8 December 2010
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
8/12/2010 2
Executive Summary
At the request of the Chief Executive of the Health Protection Agency (HPA) an
independent working group chaired by Professor Brian Duerden CBE, Inspector of
Microbiology and Infection Control, Department of Health, reviewed the International
Lyme and Associated Diseases Society’s (ILADS) “Evidence-based guidelines for the
management of Lyme disease” (Cameron et al. Exp Rev Anti-infect Ther 2004;2:S1-
13). The review group was convened in order to assess whether the guidelines were
suitable for use in the UK and should be referenced by the HPA, in response to
concerns raised by clinicians and patients. The panel consisted of experts in the
fields of general practice, infectious diseases, microbiology, parasitology, neurology
and rheumatology, all with considerable experience in the diagnosis and
management of Lyme borreliosis. The review process included a detailed
assessment of the guidelines’ content and of the references cited in support of the
guidelines.
Areas in the ILADS guidelines highlighted for special consideration
by the panel included:
• Case definition
• Clinical diagnostic criteria
• Laboratory diagnostic criteria
• Treatment recommendations
• Potential for benefit or harm to patients from use of the guidelines
The panel concluded that:
• The ILADS guidelines are poorly constructed and do not provide a
scientifically sound evidence-based approach to the diagnosis and care of
patients with Lyme borreliosis.
• The ILADS working group does not provide evidence that it used a Cochrane-
based or similar approach in developing the guidelines. Some references do
not provide evidence to support statements for which they were cited in the
guidelines. Some good-quality peer-reviewed articles are selectively quoted,
using sub-group analyses without regard for the broader findings of the full
studies. Some references were published in an advocacy group-sponsored
journal that was not Medline-listed, others are available only as conference /
symposium abstracts or are unpublished. Some reference citations are
inaccurate, demonstrating poor attention to detail.
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
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Case definitions
The ILADS guidelines’ case definitions for Lyme disease are confused, lack
specificity and are potentially dangerous, because their use can result in a high risk
of misdiagnosis. The Lyme disease symptom list is non-specific and unhelpful,
particularly for what the ILADS authors refer to as chronic Lyme disease.
Clinical diagnostic criteria
The ILADS guidelines authors acknowledge the poor specificity of the clinical
diagnostic criteria through their admission that case presentations attributed to Lyme
disease using their criteria can be identical to other multisystem disorders, including
systemic lupus erythematosus, rheumatoid arthritis and fibromyalgia. They also
include neurologic features such as demyelinating disease, neuropsychiatric
presentations and sometimes motor neurone disease, but do not offer any evidence
to substantiate a causative role for Borrelia burgdorferi infection in these conditions.
Furthermore, the symptom list is so broad-ranging and nonspecific that its application
could result in many patients being diagnosed as potential cases of “chronic Lyme
disease” without any definitive evidence of B. burgdorferi infection.
Laboratory diagnostic criteria
The ILADS guidelines contain misleading information regarding laboratory diagnostic
criteria for the diagnosis of Lyme borreliosis. It is well-recognised that laboratory
tests have only a limited place in supporting a diagnosis of erythema migrans, but
modern-generation antibody tests have a high degree of sensitivity in later stages of
infection. Internationally-accepted tests and interpretative criteria were developed for
diagnostic purposes. They were not developed primarily for epidemiological or
research purposes, as stated incorrectly in the ILADS guidelines. The ILADS
guidelines do not offer adequate evidence to support the use of less specific
immunoblot criteria than those recommended by international authorities.
Treatment recommendations
The ILADS guidelines authors do not provide credible evidence to support their
treatment recommendations, which include prolonged use of oral or parenteral
antibiotics, singly, sequentially or in combination.
There is potential for harm from use of ILADS guidelines.
• Patients with other serious conditions who receive a misdiagnosis of Lyme
disease through use of ILADS guidelines risk losing opportunities for
diagnosis and treatment of their illnesses.
• Patients receiving prolonged antibiotic treatments are at risk of organ
damage from adverse effects of the drugs as well as risk of secondary
infections such as Clostridium difficile entercolitis, multi-resistant Gram-
positive or Gram-negative bacterial infections and fungal infections.
