National
Guideline Clearinghouse:
Summary of ILADS Guidelines for Lyme Disease
NGC is
an initiative of the Agency
for Healthcare Research and Quality (AHRQ), U.S. Department
of Health and Human Services. NGC was originally created by
AHRQ in partnership with the American
Medical Association and the American Association of Health
Plans (now America’s
Health Insurance Plans [AHIP]). The NGC
mission is to provide physicians, nurses, and other health
professionals, health care providers, health plans, integrated
delivery systems, purchasers and others an accessible mechanism
for obtaining objective, detailed information on clinical practice
guidelines and to further their dissemination, implementation
and use.
Brief
Summary: Practice guidelines for the treatment of Lyme disease.
(International Lyme and Associated Diseases Society)
GUIDELINE
STATUS: This is the current release of the guideline.
MAJOR
RECOMMENDATIONS
Highlights
of Guidelines
- Since
there is currently no definitive test for Lyme disease, laboratory
results should not be used to exclude an individual from treatment.
- Lyme
disease is a clinical diagnosis and tests should be used to
support rather than supersede the physician’s judgment.
- The
early use of antibiotics can prevent persistent, recurrent,
and refractory Lyme disease.
- The
duration of therapy should be guided by clinical response,
rather than by an arbitrary (ie, 30 day) treatment course.
- The
practice of stopping antibiotics to allow for delayed recovery
is not recommended for persistent Lyme disease. In these cases,
it is reasonable to continue treatment for several months
after clinical and laboratory abnormalities have begun to
resolve and symptoms have disappeared.
Diagnostic
Concerns
The most
important method for preventing chronic Lyme disease is recognition
of the early manifestations of the disease.
Atypical
Early Presentations
Early Lyme
disease classically presents with a single erythema migrans
(EM or “bull’s-eye”) rash. The EM rash may be
absent in over 50% of Lyme disease cases, however. Patients
should be made aware of the significance of a range of rashes
beyond the classic EM, including multiple, flat, raised, or
blistering rashes. Central clearing was absent in over half
of a series of EM rashes. Rashes can also mimic other common
presentations including a spider bite, ringworm, or cellulitis.
Physicians
should be aware that fewer than 50% of all Lyme disease patients
recall a tick bite. Early Lyme disease should also be considered
in an evaluation of “off-season” onset when flu-like
symptoms, fever, and chills occur in the summer and fall. Early
recognition of atypical early Lyme disease presentation is most
likely to occur when the patient has been educated on this topic.
New
Chronic Lyme Disease Presentations
A detailed
history may be helpful for suggesting a diagnosis of chronic
Lyme disease. Headache, stiff neck, sleep disturbance, and problems
with memory and concentration are findings frequently associated
with neurologic Lyme disease. Other clues to Lyme disease have
been identified, although these have not been consistently present
in each patient: numbness and tingling, muscle twitching, photosensitivity,
hyperacusis, tinnitus, lightheadedness, and depression.
Most patients
diagnosed with chronic Lyme disease have an indolent onset and
variable course. Neurologic and rheumatologic symptoms are characteristic,
and increased severity of symptoms on wakening is common. Neuropsychiatric
symptoms alone are more often seen in chronic than acute Lyme
disease. Although many studies have found that such clinical
features are often not unique to Lyme disease, the striking
association of musculoskeletal and neuropsychiatric symptoms,
the variability of these symptoms, and their recurrent nature
may support a diagnosis of the disease.
The
Limitations of Physical Findings
A comprehensive
physical examination should be performed, with special attention
to neurologic, rheumatologic, and cardiac symptoms associated
with Lyme disease.
Physical
findings are nonspecific and often normal, but arthritis, meningitis,
and Bell’s palsy may sometimes be noted. Available data
suggest that objective evidence alone is inadequate to make
treatment decisions, because a significant number of chronic
Lyme disease cases may occur in symptomatic patients without
objective features on examination or confirmatory laboratory
testing.
Factors
other than physical findings, such as a history of potential
exposure, known tick bites, rashes, or symptoms consistent with
the typical multisystem presentation of Lyme disease, must also
be considered in determining whether an individual patient is
a candidate for antibiotic therapy.
