The New England Journal of Medicine <http://content.nejm.org/>
Notice: Because of their potential importance in the treatment of Lyme
disease, these articles are being published early (on June 12, 2001). The
final versions will appear in the July 12 issue of the Journal.
  _____

Original Article


Two Controlled Trials of Antibiotic Treatment in Patients with Persistent
Symptoms and a History of Lyme Disease


Mark S. Klempner, M.D., Linden T. Hu, M.D., Janine Evans, M.D., Christopher
H. Schmid, Ph.D., Gary M. Johnson, Richard P. Trevino, B.S., DeLona Norton,
M.P.H., Lois Levy, M.S.W., Diane Wall, R.N., John McCall, Mark Kosinski,
M.A., and Arthur Weinstein, M.D.




ABSTRACT

Background It is controversial whether prolonged antibiotic treatment is
effective for patients in whom symptoms persist after the recommended
antibiotic treatment for acute Lyme disease.
Methods We conducted two randomized trials: one in 78 patients who were
seropositive for IgG antibodies to Borrelia burgdorferi at the time of
enrollment and the other in 51 patients who were seronegative. The patients
received either intravenous ceftriaxone, 2 g daily for 30 days, followed by
oral doxycycline, 200 mg daily for 60 days, or matching intravenous and oral
placebos. Each patient had well-documented, previously treated Lyme disease
but had persistent musculoskeletal pain, neurocognitive symptoms, or
dysesthesia, often associated with fatigue. The primary outcome measures
were improvement on the physical- and mental-health–component summary scales
of the Medical Outcomes Study 36-item Short-Form General Health Survey
(SF-36) — a scale measuring the health-related quality of life — on day 180
of the study.
Results After a planned interim analysis, the data and safety monitoring
board recommended that the studies be discontinued because data from the
first 107 patients indicated that it was highly unlikely that a significant
difference in treatment efficacy between the groups would be observed with
the planned full enrollment of 260 patients. Base-line assessments
documented severe impairment in the patients' health-related quality of
life. In intention-to-treat analyses, there were no significant differences
in the outcomes with prolonged antibiotic treatment as compared with
placebo. Among the seropositive patients who were treated with antibiotics,
there was improvement in the score on the physical-component summary scale
of the SF-36, the mental-component summary scale, or both in 37 percent, no
change in 29 percent, and worsening in 34 percent; among seropositive
patients receiving placebo, there was improvement in 40 percent, no change
in 26 percent, and worsening in 34 percent (P=0.96 for the comparison
between treatment groups). The results were similar for the seronegative
patients.
Conclusions There is considerable impairment of health-related quality of
life among patients with persistent symptoms despite previous antibiotic
treatment for acute Lyme disease. However, in these two trials, treatment
with intravenous and oral antibiotics for 90 days did not improve symptoms
more than placebo.
  _____

Notice: Because of their potential importance in the treatment of Lyme
disease, these articles are being published early (on June 12, 2001). The
final versions will appear in the July 12 issue of the Journal.
  _____

Antibiotic treatment is highly effective for the acute and late septic
manifestations of Lyme disease, which is caused by the tick-borne bacterium
Borrelia burgdorferi. 1
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=1&strInstance=1#References1>  However, some patients have
persistent fatigue, myalgias, arthralgias without arthritis, dysesthesias or
paresthesias, or mood and memory disturbances after the standard courses of
antibiotics. 2
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=2&strInstance=1#References2>  3
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=3&strInstance=1#References3>  Persistent symptoms have been
reported both in patients who are seropositive for antibodies against B.
burgdorferi and in patients who are seronegative. Although the cause of
persistent symptoms has not been determined, their temporal association with
B. burgdorferi infection has led some physicians to treat patients with
prolonged courses of antibiotics. Case reports and uncontrolled trials
describe success with prolonged antibiotic therapy, often with a recurrence
of the symptoms after the discontinuation of therapy. 4
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=4&strInstance=1#References4>  In view of the substantial
morbidity and even death 5
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=5&strInstance=1#References5>  associated with prolonged
parenteral antibiotic treatment of Lyme disease, it is important to
determine the efficacy of such therapy. We report results from randomized,
placebo-controlled, double-blind trials of antibiotic therapy in
seropositive and seronegative patients who had chronic symptoms after
treatment for Lyme disease.

