Dr. Wormser crawls out again

lipanz · medicine forum addict Joined: 19 Jun 2005 Posts: 62

http://content.nejm.org/cgi/content/full/354/26/2794

Volume 354:2794-2801 June 29, 2006 Number 26
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Early Lyme Disease

Gary P. Wormser, M.D.

This Journal feature begins with a case vignette highlighting a common
clinical problem. Evidence supporting various strategies is then
presented, followed by a review of formal guidelines, when they exist.
The article ends with the author's clinical recommendations.

A 26-year-old woman with a summer home on Long Island, New York, had a
low-grade fever, malaise, arthralgias, headache, and neck pain one week
after removing a tick from her thigh. Examination reveals a nontender
oval (8 by 12 cm), homogeneously erythematous lesion at the site of the
tick bite, consistent with erythema migrans. How should this case be
managed? What if she had presented earlier, just after removing the
tick?
The Clinical Problem
Lyme disease is the most common tick-borne disease in the United States
and Europe.1,2 In the United States, Lyme disease is most often
acquired from the bite of the Ixodes scapularis tick, with the
spirochete Borrelia burgdorferi the sole cause.3 In Europe, Lyme
disease is more commonly caused by B. afzelii than by B. burgdorferi.3
Erythema migrans is the most common clinical manifestation of Lyme
disease.1,4 It typically develops 7 to 14 days (range, 3 to 30) after
tick detachment and is characterized by a rapidly expanding,
erythematous skin lesion that may be round or oval and flat or slightly
raised.5,6,7 About 75 to 80 percent of patients in the United States
who present with erythema migrans have only a single (primary)
lesion.6,8 The remainder have additional (secondary) skin lesions that
are believed to arise through hematogenous dissemination from the site
of primary infection.8 The majority of patients with erythema migrans
in the United States have symptoms resembling those of viral infection,
including arthralgias, fatigue, headache, or neck pain; fever may or
may not accompany these symptoms.5,6 Similar symptoms have been
attributed to infection with B. burgdorferi in the absence of erythema
migrans, but in this circumstance, the diagnosis is less certain.9
Prominent respiratory symptoms (such as cough or rhinorrhea) or
gastrointestinal symptoms (such as vomiting or diarrhea) would be
highly atypical.5
Even though the I. scapularis tick is approximately twice as likely to
be infected with B. burgdorferi in the adult stage as in the nymphal
stage,10 most cases of early Lyme disease occur during the late spring
and summer, when the nymph is seeking a blood meal.11 This is due at
least in part to the fact that adult ticks, which are larger than
nymphs, are more readily noticed and thus removed, resulting in
insufficient time for the spirochete to be transmitted.11,12,13 In
experiments in animals, there is almost invariably a delay of at least
36 hours between the time of tick attachment and transmission of B.
burgdorferi.14,15 During this interval, spirochetes present in the
midgut of the tick increase in number and migrate to the salivary
glands.15
Without treatment, erythema migrans resolves spontaneously within a
median of approximately four weeks.16 The more serious clinical
sequelae of Lyme disease develop as a consequence of the hematogenous
spread of the spirochete to extracutaneous sites. Spirochetemia can be
found in about 45 percent of patients with erythema migrans at the time
of presentation, irrespective of the size or duration of the skin
lesion.8 Approximately 60 percent of patients with erythema migrans who
are not treated will go on to have a monoarticular or oligoarticular
arthritis, typically involving the knee; approximately 10 percent will
have a neurologic manifestation, the most common of which is
facial-nerve palsy; and approximately 5 percent will have a cardiac
complication, usually varying degrees of atrioventricular block.17
Strategies and Evidence
Diagnosis
The diagnosis of erythema migrans is based on recognition of the
characteristic appearance of the skin lesion in persons who live in or
have recently traveled to regions in which Lyme disease is
endemic.5,6,7,18 The skin lesion is sufficiently distinctive that
serologic testing for antibodies against B. burgdorferi is generally
considered unnecessary; such testing is also insensitive, with false
negative results in as many as 60 percent of cases.19 However, the skin
lesion cannot be considered pathognomonic of Lyme disease. A similar
skin lesion - from southern tick-associated rash illness, or STARI
- occurs after the bite of the Amblyomma americanum tick (also known
as the lone star tick), which cannot transmit B. burgdorferi.20,21 A.
americanum ticks are present throughout the southeast and south central
regions of the United States and are also found in smaller numbers
along the eastern seaboard, as far north as Maine.22 Although more
common in the South, cases of STARI have occurred in Maryland23 and New
Jersey,24 and cases may have been mistaken for erythema migrans in
other mid-Atlantic or northeastern states.
Erythema migrans skin lesions are typically 5 cm or more in their
largest diameter.25 Smaller lesions may occur merely as a result of
hypersensitivity reactions to tick saliva. Early erythema migrans
lesions may be homogeneously erythematous and often do not have central
clearing or the characteristic bull's-eye or target-like appearance
(Figure 1).6,7,20 Erythema migrans lesions usually occur in locations
that would be unusual for community-acquired cellulitis, such as the
axilla, popliteal fossa, back, abdomen, and groin; this distribution
can be helpful for diagnosis.5 Typically, these lesions are minimally
tender or pruritic.20 Consequently, a complete skin examination should
be performed to look for erythema migrans lesions in patients who have
been exposed to ticks and who also have symptoms like those of a viral
infection or other potential manifestations of early Lyme disease,
including facial-nerve palsy, aseptic meningitis, radiculopathy, or
heart block.