Patients receiving prolonged treatment with parenteral antibiotics have
additional infection-related and other risks associated with long-term
intravascular access devices.
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
8/12/2010 4
• Other potential harms to patients associated with misdiagnosis include
psychological damage through fixation on an unsubstantiated diagnosis of
Lyme disease and financial hardship from recommendation and provision
of repeated and prolonged courses of oral or parenteral antibiotics that
doctors providing NHS treatment do not consider appropriate for provision
under the NHS. This can also lead to breakdown of relationships between
patients and their NHS doctors.
The panel recommends that:
• the HPA should not include the ILADS guidelines in the list of guidelines and
other references recommended by the HPA for help and support in the
diagnosis and management of Lyme borreliosis.
• the HPA should consider providing a warning against the use of the ILADS
guidelines as part of its health protection function, in view of the potential risk
to patients from misdiagnosis and inappropriate treatment.
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
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Summary of the Review Panel’s findings
The review group conducted a critical review of the ILADS guidelines (Cameron et al,
2004) from the perspectives of the reliability of the evidence base in respect of the
clinical manifestations, pathology and natural history of Lyme disease; the
appropriate and validated use of clinical and laboratory diagnostic criteria; and the
effectiveness and safety of the recommended treatment.
Background: the natural history of Lyme borreliosis, its diagnosis
and management
Lyme borreliosis is the direct consequence of infection with the spirochaete Borrelia
burgdorferi sensu lato, acquired as a result of a person being bitten by a tick carrying
B burgdorferi. The acute infection generally comprises erythema migrans, an
erythematous rash spreading from the site of a tick bite. In its typical form this rash is
readily diagnosed by clinical observation and examination. Laboratory diagnostic
tests are not required routinely for the diagnosis of erythema migrans, but they can
be helpful in occasional atypical cases. It is readily acknowledged that serological
tests may be negative at this early stage of infection, as an antibody response can
take several weeks to develop. In some untreated patients B burgdorferi can spread
to other organs and tissues and cause presentations of disseminated disease,
principally affecting the nervous and musculoskeletal systems and the skin.
Laboratory support is required for diagnosis of disseminated and late manifestations
of Lyme borreliosis as no clinical feature of later-stage disease is unique to B
burgdorferi infection. Case definitions giving detailed descriptions of clinical features
and laboratory diagnostic criteria for Lyme borreliosis in Europe were published in
1997 and have recently been revalidated. (Stanek G et al. 2010) Long-term objective
and subjective sequelae were also reviewed in that publication.
Specialist societies and national authorities in Europe and North America have
published evidence-based treatment guidelines and consensus documents, and a
comparison of first-line treatments is summarised in O’Connell 2010. The most
recent guidelines are from the European Federation of Neurological Societies
(Mygland et al 2010). The great majority of B. burgdorferi infections, including most
presentations of acute neuroborreliosis (the most common complication seen in the
UK) can be treated successfully with relatively short courses of oral antibiotics (ten to
28 days, depending on clinical presentation). Parenteral treatment for two to three
weeks is recommended for encephalitis or myelitis and for rare cases of arthritis.
It is well-recognised that some patients may have residual symptoms and objective
clinical findings following treatment. Patients who sustained severe tissue damage
prior to treatment may improve only slowly and incompletely. (Kruger et al. 1989;
Ljostad and Mygland 2010) Occasional patients with facial palsy have some residual
paresis. (Skogman et al. 2008) Some patients can have persistent non-specific
symptoms such as fatigue, headaches, myalgias, arthralgias for some time without
clinical or laboratory evidence of continuing active infection. (Marques 2008) Similar
symptoms can occur following other systemic infections. (Hickie et al. 2006) The
incidence of prolonged post-infection symptoms associated with Lyme borreliosis is
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
8/12/2010 6
unclear, but recent prospective European studies incorporating uninfected control
groups showed good outcomes for the great majority of patients with appropriately
treated Lyme borreliosis. The incidence of long-term subjective symptoms appeared
to be similar in patients and uninfected controls. (Skogman et al. 2008; Cerar et al.
2010)
General comments on the ILADS guidelines and their development
The ILADS guidelines did not undergo independent peer review prior to publication.