Methods
Patients
Patients were recruited by means of advertisements and referrals from
physicians. Between July 24, 1997, and November 14, 2000, eligible patients
were enrolled in two double-blind, placebo-controlled trials, each conducted
at three sites. Patients with a positive Western blot for IgG antibodies
against B. burgdorferi antigens 6
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=6&strInstance=1#References6>  were enrolled in a study of
seropositive patients, and patients who were seronegative were enrolled in a
separate study. Seronegative patients were required to have documentation of
an erythema migrans skin lesion provided by an experienced physician. We
initially planned to enroll 260 patients in the studies (194 seropositive
and 66 seronegative patients). Patients were eligible if they were at least
18 years old, had a history of acute Lyme disease acquired in the United
States, and had at least one of the following: a history of single or
multiple erythema migrans skin lesions, early neurologic or cardiac symptoms
attributed to Lyme disease, radiculoneuropathy, or Lyme arthritis.
Documentation by a physician of previous treatment of acute Lyme disease
with a recommended antibiotic regimen was also required. At the time of
enrollment, all patients had one or more of the following symptoms that
interfered with their functioning: widespread musculoskeletal pain,
cognitive impairment, radicular pain, paresthesias, or dysesthesias.
Profound fatigue often accompanied one or more of these symptoms. The
chronic symptoms had to have begun within 6 months after the initial
infection with B. burgdorferi and had to have persisted for at least 6
months but less than 12 years.
Patients were excluded if they had hypersensitivity to the study
medications, had previously received parenteral antibiotic therapy for 60
days or more for their current symptoms, had active inflammatory synovitis,
had a coexisting condition that could have accounted for their symptoms, or
were unable to discontinue medications that could interfere with the
evaluation of their response to the treatment regimen (e.g., narcotic
analgesics or prednisone in a dose of 10 mg per day or more). Patients with
a positive polymerase-chain-reaction (PCR) test for B. burgdorferi DNA in
plasma or cerebrospinal fluid at base line were also excluded.
Study Protocols
The study protocols were approved by the institutional review boards for
human investigations at the participating centers, and each patient gave
written informed consent. A data and safety monitoring board planned an
interim analysis after at least 110 subjects had been enrolled. Patients
were randomly assigned in a 1:1 ratio to receive either antibiotics or
placebo. The antibiotic treatment regimen consisted of intravenous
ceftriaxone for 30 consecutive days (2 g per day), followed by oral
doxycycline for 60 consecutive days (100 mg twice daily). The patients in
the placebo group received an intravenous dextrose solution that was the
same color as the ceftriaxone solution and oral placebo capsules identical
in appearance to the doxycycline, both for the same lengths of time as the
antibiotics were administered. Compliance and safety were monitored by home
visits by study nurses every other day during the intravenous-treatment
phase and twice (on days 45 and 75) during the oral-treatment phase.
Clinical and laboratory evaluations were performed at screening, at base
line, and on days 3, 5, 13, 21, 30, 45, 75, 90, and 180. The base-line
evaluation included a complete medical history taking, a detailed physical
examination, neuropsychological testing, a lumbar puncture, and sampling of
peripheral blood.
Clinical Response
The primary outcome was an improvement in the patients' health-related
quality of life, which was measured by means of the Medical Outcomes Study
(MOS) 36-item Short-Form General Health Survey (SF-36). 7
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=7&strInstance=1#References7>  8
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=8&strInstance=1#References8>  Additional measures of the
health-related quality of life included the MOS scales for pain, cognition,
and role functioning (the ability to participate in usual daily activities)
9
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=9&strInstance=1#References9>  10
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=10&strInstance=1#References10>  11
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=11&strInstance=1#References11>  and a modified version of
the Fibromyalgia Impact Questionnaire (FIQ). 12
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=12&strInstance=1#References12>  13
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=13&strInstance=1#References13>  Each of the instruments
used to measure the health-related quality of life was administered to study
participants at base line and at 30, 90, and 180 days. The SF-36 includes
eight multiple-item scales that measure physical functioning, physical
limitations on usual role-related activities, bodily pain, general health
perceptions, vitality, social functioning, emotional limitations on usual
role-related activities, and mental health. These scales provide the basis
for calculating the summary scores on the physical component and the mental
component of the SF-36. 7
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=7&strInstance=2#References7>  8
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=8&strInstance=2#References8>  The scores range from 0
(worst) to 100 (best). For each of the scales, the mean (±SD) score for
members of the general population of the United States without chronic
conditions was considered to be 50±10.
To assess changes in the health-related quality of life over time, a change
score for each SF-36 summary scale was calculated by subtracting the
base-line score from the scores at 30, 90, and 180 days. With the use of 2
SE as the criterion, 8
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=8&strInstance=3#References8>  14
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=14&strInstance=1#References14>  individual patients were
classified into three categories of change: those whose follow-up scores did
