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1. 1
Evidence-based, Patient-centered
Guidelines for the Diagnosis
and Treatment of Lyme Disease
Elizabeth L. Maloney, MD
©2016 Elizabeth Maloney, MD

2. Faculty/Presenter Disclosure
• Faculty: Elizabeth L. Maloney, MD
• Relationships with commercial interests:
• No ties to pharmaceutical, device or communications
companies
• Other relationships:
• Co-authored International Lyme and Associated
Disease Society’s 2014 treatment guidelines on Lyme
disease
• President of Partnership for Healing and Health, an
educational company providing evidence-based
presentations and materials on tick-borne diseases
• Potential for conflict(s) of interest:
• Elizabeth L. Maloney has not received any funding for this
program from any organization.
©2016 Elizabeth Maloney, MD

3. Guidelines exist to
assist physicians and serve patients
3©2016 Elizabeth Maloney, MD

4. Assist Physicians
Physicians treat the ill and relieve suffering
• Evidence-based practices are the ideal
• Clinicians may rely on summaries and guidelines
• Place trust in guideline developers
• Address clinically relevant questions
• Properly analyze evidence
• Provide meaningful recommendations
4©2016 Elizabeth Maloney, MD

5. • Road map
• Clinical starting points, expected milestones, potential
roadblocks and detours
• Relative burden of proof
• Prescriptive and Proscriptive - highest certainty
• High quality evidence, large treatment effect,
favorable risk-benefit assessment
• Permissive but not directive - less certainty
• Lowest quality evidence, equivocal risk-benefit
5
Recommendations are clinical tools,
not mandates or performance metrics
©2016 Elizabeth Maloney, MD

6. Should not unduly restrict clinical judgment
• Treating physicians decide when and how
• Patient-specific care
• Application of clinical expertise
6©2016 Elizabeth Maloney, MD

7. Serve Patients
Guidelines must be patient-centered
• Patients are final end-users
• Accommodate individual differences
• Disease severity
• Perceived quality of life impairments
• Treatment goals
• Risk aversion
• Life circumstances
7©2016 Elizabeth Maloney, MD

8. Developing
Trustworthy Guidelines
8©2016 Elizabeth Maloney, MD

9. Panel Composition
• Patients and primary care physicians
• Dominate or well-represented
• Fully participate in all stages
• Patient representatives
• Identify patient priorities and variables
• Weigh-in on defining acceptable outcomes, reasonable risk
• Primary care members
• Identify clinical realities
• Ensure recommendations are workable
9©2016 Elizabeth Maloney, MD

10. Trustworthy Evidence Base
• Transparently established, analyzed, rated
• Collegial and/or institutional conflicts problematic
• Analysis – detailed
• Things aren’t always what they seem
• Analysis – patient-centered
• Trial endpoints research/disease-centered
• Convert outcomes to be patient-centered
• EM trials: success originally resolution of EM
10©2016 Elizabeth Maloney, MD

11. Detailed Analysis ‒
because appearance and reality can conflict
• Nonstandard nomenclature
• Imprecise terminology ‒ “majority”, “expected”, “mild” …
11
“The encephalopathy was generally mild;
it interfered with the patient’s daily activities
and was apparent on mental status tests,
but seldom caused a profound confusional state.”
Dattwyler RJ Lancet 1988
Mogilyansky E.
Clin Diagn Lab Immunol.
2004
©2016 Elizabeth Maloney, MD

12. • Respected journals publish poor studies
• NEJM and PLEASE Study 3/31/2016
• Poor design
• Entrance criteria too loose
• Combined treated and untreated
• Some had baseline function 1 SD > mean gen pop.
• No placebo group
• Oral regimens: questionable choices for circumstances
• Conclusion unsupported: overly broad
12©2016 Elizabeth Maloney, MD

13. EBM Recommendations
• EBM more than research findings
• Dynamic integration
13
Research
ResearchExpertise
Expertise
Values
Values
High-quality
evidence
High-quality
evidence
©2016 Elizabeth Maloney, MD