Sensitivity
Limitations of Testing
Treatment
decisions should not be based routinely or exclusively on laboratory
findings. The two-tier diagnostic criteria, requiring both a
positive enzyme-linked immunosorbent assay (ELISA) and western
blot, lacks sensitivity and leaves a significant number of individuals
with Lyme disease undiagnosed and untreated. These diagnostic
criteria were intended to improve the specificity of tests to
aid in identifying well-defined Lyme disease cases for research
studies. Though arbitrarily chosen, these criteria have been
used as rigid diagnostic benchmarks that have prevented individuals
with Lyme disease from obtaining treatment. Diagnosis of Lyme
disease by two-tier confirmation fails to detect up to 90% of
cases and does not distinguish between acute, chronic, or resolved
infection.
The Centers
for Disease Control and Prevention (CDC) considers a western
blot positive if at least 5 of 10 immunoglobulin G (IgG) bands
or 2 of 3 immunoglobulin M (IgM) bands are positive. However,
other definitions for western blot confirmation have been proposed
to improve the test sensitivity. In fact, several studies showed
that sensitivity and specificity for both the IgM and IgG western
blot range from 92 to 96% when only two specific bands are positive.
Lumbar
puncture has also been disappointing as a diagnostic test to
rule out concomitant central nervous system infection. In Lyme
disease, evaluation of cerebrospinal fluid is unreliable for
a diagnosis of encephalopathy and neuropathy because of poor
sensitivity. For example, pleocytosis was present in only one
of 27 patients (sensitivity 3%) and with only seven cells. The
antibody index was positive (>1) in only one of 27 patients
(sensitivity 3%). An index is the ratio between Lyme ELISA antibodies
in the spinal fluid and Lyme ELISA antibodies in the serum.
The proposed index of 1.3 would be expected to have even worse
sensitivity.
Several
additional tests for Lyme disease have been evaluated. These
include antigen capture, urine antigen, and polymerase chain
reaction. Each has advantages and disadvantages in terms of
convenience, cost, assay standardization, availability, and
reliability. These tests remain an option to identify people
at high risk for persistent, recurrent, and refractory Lyme
disease but have not been standardized.
Seronegative
Lyme Disease
A patient
who has tested seronegative may have a clinical presentation
consistent with Lyme disease, especially if there is no evidence
to indicate another illness.
Although
many individuals do not have confirmatory serologic tests, surveillance
studies show that these patients may have a similar risk of
developing persistent, recurrent, and refractory Lyme disease
compared with the seropositive population.
Continued
Importance of Differential Diagnosis
The differential
diagnosis of Lyme disease requires consideration of both infectious
and noninfectious etiologies. Among noninfectious causes are
thyroid disease, degenerative arthritis, metabolic disorders
(vitamin B12 deficiency, diabetes), heavy metal toxicity, vasculitis,
and primary psychiatric disorders.
Infectious
causes can mimic certain aspects of the typical multisystem
illness seen in chronic Lyme disease. These include viral syndromes,
such as parvovirus B19 or West Nile virus infection, and bacterial
mimics, such as relapsing fever, syphilis, leptospirosis, and
mycoplasma.
The clinical
features of chronic Lyme disease can be indistinguishable from
fibromyalgia and chronic fatigue syndrome. These illnesses must
be closely scrutinized for the possibility of etiological Borrelia
burgdorferi infection.
Clinical
Judgment
Clinical
judgment remains necessary in the diagnosis of late Lyme disease.
A problem in some studies that relied on objective evidence
was that treatment occurred too late, leaving the patient at
risk for persistent and refractory Lyme disease.
As noted,
time-honored beliefs in objective findings and two-tier serologic
testing have not withstood close scrutiny. Lyme disease should
be suspected in patients with newly acquired or chronic symptoms
(headaches, memory and concentration problems, and joint pain).
Management of patients diagnosed on the basis of clinical judgment
needs to be tested further in prospective trials, and diagnostic
reproducibility must be verified.
Testing
for Coinfection
Polymicrobial
infection is a new concern for individuals with Lyme disease,
and coinfection is increasingly reported in critically ill individuals.
Although B. burgdorferi remains the most common pathogen
in tick-borne illnesses, coinfections including Ehrlichia
and Babesia strains are increasingly noted in patients
with Lyme disease, particularly in those with chronic illness.
