no known history of Lyme disease
Each sample was divided into 4 and sent blindly to 4 labs: a
university lab, a commercial lab, and 2 Lyme specialty labs.
Addendum added by Dr. Fallon after the conference given the discussion about his paper

45. Questions
Do labs differ in the likelihood of detecting a sample
as positive?
Do two labs agree that the same sample is positive?
Do some tests yield more false positives than other
tests (e.g., ELISA, IgM WB, IgG WB)?
Are “in-house” lab criteria for interpretation better than
the CDC criteria?

46. Conclusions (Fallon et al, CID, 2014)
 The University, commercial, and Lyme-specialty Labs had comparable
performance when CDC criteria were employed for ELISA & IgG WB
 “In-house” criteria for WB interpretation were not helpful and could lead
to confusion, as rate of positive results (if one including having had
either a positive IgM or IgG WB) was over 50% among healthy
individuals who had no history of prior Lyme disease.
 The IgG WB and the C6 Peptide ELISA had good specificity across all
labs – but not the IgM Western Blot which had too many false
positives.
Because of high discordance among labs, clinicians may consider sending
serum to a second lab if LD is strongly suspected clinically, if there has been
exposure to a Lyme endemic area, & if the lab test selected has high
specificity