They were published as a supplement to a peer-reviewed journal, but did not
undergo the journal’s standard peer-review process. (Manzotti 2006; personal
communication on file)
They are poorly constructed and do not have a sound evidence base
Development of evidence based medicine guidelines is a process that
usually consists of the following steps:
1. explicitly defining a question
2. explicit statement of a method of assessing quality of evidence
3. systematic review of all available evidence and determination of the data that
meets minimum requirements for inclusion
4. review of selected data, assigning each study a class of evidence, using
predefined criteria (see methodologic examples in the Appendix)
5. aggregating the data to reach conclusions, grading each conclusion based on
the strength of the available evidence. The Appendix gives examples of
evidence grading for guidelines from the Infectious Diseases Society of
America (IDSA), the American Academy of Neurology (AAN) and ILADS.
Criteria for inclusion and exclusion of data in the ILADS guidelines
The ILADS Guidelines data acquisition process was described as follows: “Our data
sources are English-language articles published from 1975 to 2003. The selection
panel synthesized the recommendations from published and expert opinion. Human
studies of Lyme disease were identified from MEDLINE (1975 to 2003) and from
references in pertinent articles and reviews. Also included are abstracts and material
presented at professional meetings and the collective experience of the ILADS
Working Group treating tens of thousands of Lyme disease patients.”
The ILADS guidelines authors do not list explicit criteria for inclusion or exclusion of
data. They do not indicate how many studies were reviewed, and do not specify how
many were accepted and rejected and the reasons for these decisions. Guidelines
generally restrict data sources to peer reviewed publications, because abstracts and
meeting presentations rarely contain sufficient information to assess study validity.
Some references used in support of the ILADS guidelines were published in an
advocacy group-sponsored journal that was not Medline-listed and is no longer
published (Journal of Spirochetal and Tickborne Diseases). Others are poor-quality
conference abstracts or appear in symposium supplements without having
undergone a full peer-review process and others are unpublished. Examples include
ILADS guidelines references 16, 17, 19, 21, 34, 47, 57, 58, 62.
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
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There is evidence of selective quotation from good-quality peer-reviewed articles; in
particular sub-group analyses are used without regard for the broader findings of the
full studies. Examples include ILADS references 24, 27.
Many of the studies cited by the ILADS authors to support their view that the
outcome of Lyme disease treated by current standard recommendations is poor were
performed in patients infected in the 1970s and 1980s. Many of those early study
participants were untreated or had inadequate treatment by modern standards.
Examples include ILADS references 3, 4, 12, 24. The ILADS guidelines authors
ignored the findings of studies showing that the major reason for non-response to
treatment for Lyme disease is misdiagnosis (ILADS references 63, 64). Other
references do not support ILADS guidelines statements and are inappropriately cited.
Examples include ILADS references 10, 37, 38, 39, 40, 44, 45, 46. Some references
are inaccurately cited.
Evidence ratings and tables in the ILADS guidelines
The ILADS authors stated that they used a method of evidence rating. They did not
include an evidence table or any indication of how they rated any of the information
they included in their reference list. In the absence of any such information, a
Review Panel member assessed the quality of evidence in the ILADS-referenced
studies, using the American Academy of Neurology (AAN) classification system.
AAN classification (see the Appendix for a more detailed description)
Class I: Randomised, controlled clinical trial with masked or objective outcome
assessment in a representative population
Class II: Prospective matched group cohort study in a representative population
with masked outcome assessment or a randomised controlled trial in a
representative population
Class III: All other controlled trails in a representative population where outcome
is independently assessed or independently derived by objective outcome
measurement.
Class IV: Contains too little information to assess methodologic validity.
The ILADS guidelines reference list indicates inclusion of 66 studies which can be
divided into eight types (table 1).
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
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Table 1. Categorisation of the studies included in the ILADS guidelines
Type of
study Description Number of
studies
1 Studies included and rated in the 2000 IDSA guideline
(Wormser et al. 2000). 11
2 Studies in progress, with no accrued data to date. 2
3 ILADS website. 1
4 Abstracts, meeting proceedings or other non-Medline
listed material. These can be categorized as AAN Class
IV, as containing too little information to assess
methodologic validity.