Bartonella is another organism that is carried by the
same ticks that are infected with B. burgdorferi, and
evidence suggests that it is a potential coinfecting agent in
Lyme disease.
Recent
animal and human studies suggest that Lyme disease may be more
severe and resistant to therapy in coinfected patients. Thus,
concurrent testing and treatment for coinfection is mandatory
in Lyme disease patients.
Treatment
Considerations
Since Lyme
disease can become persistent, recurrent, and refractory even
in the face of antibiotic therapy, evaluation and treatment
must be prompt and aggressive.
Prompt
Use of Antibiotics
Although
no well designed studies have been carried out, the available
data support the prompt use of antibiotics to prevent chronic
Lyme disease. Antibiotic therapy may need to be initiated upon
suspicion of the diagnosis, even without definitive proof. Neither
the optimal antibiotic dose nor the duration of therapy has
been standardized, but limited data suggest a benefit from increased
dosages and longer treatment, comparable to the data on tuberculosis
and leprosy which are caused by similarly slow-growing pathogens.
Choosing
an Antibiotic
In acute
Lyme disease, the choice of antibiotics should be tailored to
the individual and take into account the severity of the disease
as well as the patient’s age, ability to tolerate side
effects, clinical features, allergy profile, comorbidities,
prior exposure, epidemiologic setting, and cost.
Conversely,
persistent and refractory Lyme disease treatment is more likely
to include intravenous and/or intramuscular antibiotics. The
choices depend in part on the patient’s response to antibiotic
therapy and on the success of antibiotics in treating other
Lyme disease patients.
Therapy
usually starts with oral antibiotics, and some experts recommend
high dosages. The choice of antibiotic therapy is guided by
weighing the greater activity of intravenous antibiotics in
the central nervous system against the lower cost and easy administration
of oral antibiotics for B. burgdorferi.
Oral
Antibiotic Options
For many
Lyme disease patients, there is no clear advantage of parenteral
therapy. Along with cost considerations and pressure to treat
patients with Lyme disease with the least intervention, there
is growing interest in the use of oral therapy.
First-line
drug therapies for Lyme disease may include (in alphabetical
order): oral amoxicillin, azithromycin, cefuroxime, clarithromycin,
doxycycline, and tetracycline. These antibiotics have similar
favorable results in comparative trials of early Lyme disease.
Intravenous
Antibiotic Options
It is common
practice to consider intravenous antibiotics upon failure of
oral medications in patients with persistent, recurrent, or
refractory Lyme disease, and as the first line of therapy for
certain conditions, (i.e., encephalitis, meningitis, optic neuritis,
joint effusions, and heart block).
Ideally,
the intravenous antibiotic should be selected on the basis of
in vitro sensitivity testing or clinical experience. Intravenous
antibiotics are also justified by concern for penetration into
the central nervous system.
Until recently,
ceftriaxone, cefotaxime, and penicillin were the only intravenous
antibiotics routinely studied for use in Lyme disease. Intravenous
imipenem, azithromycin, and doxycycline have an adequate antispirochetal
spectrum of activity and may represent suitable alternative
therapies. However, the latter two drugs are often considered
for intravenous use only if they are not tolerated orally.
Intramuscular
Antibiotic Options
Intramuscular
benzathine penicillin (1.2 to 2.4 million units per week) is
sometimes effective in patients who do not respond to oral and
intravenous antibiotics. If intramuscular benzathine penicillin
is used, long-term therapy may be necessary due to the low serum
concentration of this form of penicillin. Benzathine penicillin
has mainly been used in patients who have had multiple relapses
while receiving oral or intravenous antibiotic therapy or who
are intolerant of oral or intravenous antibiotics.
Combination
Antibiotic Treatment
Combination
therapy with two or more antibiotics is now increasingly used
for refractory Lyme disease and has also been given as initial
therapy for some chronic presentations.
This approach
is already used for another tick-borne illness, babesiosis.
Oral amoxicillin, cefuroxime, or (more recently) cefdinir combined
with a macrolide (azithromycin or clarithromycin) are examples
of combination regimens that have proven successful in clinical
practice, although controlled clinical trials are lacking in
persistent, recurrent, and refractory Lyme disease.
