Monday, November 9, 2015

Lyme Disease Guideline Project Plan

To: The Infectious Diseases Society of America (IDSA), the American Academy of Neurology
(AAN) and the American College of Rheumatology (ACR)

From: The International Lyme & Associated Diseases Society (ILADS)

Re: IDSA/AAN/ACR Lyme Disease Guideline Project Plan

Dear IDSA/AAN/ACR Lyme Disease Clinical Practice Guideline Development Panel:
The IDSA/AAN/ACR Lyme Disease Clinical Practice Guideline (CPG) Development Panel has
requested public comments in order to “fine-tune” its plan to revise the outdated 2006 IDSA
Lyme guidelines. The International Lyme & Associated Diseases Society (ILADS) appreciates
having the opportunity to weigh-in on this topic. ILADS is a professional medical society that
promotes scientific knowledge, clinical expertise and healthcare policy related to Lyme and
associated tick-borne diseases. ILADS healthcare providers currently serve more than 100,000
patients with Lyme and associated tick-borne diseases in the USA and around the world. Based
on the collective work of its members, the organization has a wealth of clinical expertise in
treating complex and advanced cases of Lyme disease.

ILADS has profound reservations regarding the panel’s proposed project plan because it
consistently violates fundamental principles established by the Institute of Medicine (IOM) for
the formulation of high-quality and trustworthy guidelines.1 The specific violations that ILADS
would like the panel to address and our remedial recommendations for your Lyme disease
guideline development plan are outlined below:

1. Page 4, lines 23 -40. The IDSA/AAN/ACR CPG development panel does not include
physicians with substantial experience in using antibiotic therapies to treat chronic
manifestations of Lyme disease. We specifically note that there are no ILADS members on the
panel.2 Given that the IOM concluded that any failure to include stakeholders in CPG
deliberations undermines the quality and trustworthiness of the CPG, this omission is
unacceptable.

1. ILADS recommends that the IDSA/AAN/ACR CPG development panel include ILADS
physicians with experience in treating chronic manifestations of Lyme disease in its CPG
formulation process.

2. Page 6, line 63-65; pages 9-16, lines 130-281. The IDSA/AAN/ACR CPG development plan
lists 81 questions which are characterized by the CPG development panel as satisfying the
Population/Patient, Interventions/Treatments, Comparator, and Outcomes format. The plan states
these questions will frame the guidelines development process, guide the literature searches and
the formal recommendations. Given the overall importance of the questions we think it is
important to point out that they were generated via a flawed process and have several
inadequacies.

Not only did the CPG development panel fail to include ILADS members, it also made no effort
to include patient stakeholders or their advocates when formulating its clinical questions.2 This
decision directly conflicts with IOM position 3.2 regarding guideline development groups in
which the IOM clearly states that patients should be involved in formulating clinical questions.1
Additionally, many of the questions do not align with the PICO format and many exhibit framing
bias (i.e., “should we use unvalidated tests for Lyme disease?”).

ILADS recommends that the IDSA/AAN/ACR CPG development panel be expanded to
include patient stakeholders and that the proposed list of questions be reviewed (and
necessary revisions made) following the addition of patient stakeholders. ILADS also
recommends that all questions follow a PICO format and that the IDSA/AAN/ACR CPG
development panel frame questions in an unbiased manner

3. Page 6, lines 70-80; page 3, lines 16-22. The IDSA/AAN/ACR CPG development panel
proposes to use “well-performed existing systematic reviews” to establish its evidence base
without defining what constitutes a “well-performed” review. And, while the plan’s wording
suggests that the IOM recommends using existing reviews, this is only true when the systematic
review and the CPG activities “are independent of one another”.1 Clearly this is not the case
given that many of the CPG development panel members have conducted systematic reviews on
Lyme disease, some of which appear to have been done as a prelude to the current CPG
development panel (i.e., the paper by panel members Lantos and Wormser, Am J Med 2014;
127: 1105-1110.3) We could not help but note that while the background section mentions the
existence of several different guidelines on Lyme disease, it failed to include ILADS’ GRADEbased
guidelines which were published in 2014.4

The use of existing reviews poses many problems. The reviews may not include the most recent
studies or basic science information. Reviews authored by current CPG development panel
members may unduly bias the group’s findings regarding the quality of the review itself or the
implications of its findings.1 Many of the existing reviews on the treatment of Lyme disease are
based on poor-quality studies some of which were authored by the reviewers themselves, setting
up situations where the quality of the evidence and the strength of its findings were overstated.
For example, ILADS’ GRADE-based analysis of the clinical trial evidence regarding the
management of known tick bites, the treatment of erythema migrans and the usefulness of
antibiotic retreatment consistently found that the evidence was of very low quality.4 Hayes and
Mead of the CDC came to a similar conclusion regarding the literature on late neurologic Lyme
disease5 yet the 2006 IDSA CPG development panel often assigned the highest possible rating to
the trial evidence.6 Given that 20% of the current CPG development panel, including co-chair
Bockenstedt, co-authored the 2006 IDSA guidelines,2,6 this apparent inability to objectively
assess the evidence is especially concerning.