not change more than would be expected by chance (unchanged group); those
whose follow-up scores improved by more than 2 SE (improved group); and
those whose follow-up scores declined by more than 2 SE (worse group).
According to previous studies, a change of 2 SE is 6.5 points on the SF-36
physical-health summary scale and 7.9 points on the SF-36 mental-health
summary scale. 8
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=8&strInstance=4#References8>  14
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=14&strInstance=2#References14>  The overall change in
health status was calculated for each patient. Patients were categorized as
having improved health status if they had better scores on both scales or
had a better score on one scale and a score on the other scale that was not
worse. Patients were categorized as having worsened health status if they
had worse scores on one or both of the scales and as having the same health
status if their scores on both the physical- and mental-component scales
were unchanged.
Three additional multiple-item scales from the MOS were used as secondary
measures of cognitive functioning, pain, and functioning in role-related
activities. 9
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=9&strInstance=2#References9>  10
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=10&strInstance=2#References10>  11
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=11&strInstance=2#References11>  15
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=15&strInstance=1#References15>  Clinical response was also
measured with the use of the modified version of the FIQ, for which the
scores range from 0 (best) to 110 (worst). This version of the FIQ has been
validated for patients who have persistent symptoms after treatment for Lyme
disease. 13
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=13&strInstance=2#References13>  In a control population
without chronic illness, the mean total score on the modified FIQ was 14.0,
whereas the mean for patients with chronic Lyme disease after treatment was
50.2. 13
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=13&strInstance=3#References13>  Previous studies have
indicted that a change of 16.0 points is clinically meaningful. 16
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=16&strInstance=1#References16>  17
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=17&strInstance=1#References17>  18
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=18&strInstance=1#References18>  19
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=19&strInstance=1#References19>
Laboratory Studies
Western blotting for IgG antibodies against B. burgdorferi antigens was
performed with the IgG MarBlot (MarDx Diagnostics, Carlsbad, Calif.)
according to the manufacturer's instructions. 6
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=6&strInstance=2#References6>  The intrathecal production of
antibodies against B. burgdorferi was measured as previously described. 20
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=20&strInstance=1#References20>  Base-line specimens of
cerebrospinal fluid and plasma specimens obtained at base line and on days
3, 5, 21, and 45 were tested by PCR for the presence of B. burgdorferi DNA,
as previously described. 21
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=21&strInstance=1#References21>  All samples of
cerebrospinal fluid were cultured in Barbour–Stoenner–Kelly II medium to
detect B. burgdorferi and were monitored by dark-field microscopy for six
weeks. 22
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=22&strInstance=1#References22>  Some blood samples were
cultured for B. burgdorferi in hypertonic medium. 23
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=23&strInstance=1#References23>
Adverse Events
Adverse events and changes in laboratory values were evaluated and graded
with the use of scales derived from the Common Toxicity Criteria of the
National Cancer Institute.
Compliance
Compliance with the regimen of medications was assessed by counts of both
the number of doses of the intravenous medication the patients received and
the pills they had remaining. The actual pill counts were compared with the
number of pills that the patient should have had remaining at the time of
the home visit by a nurse on day 75.
Statistical Analysis
The primary analysis was an intention-to-treat analysis of all the patients
enrolled in the studies. The primary clinical end point was the proportion
of patients whose condition was categorized as improved, unchanged, and
worse on the basis of the summary scores for the mental and physical
components of the SF-36 at 180 days. Patients who withdrew from the study
were categorized as having worsened health status on both of these scales.
The study of seropositive patients was designed to have a power of 90
percent, with a 5 percent level of significance in a two-sided test and a
sample size of 194, to detect a difference of 25 percent between the
antibiotic group and the placebo group in the proportion of patients with
improved health status. 24
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=24&strInstance=1#References24>  With the enrollment of 66
patients, the study of seronegative patients would have 80 percent power,
with a 5 percent level of significance in a two-sided test, to detect a 35
percent difference between the antibiotic group and the placebo group. 24
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=24&strInstance=2#References24>
In the interim analysis of the primary outcome, the O'Brien–Fleming
adjustment for multiple testing and the B-value stochastic curtailment
method were used. 25
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=25&strInstance=1#References25>  The primary outcome for
each trial was analyzed by the chi-square test with individual type I error
rates of 0.05. The efficacy of the treatment in each trial was estimated as
the difference in risk (with 95 percent confidence interval). Secondary
outcomes included improvement or worsening as measured by the SF-36 at 30
and 90 days, the total FIQ score, and the MOS pain, cognition, and
role-functioning scores at 30, 90, and 180 days.