Combination
therapy in patients with Lyme disease raises the risk of adverse
events. This risk must be weighed against the improved response
to combination therapy in Lyme disease patients failing single
agents.
Sequential
Treatment
Clinicians
increasingly use the sequence of an intravenous antibiotic followed
by an oral or intramuscular antibiotic. In two recent case series
that employed combination therapy and sequential therapy, most
patients were successfully treated. A logical and attractive
sequence would be to use intravenous therapy first (e.g., intravenous
ceftriaxone), at least until disease progression is arrested
and then follow with oral therapy for persistent and recurrent
Lyme disease.
Dosage
Increasingly,
clinicians recommend that certain drugs used for Lyme disease
be given at higher daily doses: for example, 3,000–6,000
mg of amoxicillin, 300–400 mg doxycycline, and 500–600
mg of azithromycin. Some clinicians prescribe antibiotics using
blood levels to guide higher doses. Close monitoring of complete
blood counts and chemistries are also required with this approach.
With higher
doses, there may be an increase in adverse events in general
and gastrointestinal problems in particular. Acidophilus has
reportedly reduced the incidence of Clostridium difficile
colitis and non-C. difficile antibiotic-related diarrhea.
Serious
adverse effects of antibiotics, however, were less common than
previous estimates. In a recent clinical trial of chronic Lyme
disease, the overall serious adverse event rate was 3% after
three months of antibiotics, including 1 month of intravenous
antibiotics. Clinicians who have experience with higher dose
antibiotic therapy must balance the benefit of higher drug levels
achieved with this therapy against the modest risk of gastrointestinal
and other side effects.
Duration
of Therapy
Because
of the disappointing long-term outcome with shorter courses
of antibiotics, the practice of stopping antibiotics to allow
for a delayed recovery is no longer recommended for patients
with persistent, recurrent, and refractory Lyme disease. Reports
show failure rates of 30–62% within 3 years of short-course
treatment using antibiotics thought to be effective for Lyme
disease. Conversely for neurologic complications of Lyme disease,
doubling the length of intravenous ceftriaxone treatment from
2 to 4 weeks improved the success rate from 66 to 80%.
The management
of chronic Lyme disease must be individualized, since patients
will vary according to severity of presentation and response
to previous treatment.
Concurrent
risk factors (i.e., coinfections, previous treatment failures,
frequent relapses, neurologic involvement, or previous use of
corticosteroids) or evidence of unusually severe Lyme disease
should lead to the initiation of prolonged and/or intravenous
antibiotic treatment. Physicians should always assess the patient’s
response to treatment before deciding on appropriate duration
of therapy (i.e., weeks versus months).
Empiric
Treatment
The importance
of establishing the diagnosis of Lyme disease is heightened
in light of increasing concern about antibiotic overuse. After
an appropriate history, physical examination, and laboratory
testing are completed, empiric antimicrobial therapy should
be initiated on the basis of clinical clues, the severity of
the patient’s acute illness, underlying disease, and the
likelihood of B. burgdorferi infection. The International Lyme
and Associated Diseases Society (ILADS) working group recommends
that empiric treatment be considered routine for patients with
a likely diagnosis of Lyme disease.
Persistent
Lyme Disease
Persistent
Lyme disease is more resistant to treatment and more likely
to produce a relapse. Although persistent Lyme disease may resolve
without additional therapy, many experts believe that this condition
should be treated with repeated and prolonged antibiotics. Physicians
should extend the duration of antibiotics to prevent or delay
recurrent and refractory Lyme disease.
Recurrent
Lyme Disease
Despite
previous antibiotic treatment, Lyme disease has a propensity
for relapse and requires careful follow-up for years. The data
suggest that failure to eradicate the organism may be the reason
for a recurrence of symptoms. Early and aggressive treatment
with antibiotics is indicated for recurrent Lyme disease. The
ultimate impact from retreating each episode of recurrent Lyme
disease is currently unclear.
Refractory
Lyme Disease
Refractory
Lyme disease is a devastating condition that usually affects
patients with persistent symptomatology and long-term disability.