9
5 Review articles and other material expressing opinions but
not data. These can also be categorised as AAN Class IV. 16
6 Studies not related to treatment of Lyme disease. 18
7 Studies demonstrating that excessive treatment is bad. 4
8 Papers addressing treatment and not included in the 2000
IDSA Guidelines (Wormser et al. 2000). 5 (see
details in
table 2)
Total 66
The reasons why five treatment studies included in the ILADS guidelines were
omitted from the IDSA 2000 guidelines are given in table 2.
Table 2. Studies included in ILADS guidelines that were omitted from the 2000
IDSA guidelines
ILADS
reference
number
Authors Reason for omission from 2000 IDSA
guidelines.
18 Cimmino and Accardo 1992 An anecdotal description of two patients
with Lyme arthritis (AAN Class IV).
20 Lawrence et al. 1995 A case report of one patient (AAN Class
IV).
29 Petrovic et al. 1998 An observational study of four patients
(AAN Class IV.)
41 Barsic et al. 2000 A comparative study showing equivalence
of doxycycline and azithromycin treatment
(i.e. not relevant).
61 Wahlberg et al. 1994 A non-randomized, non-blinded treatment
of 100 patients with “late Lyme disease”;
with limited definitions of “late Lyme
disease” or “treatment response”. (At best
this is AAN Class III evidence).
In summary, the literature cited in the ILADS guidelines but omitted in the IDSA 2000
guidelines adds no AAN Class I or Class II evidence to those cited by the 2000 IDSA
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
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guidelines. The literature adds only one Class III and a number of Class IV studies.
Class III or IV evidence generally cannot lead to high level recommendations.
Despite the absence of any additional high level data, the ILADS guideline
consistently gives higher grades to recommendations compared to those of the IDSA
(Cameron et al 2004; Table 1). This is at variance with all standard evidence based
medicine methodology.
ILADS Clinical case definitions
The ILADS case definitions are poorly constructed, incoherent and unsupported by
credible peer-reviewed evidence.
The list of Lyme disease symptoms given in the guidelines comprises many non-
specific symptoms. The ILADS guidelines authors state that the clinical presentation
of what they consider to be “chronic Lyme disease” can be identical to those of other
multisystem disorders, including systemic lupus erythematosus, rheumatoid arthritis,
fibromyalgia and chronic fatigue syndrome. They also include neurologic disorders
such as demyelinating disease, sometimes motor neurone disease as well as
neuropsychiatric presentations as being consistent with chronic Lyme disease, but do
not offer any evidence to substantiate these claims. The authors do not address the
likelihood that their poorly specific criteria will result in over-diagnosis of Lyme
disease and missed opportunities for accurate diagnosis and treatment for patients
who have other conditions.
Diagnostic tests
The ILADS guidelines authors ignore the large body of published peer-reviewed
evidence showing that laboratory tests are valuable and reliable in support of a
diagnosis of disseminated Lyme disease. Antibody tests performed to internationally
agreed and validated criteria have a high sensitivity in established infection. and
patients with late-stage Lyme borreliosis are rarely seronegative. (Stanek et al. 2010;
Wilske et al. 2007; Aguero-Rosenfeld et al. 2005; MiQ 2000). The evidence-based
serological diagnostic approach requires a two-tier test system. A sensitive but
insufficiently specific initial screening test for B. burgdorferi antibodies is followed by
supplementary testing of samples giving reactive or equivocal results in the initial
test, to assess the specificity of reactions. Immunoblots are widely used as second-
stage tests and strict interpretative criteria are important to ensure appropriate
specificity tests and avoid false positive interpretations.