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Figure 1. Erythema Migrans Lesions in Patients from New York State
with Culture-Confirmed Lyme Disease.
Panel A shows a single erythema migrans lesion (8.5 by 5.0 cm) on the
abdomen that was homogeneous in color except for a prominent central
punctum (the presumed site of the tick bite). Panel B shows a single
erythema migrans lesion (11.5 by 7.5 cm) in the popliteal fossa of the
left leg, with more intense erythema to the right of the center of the
lesion. Panel C shows erythema migrans lesions, with prominent central
clearing, on the abdomen. This patient had more than 40 lesions
altogether.

Serologic testing is warranted only in atypical cases and then in
conjunction with serologic testing during the convalescent phase.19 For
most patients, a serum sample obtained two weeks after the initial
sample will be positive, but prompt antibiotic treatment of a
seronegative patient may prevent seroconversion.26 Although helpful in
research studies, polymerase-chain-reaction (PCR) assay of a
skin-biopsy sample and borrelial cultures of skin or blood are too
cumbersome and expensive to be carried out in routine clinical
practice.19
Analogous to antibody testing in patients infected with the human
immunodeficiency virus, a two-tier serologic-testing protocol was
introduced in 1995 for the diagnosis of Lyme disease.27 In this
protocol, a serum sample that is positive or equivocal according to a
first-stage assay, such as a polyvalent enzyme immunoassay, is retested
with the use of separate IgM and IgG immunoblots. To improve test
accuracy further, evidence-based guidelines for immunoblot
interpretation were also recommended.27 The change to two-tier testing
was prompted by the lack of specificity of the commercially available
enzyme immunoassays. As compared with the use of immunoblot testing
alone, the two-tier protocol is slightly more specific and considerably
less expensive.28,29
Coinfection
The same ixodes tick species that transmit B. burgdorferi may be
infected with and transmit Anaplasma phagocytophilum (previously
referred to as Ehrlichia phagocytophila), which causes human
granulocytic anaplasmosis (HGA) (previously called human granulocytic
ehrlichiosis). I. scapularis ticks may also be infected with Babesia
microti, the primary cause of babesiosis, but infection with the
parasite in humans has been recognized only in limited parts of the
regions in which Lyme disease is endemic. As many as 2 to 12 percent of
patients with early Lyme disease may also have HGA,30,31,32 and 2 to 40
percent of patients with early Lyme disease may also have babesiosis,
depending on the region.30,32,33 Diagnostic testing (e.g., blood
smears, antibody assays, PCR assays) for these infections should thus
be considered in patients with erythema migrans with symptoms that are
more severe than those typical of Lyme disease alone (e.g., high-grade
fever for more than 48 hours despite antibiotic therapy), with symptoms
resembling those of a viral infection that fail to improve or that
worsen despite resolution of the skin lesion, or who present with
leukopenia, thrombocytopenia, or anemia.
Treatment
Randomized, prospective studies demonstrate that doxycycline,
amoxicillin, and cefuroxime axetil are effective treatments for
erythema migrans.18,34,35 No available data indicate the superiority of
one of these antibiotics over the others, and serious adverse events
are infrequent with all of them (Table 1). Doxycycline has the
advantage of effectively treating HGA, which may occur simultaneously
with Lyme disease.18,30,31,32

Table 1. Treatment and Prevention of Early Lyme Disease.