Prompt and aggressive institution of antibiotic therapy may
be essential to prevent refractory disease. Increasing evidence
shows that antibiotics have a beneficial effect on the course
of refractory Lyme disease even in cases where the patient is
intolerant of antibiotics or when a previous regimen has failed.
Several months of therapy are often required to produce clear
evidence of improvement. During this time, symptomatic treatment
may be combined with antibiotic treatment.
Treatment
Failure
When patients
fail to respond or their conditions deteriorate after initiation
of empiric therapy, a number of possibilities should be considered
other than Jarisch-Herxheimer reaction. These include adverse
events that limit treatment, allergic history to medication,
inappropriate or inadequate dosing regimen, compliance problems,
incorrect medication, immune sequelae, and sequestering of the
organism (e.g., in the central nervous system). An alternative
diagnosis or coinfection should also be considered.
Symptomatic
Treatment
Although
there may be a potential role for symptomatic treatment in chronic
Lyme disease, this approach has little support due to the strong
possibility of persistent infection. Owing to the potential
hazard of immunosuppression and the poor outcome in one study,
steroid therapy is not recommended. Surgical synovectomy is
associated with significant morbidity and does not address neurologic
presentations; it should be reserved for knee pain failing antibiotic
treatment. Intra-articular steroid injection may be useful as
a temporizing procedure in patients with persistent knee pain
but this runs the risk of masking persistent infection.
Symptomatic
therapy (particularly anti-inflammatory medications, tricyclic
antidepressants, selective serotonin re-uptake inhibitors, and
hydroxychloroquine) may be useful in concert with antibiotics
and in individuals failing antibiotics.
Hyperbaric
oxygen therapy (HBOT) is under study but is not recommended
for routine therapeutic use. Other treatments, including cholestyramine
(CSM), antifungal therapy, and antiviral agents require further
study.
Since patients
are becoming more interested in alternative therapies (e.g.,
traditional Chinese medicine, anti-oxidants, hyperthermia, bee
venom, naturopathy and homeopathy), physicians should be prepared
to address questions regarding these topics.
Fibromyalgia
The outcome
of treating fibromyalgia secondary to Lyme disease with nonantibiotic
regimens has been poor. The most encouraging clinical trial
showed success in only one of 15 patients and only modest improvement
in 6 of 15 individuals with fibromyalgia despite 2 years of
treatment.
Antibiotic
therapy has been much more effective than supportive therapy
in symptomatic patients with fibromyalgia secondary to Lyme
disease.
Fibromyalgia
treatment alone without antibiotics raises the risk of conversion
to refractory chronic Lyme disease and/or exacerbation of an
undiagnosed persistent infection and is not recommended. Increasingly,
clinicians do not feel comfortable treating fibromyalgia in
Lyme disease without antibiotics.
Decision
to Stop Antibiotics
Several
studies of patients with Lyme disease have recommended that
antibiotics be discontinued after 30 days of treatment. Complicating
the decision to stop antibiotics is the fact that some patients
present with disease recurrence after the resolution of their
initial Lyme disease symptoms. This is consistent with incomplete
antibiotic therapy. Although the optimal time to discontinue
antibiotics is unknown, it appears to be dependent on the extent
of symptomatology, the patient’s previous response to antibiotics,
and the overall response to therapy (see below).
Rather
than an arbitrary 30-day treatment course, the patient’s
clinical response should guide duration of therapy. Patients
must therefore be carefully evaluated for persistent infection
before a decision is made to withhold therapy.
The decision
to discontinue antibiotics should be made in consultation with
the patient and should take into account such factors as the
frequency and duration of persistent infection, frequency of
recurrence, probability of refractory Lyme disease, gains with
antibiotics, the importance to the patient of discontinuing
antibiotics, and potential for careful follow-up.
The ideal
approach would be to continue therapy for Lyme disease until
the Lyme spirochete is eradicated. Unfortunately there is currently
no test available to determine this point. Therefore, the clinician
must rely on the factors outlined above to decide on the length
of antibiotic therapy for chronic Lyme disease.
Alternative
Antibiotics
There is
compelling evidence that Lyme disease can result in serious
and potentially refractory illness. Use of alternative antibiotics
to treat early Lyme disease with erythema migrans is generally
not indicated unless coinfection is suspected.