The ILADS guidelines recommendation for using tests with lower specificity
increases the risk of misdiagnosis and potential harm. Examples include
immunoblots interpreted using unvalidated and less stringent criteria on specimens
that had not undergone first-stage (screening) testing, or which had tested negative
in first-stage tests. Other unreliable tests include lymphocyte transformation tests,
CD-57 tests, urinary antigen detection, spirochaete detection by microscopy and
PCR applied to blood and urine. (Marques et al 2009; Wilske et al. 2007; Duerden
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
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2006; Anon 2005; Aguero-Rosenfeld et al. 2005; Klempner et al. 2001a; Marques et
al. 2000)
Microbiological evidence
The ILADS guidelines authors advocate prolonged antibiotic therapy for patients with
“chronic Lyme disease” diagnosed by the non-specific ILADS criteria, on the basis
that they believe that there is ongoing active infection, but they offer no supporting
microbiological evidence to support this approach. Studies such as those of
Klempner et al (Klempner et al. 2001b – ILADS reference 23) performed thorough
and detailed investigations using validated and sensitive methods to seek evidence
of active infection in patients with persistent symptoms following previously treated
infections. No evidence was found to support the proposition that these patients had
persistent active infection, and antibiotic treated patients had similar outcomes to
those receiving placebo. More recent studies of prolonged treatments have shown
no sustained benefit to patients with persistent symptoms. (Fallon et al. 2008 [ILADS
reference 57 – unpublished at the time of ILADS guidelines publication]; Oksi et al.
2007; Krupp et al. 2003) Other studies have shown that Borrelia burgdorferi has not
shown development of resistance to antibiotics recommended in standard guidelines.
Experience with syphilis (another spirochaetal infection with early and late disease
manifestations) has shown good success rates using appropriate antibiotic regimens
for limited periods. (Tramont, 2010) ILADS fails to present evidence for active
infection in “chronic Lyme disease” in support of the recommendation for use of
potentially hazardous prolonged treatment for patients.
Antibiotic treatment
The ILADS guidelines authors give no coherent guidance on the type and duration of
antibiotic treatment. There is no logical reason to use benzathine penicillin, which
does not reliably achieve good CSF levels (Tramont 2010), in patients with “chronic
Lyme disease” a disorder suggested by some to be due to nervous system infection.
Oral doxcycline or parenteral ceftriaxone have been shown to be effective for
neuroborreliosis. (Mygland et al. 2010) The ILADS guidelines authors offer no
credible peer-reviewed scientific support for using agents such as metronidazole or
imipenem, or for the use of combinations of two or more antibiotics in the treatment
of Lyme borreliosis. No evidence is provided to support the prolonged use of
antibiotics such as amoxicillin, doxycycline or azithromycin at much higher doses
than usual.
The guidelines recommend continuation of antibiotic treatment until all symptoms
have resolved. Lack of response to standard treatment should be an indication to
review the diagnosis rather than taken as an indication for prolonging antibiotic
treatment, especially when ILADS’ poorly specific diagnostic criteria have been
applied. (Wormser et al. 2009; Hassett et al. 2009; Carrington-Reid et al. 1998-
ILADS reference 63; Steere et al. 1993- ILADS reference 64)
The ILADS authors also fail to acknowledge that numerous peer reviewed studies,
including some quoted in their guidelines (eg ILADS guidelines references 12, 51,
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
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52), showed that response to appropriate treatment in previously untreated or
inadequately treated later-stage Lyme borreliosis can continue for some time after a
treatment course has finished, and that response may be incomplete if there was
severe tissue damage prior to treatment. Lack of immediate complete response
should not be used as an indicator of treatment failure, and it is not an indication for
long-term treatment
The authors did not sufficiently consider non-antimicrobial effects of antibiotics such
as tetracyclines, macrolides and ceftriaxone, which include anti-inflammatory, anti-
arthritic or neuroprotective effects. (Rothstein et al. 2005; Rubin and Tamaoki 2005)
These agents can have some disease-modifying effects when used by patients with
inflammatory or autoimmune disorders or even neurological conditions such as motor
neurone disease who have been misdiagnosed as having Lyme disease by the
poorly-specific ILADS criteria.
The authors did not consider placebo effects or the natural history of variation of
symptomatology in patients with chronic fatigue syndrome, fibromyalgia or other
longterm conditions (Klempner et al. 2001; Tilley et al. 1995)
Potential for harm through use of ILADS guidelines
Patients with other serious conditions misdiagnosed as “chronic Lyme disease” using
the poorly specific ILADS guidelines risk losing opportunities for appropriate
diagnosis and management. Patients misdiagnosed and mistreated for “chronic
Lyme disease” include those with longstanding, painful and debilitating conditions
such as multiple sclerosis, rheumatoid arthritis or other autoimmune diseases. Some
have life-threatening conditions such as motor neurone disease. (ALSUntangled
Group, 2009) A diagnosis of “chronic Lyme disease” holds out the hope of a
potentially treatable condition to these vulnerable groups of patients and their
families. If non-response to treatment is used as an indication for more treatment,
many patients may endure months or years of inappropriate therapies for no benefit.