A Jarisch-Herxheimer-like reaction - characterized by an increase
in systemic symptoms and in the size or intensity of the erythema of
the skin lesion - occurs in about 15 percent of patients within 24
hours after the initiation of antimicrobial therapy.35 Erythema migrans
lesions typically resolve within one to two weeks after the start of
antibiotic therapy, but systemic symptoms often take longer to
disappear; three months later, approximately 25 percent of patients may
still have mild symptoms.37 The development of objective complications
is extremely rare in treated patients.18,38 Erythema migrans may recur,
however, if the patient is bitten by another infected tick in a
subsequent summer or, rarely, later during the same summer.7,37,38
The duration of antibiotic therapy was addressed in a double-blind,
controlled treatment trial of 180 patients with erythema migrans.37
Patients were randomly assigned to receive a 10-day course of
doxycycline, a single intravenous dose of ceftriaxone followed by a
10-day course of doxycycline, or a 20-day course of doxycycline. The
outcomes were similar in all three treatment groups over a follow-up
period of 30 months. In view of the much shorter serum half-lives of
amoxicillin and cefuroxime axetil, it is unclear whether a 10-day
course of these drugs would be as effective as a 10-day course of
doxycycline. For uniformity, a 14-day course of therapy has been
recommended for all first-line oral agents.18
The results of a head-to-head trial that enrolled only patients with
erythema migrans who also had objective evidence of the widespread
dissemination of spirochetes indicate that parenteral antibiotic
therapy with ceftriaxone is not more effective than oral treatment with
doxycycline.39 Parenteral therapy is much more expensive and has
greater potential for serious adverse effects.40 Therefore, such
therapy is not recommended for patients with erythema migrans, except
in unusual circumstances (i.e., in patients with advanced heart block
from Lyme carditis or with neurologic manifestations of Lyme disease,
aside from uncomplicated facial-nerve palsy) (Table 1).18
Evidence from controlled trials indicates that macrolides
(specifically, erythromycin, azithromycin, and roxithromycin) are
significantly less effective than other antibiotic therapies in the
resolution of erythema migrans or associated symptoms.34,41,42 Thus,
macrolides are not recommended as a first-line therapy.18
Cephalexin and other first-generation cephalosporins are not effective
for the treatment of Lyme disease.43,44 In cases in which there is
uncertainty whether a skin lesion is erythema migrans or bacterial
cellulitis, either cefuroxime axetil or amoxicillin-clavulanic acid
is a reasonable choice, since each will effectively treat both types of
infection.18,43
Prevention
People can prevent Lyme disease by avoiding tick-infested environments
and, when in such environments, by covering up the skin as much as
possible and using insect repellents containing
N,N-diethyl-3-methylbenzamide (DEET) on exposed skin.18,36 The
acaricide permethrin kills ticks on contact but should be applied to
clothing rather than to skin. Daily inspections of the entire surface
of the skin (including the scalp) and removal of any attached ticks are
recommended. Clinical studies have demonstrated that without any other
intervention, more than 96 percent of patients who find and remove an
attached I. scapularis tick will remain free of Lyme disease, even in
regions in which the disease is the most highly endemic.12,18 If a tick
is not found and removed within 72 hours after attachment, the
probability of infection approaches the rate of infection in the
regional tick population (typically, 20 to 40 percent of I. scapularis
nymphs are infected in areas of the Northeast and Midwest in which the
disease is highly endemic).12,45
Doxycycline chemoprophylaxis can further reduce the chance of Lyme
disease after a bite from an I. scapularis tick. In a randomized trial,
a single 200-mg dose of doxycycline administered within three days
after tick removal reduced the risk of erythema migrans at the bite
site from 3.2 to 0.4 percent - that is, a risk reduction of 87
percent.12 In regions in which the disease is highly endemic, the use
of a single dose of doxycycline should be considered for persons who
are known to have been bitten by a nymphal or adult I. scapularis tick
that was estimated to have been attached for at least 36 hours.36
(Larval I. scapularis ticks are not infected, owing to the absence of
transovarian transmission, and pose no risk of Lyme disease.) Since the
patient's own estimate of the duration of tick attachment is often
unreliable (usually an underestimate), it is useful for physicians to
learn to differentiate engorged from unengorged I. scapularis ticks on
the basis of appearance (Figure 2).12,45,47 The use of culture or PCR
to determine whether the tick is infected with B. burgdorferi is not
recommended, because the clinical utility of such testing is unknown.45
A previously licensed vaccine was effective in preventing Lyme disease
in approximately 80 percent of patients, but it was withdrawn from the
market by the manufacturer in 2002.48