The ILADS
Working Group believes that the risk of alternative antibiotics
is acceptable in selected Lyme disease patients presenting with
chronic Lyme disease. Alternative antibiotics include less commonly
used oral antibiotics (cefixime, cefdinir, metronidazole) and
intravenous antibiotics (imipenem, azithromycin). The role of
alternative antibiotics in low-risk patients is less certain
and there is less consensus among the guideline developers as
to whether the potential benefits outweigh the risks.
Therapy
for Coinfection
Therapy
for polymicrobial infection in Lyme disease is a rapidly changing
area of clinical practice. Uncomplicated Lyme disease may be
managed without addressing coinfection by means of standard
oral or parenteral antibiotic therapy. Some but not all experts
recommend therapy for subclinical or chronic coinfection with
Ehrlichia, Babesia, or Bartonella on the basis of their belief
that responses are more prompt with this approach.
The dose,
duration, and type of treatment for coinfections have not been
defined. Published reports of coinfection are limited to a small
number of patients treated in open-label, nonrandomized studies.
Doxycycline has been indicated for Ehrlichia. A recently published
randomized trial determined that treatment of severe Babesia
microti with the combination of atovaquone and azithromycin
was as effective as the use of standard oral therapy with clindamycin
and quinine.
The decision
to use alternative antibiotics should be based on the individual
case, including a careful assessment of the patient’s risk
factors and personal preferences. Patients managed in this way
must be carefully selected and considered reliable for follow-up.
Further controlled studies are needed to address the optimal
antimicrobial agents for coinfections and the optimal duration
of therapy.
BIBLIOGRAPHIC
SOURCE(S) ·
Evidence-based
guidelines for the management of Lyme disease. Expert Rev
Antiinfect Ther 2004;2(1 Suppl):S1-13. [66 references]
DATE
RELEASED: 2004
GUIDELINE
DEVELOPER(S): International Lyme and Associated Diseases
Society — Disease Specific Society
SOURCE(S)
OF FUNDING: International Lyme and Associated Diseases Society
GUIDELINE
COMMITTEE: The ILADS Working Group
COMPOSITION
OF GROUP THAT AUTHORED THE GUIDELINE: Working Group Members:
Daniel Cameron, MD, MPH, Internal Medicine and Epidemiology,
Mt. Kisco, New York; Andrea Gaito, MD, Rheumatology, Basking
Ridge, New Jersey; Nick Harris, PhD, Immunology, Pal Alto, California;
Gregory Bach, DO, Family and Integrative Medicine, Colmar, Pennsylvania;
Sabra Bellovin, MD, Family Practice, Portsmouth, Virginia; Kenneth
Bock, MD, Family Practice, Rhineback, New York; Steven Bock,
MD, Family Practice, Rhineback, New York; Joseph Burrascano,
MD, Internal Medicine, East Hampton, New York; Constance Dickey,
RN, Registered Nurse, Hampden, Maine; Richard Horowitz, MD,
Internal Medicine, Hyde Park, New York; Steven Phillips, MD,
Internal Medicine, Ridgefield, Connecticut; Laurence Meer-Scherrer,
MD, Internal Medicine, Flamatt, Switzerland; Bernard Raxlen,
MD; Psychiatry, Greenwich, Connecticut; Virginia Sherr, MD,
Psychiatry, Holland, Pennsylvania; Harold Smith, MD, Emergency
Medicine, Danville, Pennsylvania; Pat Smith, President, Lyme
Disease Association, Inc., Jackson, New Jersey; Raphael Stricker,
MD, Hematology and Immunotherapy, San Francisco, California
FINANCIAL
DISCLOSURES/CONFLICTS OF INTEREST: Not stated
GUIDELINE
STATUS: This is the current release of the guideline.
GUIDELINE
AVAILABILITY: Electronic copies: Not available at this time.
Print copies: Available from the International Lyme and Associated
Diseases Society, PO Box 341461, Bethesda, Maryland 20827-1461;
Phone: (301) 263–1080; Fax: (301) 263–0776; Email:
lymedocs@aol.com
NGC
STATUS: This NGC summary was completed by ECRI on August
26, 2004. The information was verified by the guideline developer
on October 13, 2004.
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