This can cause physical and psychological harm, with some patients and their
families also facing considerable financial hardship through self-funding of expensive
treatments.
Furthermore, there are significant hazards associated with inappropriate antibiotic
treatment, particularly from long-term use of broad spectrum agents. (Holzbauer et al
2010; Hassett et al 2009; Patel et al. 2000; Carrington-Reid et al, 1998; Ettestad et
al. 1995). These include toxicity of the agents, hypersensitivity (allergy), and
predisposition to infection with Clostridium difficile or antibiotic-resistant bacteria.
Children misdiagnosed with “chronic Lyme disease” are a particularly vulnerable
group, and one of the references cited by the ILADS guidelines authors (ILADS
guidelines reference 17) illustrated the dangers of misdiagnosis and gross and
painful mistreatment. Experience from other clinicians has indicated that some
children diagnosed as having “chronic Lyme disease” according to the ILADS criteria
received oral and parenteral antibiotics for years, and had unnecessary interruption
of schooling and social development, to the extent that there has been a loss of
childhood. Serious physical harm to children from adverse events related to over-
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
8/12/2010 12
use of broad spectrum antibiotics for unsubstantiated Lyme disease has also been
well-documented. (Ettestad et al.1995)
Many people suffering from medically unexplained chronic conditions such as chronic
fatigue syndrome and other illnesses are desperate for an explanation and possible
cure for their illnesses. They provide a ready customer base for any treatment that
holds out promise of a cure, however lacking in evidence. The widespread use of the
unreliable ILADS clinical guidelines in this large group of patients would result in
inappropriate treatment and potentially serious morbidity.
Conclusions of the Review Panel
The ILADS guidelines are not evidence-based and are poorly constructed.
Application of the ILADS guidelines’ poorly defined case definitions will result in a
very high risk of misdiagnosis.
Use of ILADS guidelines’ vague treatment recommendations, including
prolonged use of antibiotics, has potentially serious consequences.
Patients misdiagnosed with Lyme disease risk losing opportunities for diagnosis and
treatment of other conditions. They also risk serious physical, psychological social
and financial adverse events.
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
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REFERENCES
ALSUntangled Group. ALSUntangled Update No. 1: Investigating a bug (Lyme
disease) and a drug (Iplex) on behalf of people with ALS. Amyotrophic Lateral
Sclerosis 2009;10:248-50.
Aguero-Rosenfeld MME, Wang G, Schwartz I, Wormser GP. Diagnosis of Lyme
borreliosis. Clin Microbiol Rev 2005;18:484-509
Anon. Notice to readers: Caution regarding testing for Lyme disease. MMWR
2005;54:125.
Cameron D et al. International Lyme and Associated Diseases Society. Evidence-
based guidelines for the management of Lyme disease. Expert Rev. Anti-infect Ther.
2004;2: S1-S13
Carrington-Reid M, Schoen RT, Evans J, Rosenberg JC, Horowitz RI. The
consequences of overdiagnosis and overtreatment of Lyme disease: an
observational study. Ann Intern Med 1998;128:354-62. (ILADS guidelines reference
63)
Cerar D, Cerar T, Ruzic-Sabljic E et al. Subjective symptoms after treatment of early
Lyme disease. Am J Med 2010;2010;123:79-86.
Duerden BI. Unorthodox and unvalidated laboratory tests in the diagnosis of Lyme
borreliosis and in relation to medically unexplained symptoms. Report to the Chief
Medical Officer, Department of Health. 2006.
http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/document
s/digitalasset/dh_4138917.pdf
Ettestad PJ, Campbell GL, Welbel SF et al. Biliary complications in the treatment of
unsubstantiated Lyme disease. J Infect Dis 1995;171:356-61
Fallon B, Keilp JG, Corbera KM et al. A randomized, placebo-controlled trial of
repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 2008;70:992-
1003.