Figure 2. Ixodes scapularis Ticks.
Panel A (left to right) shows an I. scapularis larva, nymph, and adult
female. Panel B shows nymphal I. scapularis ticks in various stages of
engorgement with blood according to the hours of attachment to humans.
The ticks at 0 hour correspond in size to the middle (nymphal) tick in
Panel A. Photographs courtesy of Dr. Richard Falco and James Vellozzi.
Reprinted from Wormser and Fish46 with the permission of the publisher.

Areas of Uncertainty
The majority of patients with erythema migrans who are treated with an
appropriate antibiotic regimen have an excellent
outcome.7,18,34,35,37,49 Nevertheless, when evaluated 6 to 12 months
after treatment, approximately 5 to 15 percent of patients report
subjective symptoms such as fatigue or musculoskeletal pains,37,38 and
about 10 percent of patients have similar types of symptoms 5 or more
years after treatment.38 These subjective symptoms are typically mild
and may wax and wane in intensity.38 If the symptoms interfere with
function, some refer to them as post-Lyme disease syndrome,
post-treatment chronic Lyme disease, or chronic Lyme disease.50
Research on post-Lyme disease syndrome has been hampered by the lack
of a standardized case definition, although one is under development by
the Infectious Diseases Society of America. A prospective investigation
is needed to clarify whether the rates of such symptoms after early
Lyme disease are greater than the rates in appropriate control
populations. Studies indicate that the retreatment of patients with
prolonged subjective symptoms after treatment for Lyme disease, with
additional oral and parenteral courses of antibiotics, is no more
effective than treatment with placebo.50,51 Therefore, symptomatic
treatment is recommended.18
Guidelines
Guidelines for the treatment of Lyme disease have been published by the
Infectious Diseases Society of America (www.idsociety.org)18 and are
currently being updated. The recommendations in this article are
consistent with these guidelines.
Conclusions and Recommendations
The patient described in the vignette apparently has erythema migrans
at the site of a tick bite. Had she presented with an engorged tick in
hand within three days after removing it, I would have prescribed a
single 200-mg dose of doxycycline (in the absence of
contraindications). I would not prescribe the drug, however, if she did
not have the tick or had presented later than three days after being
bitten, since reported tick bites are frequently not from the relevant
tick species (or not from a tick at all) and the efficacy of
single-dose chemoprophylaxis beyond the three-day time limit is
unknown. With or without chemoprophylaxis, the patient should be
educated about the signs and symptoms of tick-borne diseases (such as
rash or illness similar to that from viral infection). Besides Lyme
disease, HGA and babesiosis should be considered in patients who have
fever after being bitten by an ixodes tick in a region in which these
infections are endemic.
In a patient who presents with erythema migrans, doxycycline for 10 to
14 days would be my first treatment choice, because it is also
effective against HGA. However, if exposure to the sun is likely or if
the patient may be pregnant or is breast-feeding, I would prescribe
amoxicillin. Cefuroxime axetil is also effective but is more expensive
than these agents. Because reinfection may occur, the patient should be
told how to prevent tick bites (including wearing protective clothing
and using insect repellents that contain DEET on exposed skin when in
tick-infested areas). Useful information about Lyme disease is
available at www.acponline.org and www.cdc.gov.

Dr. Wormser reports having received consulting fees from Baxter and
research support from Immunetics and being a founder of Diaspex, a
company that does not yet offer products or services. No other
potential conflict of interest relevant to this article was reported.
I am indebted to Lisa Giarratano and Richard Minott for their
assistance with the preparation of the manuscript and to Ira Schwartz,
Robert Nadelman, Barbara Johnson, John Halperin, Franc Strle, Gerold
Stanek, and Maria Aguero-Rosenfeld for their helpful comments.

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eugeneshapiroisapig · medicine forum Guru Joined: 24 Mar 2005 Posts: 2108

Is gary wormser really an MD? I was under the impression he was a CPA.

lipanz wrote:

lipanz · medicine forum addict Joined: 19 Jun 2005 Posts: 62

pamp danties wrote:

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