Results
Characteristics of the Patients
A total of 129 patients were enrolled in the studies (78 seropositive and 51
seronegative). The base-line characteristics of the patients are shown in
Table 1
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=1&strInstance=1#Table1> . A total of 42 (33 percent) of the
patients had previously received intravenous antibiotic treatment for a mean
(±SD) of 30±12 days. All other previous treatment consisted of oral
antibiotics. There were no significant differences between the seropositive
patients and the seronegative patients other than the presence or absence of
serum antibodies to B. burgdorferi. All cultures of cerebrospinal fluid in
standard Barbour–Stoenner–Kelly II medium and of blood in hypertonic medium
were negative for B. burgdorferi. B. burgdorferi DNA was not detected in any
base-line sample of cerebrospinal fluid or blood, nor was it detected in any
of the blood samples obtained during the treatment phase (on days 3, 5, 21,
and 45). Given a cutoff of 1.2 for the ratio of antibody against B.
burgdorferi in cerebrospinal fluid to antibody in serum, the intrathecal
production of antibody was detected in eight patients (five in the combined
antibiotic groups and three in the combined placebo groups).
Treatment was discontinued in 14 patients (8 seropositive and 6
seronegative). The reasons for the discontinuation of treatment were similar
across the groups of patients. An adverse event was the reason for the
discontinuation of treatment in three of the patients in the combined
antibiotic groups (5 percent) and three of those in the combined placebo
groups (5 percent). Treatment was discontinued in the other eight patients
for reasons other than an adverse event.
In the combined population of both studies, the mean base-line summary score
for the physical component of the SF-36 was approximately 1.5 SD below that
of age-matched members of the general population of the United States who
did not have a chronic illness, and the mean base-line summary score for the
mental component was approximately 0.5 SD below that of such a control
group. Similarly, the base-line FIQ scores were markedly abnormal.
Compliance
All patients who completed 180 days in one of the trials took at least 75
percent of the prescribed medications. There were no differences between the
treatment groups in either the seropositive or the seronegative study in
patients' compliance with medication.
Efficacy
The interim analysis was performed with the use of data on 107 patients who
had completed 180 days in one of the trials. This analysis indicated that
there was a 1.4 percent chance in the seropositive study and a 4.0 percent
chance in the seronegative study that a significant difference in the
efficacy of treatment between the antibiotic group and the placebo group
would be observed when the full projected enrollment was reached. An
analysis that included the patients in both studies indicated that there was
a 3.9 percent chance of observing a significant difference at full
enrollment. Because of the lack of efficacy of the antibiotic treatment at
the time of the interim analysis, the data and safety monitoring board
recommended discontinuation of the active treatment of enrolled patients and
of further enrollment in the treatment phase of the studies.
The responses of the 115 patients who were enrolled in the studies at least
180 days before enrollment was stopped are shown in Table 2
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=2&strInstance=1#Table2>  and Figure 1
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=1&strInstance=1#Figure1> . Intention-to-treat analyses at
30, 90, and 180 days showed no significant differences in the measures of
the health-related quality of life between the patients in the antibiotic
groups and those in the placebo groups in the seropositive study, the
seronegative study, or both studies combined.
In the combined study populations, changes in the score on the modified FIQ
at 180 days also revealed no significant differences between the antibiotic
groups and the placebo groups. We defined a decrease of 25 percent from the
base-line score on the modified FIQ as indicative of clinical improvement
and an increase of 25 percent as indicative of clinical worsening. Given
these definitions, 28 of the 51 patients in the combined antibiotic groups
(55 percent) had improved health status as measured by the FIQ at 180 days,
as compared with 22 of the 53 patients in the combined placebo groups (42
percent) (P=0.17). Conversely, 14 percent of the patients in the antibiotic
groups (7 of 51) had worsened health status as measured by the FIQ at 180
days, as compared with 19 percent (10 of 53) in the placebo groups (P=0.48).
Separate comparisons of the FIQ scores in the antibiotic group and the
placebo group of the seropositive study and of those in the two treatment
groups in the seronegative study found no statistically significant
differences according to treatment.
Adverse Events
At least one study-related adverse event occurred in 16 of the 64 patients
in the combined antibiotic groups (25 percent) and 11 of the 65 patients in
the combined placebo groups (17 percent). Most of the adverse events were
minor and resolved without intervention or sequelae. However, the two
patients in whom a study-related serious adverse event occurred were both in
the antibiotic group. During intravenous treatment, one had a
life-threatening pulmonary embolism and the other had fever, anemia, and
gastrointestinal bleeding. Although the overall rate of adverse events was
not significantly different in the two treatment groups, rash, diarrhea, and
vaginal pruritus occurred more frequently among the patients in the
antibiotic groups (9 of 64 patients) than among those in the placebo groups
(2 of 65 patients). There were no infections associated with the intravenous
catheter, and there were no deaths.