Hassett AL, Radvanski DC, Buyske S et al. Psychiatric comorbidity and other
psychological factors in patients with “chronic Lyme disease” Am J Med
2009;122:843-50
Hickie I, Davenport T, Wakefield D, et al. Postinfective and chronic fatigue
syndromes precipitated by viral and nonviral pathogens: prospective cohort study.
BMJ 2006;333(7568):575.
Holzbauer S, Kemperman M, Lynfield R. Death due to community-associated
Clostridium difficile in a woman receiving prolonged antibiotic therapy for suspected
Lyme disease. CID 2010;51:369-70.
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
8/12/2010 14
Klempner MS, Schmid CH, Hu L. et al. Intralaboratory reliability of serologic and
urine testing for Lyme disease. Am J Med. 2001;110:217-9.
Klempner M et al. Two controlled trials of antibiotic treatment in patients with
persistent symptoms and a history of Lyme disease. N Engl J Med 2001;345:85-92;
(ILADS guidelines reference 23)
Kruger H, Reuss K, Pulz M. et al. Meningoradiculitis and encephalomyelitis due to
Borrelia burgdorferi: a follow-up study of 72 patients over 27 years. et al. J Neurol
1989;236:322-328
Krupp L. et al. Study and treatment of post-Lyme disease (STOP-LD) a randomised
double-masked clinical trial. Neurology 2003;60:1923-1930
Ljostad U, Mygland A. Remaining complaints one year after treatment of acute
neuroborreliosis; frequency, pattern and risk factors. Eur J Neurol 2010;17:118-23.
Manzotti E. (Editorial director, Futuremedicine.com) -personal communication 9th
August 2006.
Marques AR, Stock F, Gill V. Evaluation of a new culture medium for Borrelia
burgdorferi. J Clin Microbiol 2000;38:4239-41.
Marques A. Chronic Lyme disease: a review. Infect Dis Clin N Am 2008;22:341-60.
Marques A, Brown MR, Fleisher TA. Natural killer cell counts are not different
between patients with post-Lyme disease syndrome and controls. Clin Vaccine
Immunol. 2009 Aug;16(8):1249-50.
MIQ 12-2000. German Society for Hygiene and Microbiology Quality Standards for
Microbiological Diagnosis of Infectious diseases - Lyme borreliosis:
http://pollux.mpk.med.uni-muenchen.de/alpha1/nrz-borrelia/miq-lyme/index.html
Mygland A, Ljostad U, Fingerle V et al. EFNS guidelines on the diagnosis and
management of European Lyme neuroborreliosis. Eur J Neurol 2010;17:8-16.
(Appendix V)
O’Connell, S. Recommendations for diagnosis and treatment of Lyme borreliosis:
guidelines and consensus papers from specialist societies and expert groups in
Europe and North America. Poster presentation: 12th International Conference on
Lyme Borreliosis and other Tick-borne diseases, Ljubljana, Slovenia 2010
Oksi J, Nikoskelainen J, Hiekkanen et al. Duration of antibiotic treatment in
disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled,
multicenter clinical trial. Eur J Clin Microbiol Infect Dis 2007;26:571-81.
Patel R, Grogg KL, Edwards WD, Wright AJ, Schwenk NM. Death from inappropriate
therapy for Lyme disease. Clin Infect Dis 2000;31:1107-9.
Independent Appraisal and Review of ILADS 2004 guidelines on Lyme disease
8/12/2010 15
Rothstein JD, Patel S, Regan MR et al. B-lactam antibiotics offer neuroprotection by
increasing glutamate transporter expression. Nature 2005;433:73.
Rubin BK, Tamaoki J. (Eds.) Antibiotics as anti-inflammatory and immunomodulatory
agents. Birkhauser Verlag, Boston, 2005.
Skogman BH, Croner S, Nordvall M et al. Lyme neuroborreliosis in children: a
prospective study of clinical features, prognosis and outcome. Pediatr Infect Dis J
2008;27:1089-94.
Stanek G, Fingerle , Hunfeld K-P et al. Lyme borreliosis: clinical case definitions for
diagnosis and management in Europe. CMI 2010; 10.1111/j.1469-
0691.2010.03175.x
Steere AC, Taylor E, McHugh GL, Logigian EL. The overdiagnosis of Lyme disease.