Another problem with using existing systematic reviews as opposed to conducting a new
systematic review is that although the current CPG is intended to “focus on patient-important
outcomes” the existing reviews are disease- and not patient-centered. This is due to the fact that
the reviews were based on trials which typically selected easily measured endpoints rather than
the outcomes that mattered most to patients. Hence, patients with persistent and sometimes
disabling symptoms were categorized as successfully treated because their rash cleared or their
joint swelling diminished.7,8

Finally, it should be noted that existing reviews often relied too heavily on the work of certain
authors and did not reflect the broad spectrum of clinical evidence in the medical literature.
ILADS recommends that the IDSA/AAN/ACR panel not using existing systematic
reviews as surrogates for carefully constructed analyses of all of the evidence retrieved
via properly conducted searches of the medical literature.

4. Pages 5-7, lines 61-94. The IDSA/AAN/ACR CPG development panel does not explicitly
include all of the principle elements of evidence-based medicine in their project plan. While the
IOM acknowledges that “health professionals increasingly understand that health care must be
based on a combination of scientific evidence, knowledge gained from clinical experience, and
patient value judgments and preferences”1 it is unclear whether the panel agrees with this
viewpoint. Given that ILADS members with extensive clinical expertise were not invited to
participate on the panel, despite the limited quantity of high-quality the trial evidence, we are
concerned that the CPG development panel will attribute undue significance to trial evidence
while downplaying the importance of clinical expertise.

ILADS recommends that the IDSA/AAN/ACR panel should appropriately value the
relative contributions from clinical trials and clinical experiences.

5. Pages 5-7, lines 61-94: The IDSA/AAN/ACR CPG development plan does not intend to
include patient stakeholders or their advocates when analyzing the evidence or conducting riskbenefit
analyses and it includes no methodology for identifying which outcomes are most
important to patients. This is a critical shortcoming because, as previously mentioned, the IOM
recognizes the importance of considering patient values and preferences in the context of
providing evidence-based care.

As we learned in developing ILADS’ 2014 treatment guidelines, Lyme patients are a very
heterogeneous group. The degree of their quality of life impairments and their values with regard
to risk-benefit tradeoffs fall along a wide spectrum. Given these variables, it could be difficult
for one patient to adequately represent the interests of this group. Yet, despite the obvious need
for broad patient representation, the CPG development panel has but a single consumer
representative. Furthermore, it is our understanding that this representative lacks any personal or
family experience with the medical complications arising from the infection or the problems
patients encounter when attempting to secure insurance coverage for treatment-related expenses.
Without patient involvement in this phase of the guideline development process, the proposed
plan will be unable to fulfill its goal regarding patient-centeredness.

ILADS recommends that the IDSA/AAN/ACR CPG development panel include patient
stakeholders during all phases of evidence analysis, especially when considering the
relative merits of various treatment options.

Pages 4-16, lines 23-281. In light of the significant deficiencies in the proposed project plan,
ILADS urges the IDSA/AAN/ACR CPG development panel to address these concerns before
proceeding further. Moving ahead without taking corrective action can only lead to the
production Lyme disease guidelines that will be appropriately viewed as biased, non-inclusive
and ultimately detrimental to patient care.

Sincerely,

Daniel J. Cameron, MD

President, ILADS

cc: Stephen B. Calderwood, MD, FIDSA, President, IDSA (scalderwood@partners.org)
Timothy A. Pedley, MD, FAAN, President, AAN (tap2@columbia.edu)
E. William St. Clair, MD, FACR, President, ACR (stcla003@mc.duke.edu)
Robert L. Wergin, MD, FAAFP, President, AAFP (contactcenter@aafp.org)
Sandra G. Hassink, MD, FAAP, President, AAP (shassink@nemours.org)
David A. Fleming, MD, MA, MACP, President, ACP (flemingd@health.missouri.edu)
Professor Daniel B. Gregson, President, AMMI-CA (dgregson@ucalgary.ca)
Nina F. Schor, MD, PhD, President, CNS (nina_schor@urmc.rochester.edu)
Phillip G. Mulder, PhD, President, ESA (phil.mulder@okstate.edu)
Professor Murat Akova, President, ESCMID (murat.akova@escmid.org)
Professor David W. Kimberlin, President, PIDS (dkimberlin@uab.edu)
1 Institute of Medicine. Clinical Practice Guidelines We Can Trust. Available at:
https://www.iom.edu/Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust.aspx.
Accessed March 31, 2015.
2 Project plan: Guidelines for the prevention, diagnosis, and treatment of Lyme disease by the Infectious Diseases
society of America, the American Academy of Neurology, and the American College of Rheumatology. Available at
http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-
Patient_Care/PDF_Library/LD%20Project%20Plan%20March%202015%282%29.pdf
Accessed March 31, 2015.
3 Lantos PM, Wormser GP. Chronic coinfections in patients diagnosed with chronic Lyme disease: A systematic
review. Am J Med 2014; 127:1105-1110
4 Cameron DJ, Johnson LB, Maloney EL Evidence assessments and guideline recommendations in Lyme disease:
the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev Anti Infect
Ther. 2014;12:1103-35
5 Hayes E, Mead P. Lyme disease. Clin Evid 2003;10:887-99.
6 Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease,
human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of
America. Clin Infect Dis. 2006;43:1089-134.
7Nadelman RB, Lugar SW, Frank E, et al. Comparison of cefuroxime axetil and doxycycline in the treatment of
early Lyme disease. Ann Intern Med 1992:117:273-80.
8 Dattwyler RJ, Wormser GP, Rush TJ, et al. A comparison of two treatment regimens of ceftriaxone in late Lyme
disease. Wien Klin Wochenschr. 2005;117:393-7.