14. Diagnostic Guidelines
14©2016 Elizabeth Maloney, MD

15. “A clinical diagnosis is made for the purpose of
treating an individual patient and should consider
the many details associated with that patient's
illness.
Surveillance case definitions are created for the
purpose of standardization, not patient care; they
exist so that health officials can reasonably
compare the number and distribution of "cases“
over space and time.
Paul Mead, MD, MPH Medical Epidemiologist, CDC Division of Vector-Borne Infectious Diseases
Testimony to Connecticut Department of Public Health and the Connecticut Attorney General's
Office on January 29, 2004
15©2016 Elizabeth Maloney, MD

16. Whereas physicians appropriately err on the
side of over-diagnosis, thereby assuring they
don't miss a case,
surveillance case definitions appropriately err
on the side of specificity, thereby assuring
that they do not inadvertently capture
illnesses due to other conditions.”
16©2016 Elizabeth Maloney, MD

17. Support, not Subvert Clinical Diagnosis
In general, guidelines should:
• Acknowledge need for direct tests; tests of cure
• Reflect established diagnostic process
• Order and relative importance of history, exam, testing
• Recognize situational nature of diagnostic criteria
• Prioritize sensitivity over specificity
• De-emphasize pre-test probability
• Presentations under-recognized
• Prevalence unknown; higher in ill than well
17©2016 Elizabeth Maloney, MD

18. • Less stringent lab criteria for clinical cases
• Address inadequacies of available tests
• Serology-based algorithms not patient-centered
• Unproven assumptions: immune response, test quality
• Insensitive
• Tests licensed in US: cleared, NOT approved
• Clinical validity not established
• Reject current two-tier strategy
• Prioritizes specificity
• Overall specificity ≥ step 2
• Overall sensitivity ≤ step 2
18
Recommendations: Immediate
©2016 Elizabeth Maloney, MD

19. • Change IgG Western blot interpretive criteria
• Clinical performance biased against neuroLyme
• Seropositivity of Dressler’s well-characterized pts
• 72% active neuroborreliosis
• 96% active arthritis
• 17% of Logigian’s 1999 encephal subjects seronegative
• Clinicians report that neuro cases > CDC data suggests
Recommendations: Future
• Should not endorse: Two-tier without Western blot
• Deprives clinicians of useful diagnostic information
19©2016 Elizabeth Maloney, MD

20. Treatment Guidelines
20©2016 Elizabeth Maloney, MD

21. Roles: Physician vs Panelist
• Panelists guide, physicians perform
• Evidence analysis also considers generalizability
• Scientific “grey” zones
• “Close calls”
• Varying risk-benefit assessments on same facts
• Whose/what values in play
21©2016 Elizabeth Maloney, MD

22. Evidence Quality
Preponderance of
Benefit or Harm
Balance of
Benefit and Harm
Well-designed RCT or diagnostic
studies on relevant population
OPTIONRCT or diagnostic studies with
minor limitations; consistent
evidence from observational studies
Observational studies
Expert opinion, case studies,
reasoning from 1st principles OPTION
No
Recommendation
22
Strong
Recommendation
Recommendation
No
Recommendation
Option
Option
• Shared decision-making
• Clinician-patient discussion of variables
• Clinician ultimately responsible
Approaches to the Grey Zone
• American Academy of Pediatrics
©2016 Elizabeth Maloney, MD

23. Treating When Science Uncertain
“First, do no harm” may be harmful
• Assumes risk is present when risk-benefit unknown
• Prioritizes non-maleficence over beneficence
• Not patient-centered
• Denies hope by blocking access to potentially useful therapy
• Today’s patients can’t wait for tomorrow’s research
• Discourages clinical innovation
23
(duty not to harm) (act in patient’s best interest)
©2016 Elizabeth Maloney, MD

24. Management Flexibility Required
• Allows for clinical innovation
• Primary purpose: benefit individual
• Uses existing therapies in new ways
• 1st line agents: different dosages, durations, pulsing,
combinations
• Agents not historically promoted for Lyme
24©2016 Elizabeth Maloney, MD