JAMA 1993;269:1812-1816. (ILADS guidelines reference 64)
Tilley BC, Alarcon GS, Heyse SP et al. Minocycline in rheumatoid arthritis: a 48-
week, double-blind, placebo-controlled trial. Ann Intern Med 1995;122:81-9.
Tramont EC. Treponema pallidum (syphilis) in Mandell, Douglas and Bennett,
Principles and Practice of Infectious Disease, 2010, 7th Edition Ch 238;3035-58.
Churchill Livingston Elsevier, Philadelphia PA. ISBN 978-0-4430-6839-3.
Wilske B, Fingerle V, Schulte-Spechtel U, Microbiological and serological diagnosis
of Lyme borreliosis. FEMS Immunol Med Microbiol 2007;49: 13–21.
Wormser GP, Nadelman RB, Dattwyler RJ et al. Practice Guidelines for the
Treatment of Lyme disease. Clin Infect Dis. 2000;31 [Suppl1] S1-14,
Wormser GP, Shapiro ED, Halperin JJ, Porwancher RB, O'Connell S, Nadelman RB,
Strle F, Radolf JD, Hovius JW, Baker PJ, Fingerle V, Dattwyler R. Analysis of a
flawed double-blind, placebo-controlled, clinical trial of patients claimed to have
persistent Lyme disease following treatment. Minerva Med. 2009 Apr;100(2):171-2.
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Appendix: Examples of evidence grading:
IDSA Guideline
(Wormser G, Dattwyler R, 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. CID, 2006;43:1089-1134)
Quality of evidence
I Evidence from >1 properly randomized, controlled trial
II Evidence from >1 well-designed clinical trial, without randomization; from cohort
or case controlled analytic studies (preferably from >1 center); from multiple time
series studies; or from dramatic results from uncontrolled experiments
III Evidence from opinions of respected authorities, based on clinical experience,
descriptive studies, or reports of expert Committees
American Academy of Neurology
(French J, Gronseth G. Lost in a jungle of evidence; we need a compass.
Neurology 2008;71:1634-38)
Table Classification scheme requirements for therapeutic questions
Class I. A randomized, controlled clinical trial of the intervention of interest with
masked or objective outcome assessment, in a representative population. Relevant
baseline characteristics are presented and substantially equivalent among
treatment groups or there is appropriate statistical adjustment for differences.
The following are also required:
a. Concealed allocation
b. Primary outcome(s) clearly defined
c. Exclusion/inclusion criteria clearly defined
d. Adequate accounting for dropouts (with at least 80% of enrolled subjects
completing the study) and crossovers with numbers sufficiently low to have minimal
potential for bias
e. For non-inferiority or equivalence trials claiming to prove efficacy for one or both
drugs, the following are also required:
• The standard treatment used in the study is substantially similar to that used
in previous studies establishing efficacy of the standard treatment (e.g., for a
drug, the mode of administration, dose, and dosage adjustments are similar
to those previously shown to be effective).
• The inclusion and exclusion criteria for patient selection and the outcomes
of patients on the standard treatment are substantially equivalent to those of
previous studies establishing efficacy of the standard treatment.
• The interpretation of the results of the study is based on an observed-cases
analysis.
Class II. A randomized controlled clinical trial of the intervention of interest in a
representative population with masked or objective outcome assessment that lacks
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one criteria a–e above or a prospective matched cohort study with masked or
objective outcome assessment in a representative population that meets b–e
above.
Relevant baseline characteristics are presented and substantially equivalent
among treatment groups or there is appropriate statistical adjustment for
differences.
Class III. All other controlled trials (including well-defined natural history controls or
patients serving as their own controls) in a representative population, where
outcome is independently assessed, or independently derived by objective
outcome measurement.
Class IV. Studies not meeting Class I, II, or III criteria including consensus or
expert opinion.
*Note that numbers 1–3 in Class Ie are required for Class II in equivalence trials. If
any one of the three is missing, the class is automatically downgraded to a Class
III.
ILADS
A rating of I indicates that at least one randomized controlled trial supports the
recommendation; II, evidence from at least one well-designed clinical trial without
randomization supports the recommendation; and III, ‘expert opinion’. (The ILADS
Working Group, 2004)