25. Patient Needs Primary
25
• Treatment guidelines ≠ Policy documents
• Policies may have other considerations, priorities
• Cost, societal goals
• Antibiotic Stewardship universal necessity
• Burden must be appropriately placed
Antibiotic
Stewardship
Antibiotic
Stewardship
©2016 Elizabeth Maloney, MD

26. Guidelines exist to
assist physicians and serve patients
26©2016 Elizabeth Maloney, MD

27. References
• Institute of Medicine (Committee on Quality of Health Care in America).
Crossing the Quality Chasm: A New Health System for the 21st Century.
(Ed.^(Eds) (National Academies Press, Washington, DC, 2001) 360.
• Committee on Standards for Developing Trustworthy Clinical Practice
Guidelines; Institute of Medicine. Clinical Practice Guidelines We Can Trust.
2011. National Academies Press. Last accessed 3/28/12
http://www.nap.edu/catalog.php?record_id=13058.
• Atkins D, Best D, Briss PA et al. Grading quality of evidence and strength of
recommendations. BMJ, 328(7454), 1490 (2004).
• Mogilyansky E, Loa CC, Adelson ME, Mordechai E, Tilton RC. Comparison of
Western immunoblotting and the C6 Lyme antibody test for laboratory detection
of Lyme disease. Clin Diagn Lab Immunol. 2004 Sep; 11(5):924-9.
• Dattwyler RJ, Halperin JJ, Volkman DJ, Luft BJ. Treatment of late Lyme
borreliosis—randomized comparison of ceftriaxone and penicillin. Lancet 1988;
1:1191-4.
• Berende A, ter Hofstede HJ, Vos FJ, et al. Randomized Trial of Longer-Term
Therapy for Symptoms Attributed to Lyme Disease. N Engl J Med. 2016 Mar
31;374(13):1209-20. doi: 10.1056/NEJMoa1505425
27©2016 Elizabeth Maloney, MD

28. • Sackett D, Straus S, Richardson W, Rosenberg W, Haynes R. Evidence-based
medicine: how to practice and teach EBM (Churchill Livingstone, Edinburgh,
2000).
• Peterson MC, Holbrook JH, Hales D, Smith NL, Von Staker LV. Contributions of
the History, Physical Examination, and Laboratory Investigation in Making
Medical Diagnoses. West J Med 1992; 156:163-5.
• Markert RJ, Haist SA, Hillson HD, Rich EC, Sakowski HA, Maio AC.
Comparative Value of Clinical Information in Making a Diagnosis. MedGenMed.
2004; 6(2): 64.
• Dressler F, Whalen JA; Reinhardt BN; Steere AC. Western blotting in the
serodiagnosis of Lyme disease. J Infect Dis 1993;167(2): 392-400.
• Logigian EL, Kaplan RF, Steere AC. Successful treatment of Lyme
encephalopathy with intravenous ceftriaxone. J Infect Dis 1999;180:377-83.
• Guyatt GH, Oxman AD, Kunz R, et al. Going from evidence to
recommendations. BMJ. May 10 2008;336(7652):1049-1051.
• AAP: Steering Committee on Quality Improvement and Management.
Classifying recommendations for clinical practice guidelines. Pediatrics
2004;114(3) 874-877.
28©2016 Elizabeth Maloney, MD

29. • What is Shared Decision Making? Available from
http://www.informedmedicaldecisions.org/what-is-shared-decision-making/, Last
accessed 3/1/14.
• R Macklin. Applying the four principles. J Med Ethics 2003;29:275–280.
• Resnik DB. The precautionary principle and medical decision making. J Med
Philos. 2004 Jun;29(3):281-99.
• Woodcock J. A Conversation About the FDA and Drug Regulation.
http://www.fda.gov/fdac/special/testtubetopatient/woodcock.html. Accessed
3/3/09
• Union of Concerned Scientists. Prescription for Trouble: Using Antibiotics to
Fatten Livestock. http://www.ucsusa.org/food_and_agriculture/our-failing-food-
system/industrial-agriculture/prescription-for-trouble.html#.Vxp1kkf3h30.
Accessed 4/12/16.
29©2016 Elizabeth Maloney, MD