Discussion
The primary goals of these studies in patients with symptoms that persist
after recommended antibiotic treatment for Lyme disease were to characterize
the impairment in health-related quality of life among such patients and to
determine the efficacy of prolonged treatment with antibiotics. The effect
of chronic Lyme disease on the health-related quality of life was
substantial in both seropositive and seronegative patients. The deficits in
physical health status as measured by the SF-36 were equivalent to those
observed in patients with congestive heart failure or osteoarthritis and
were more than 0.5 SD greater than the impairment observed in patients with
type 2 diabetes or a recent myocardial infarction. 7
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=7&strInstance=3#References7>  8
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=8&strInstance=5#References8>  Chronic pain was an important
contributor to the impairment of physical health and was similar to that
reported by patients with osteoarthritis. 7
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=7&strInstance=4#References7>  8
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=8&strInstance=6#References8>  The impairment of mental
health status was similar to that observed in patients with subthreshold
lifetime depression (a depressive disorder that does not meet all of the
criteria for major depression of the Diagnostic and Statistical Manual of
Mental Disorders, third edition). 7
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=7&strInstance=5#References7>  8
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=8&strInstance=7#References8>  26
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=26&strInstance=1#References26>  The study patients also had
some impairment in cognitive functioning. Their base-line FIQ scores
reflected the impairments in health status that were evident in the SF-36
scores and were similar to those in previous studies of patients with
fibromyalgia or those with chronic Lyme disease after treatment. 8
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=8&strInstance=8#References8>  9
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=9&strInstance=3#References9>  10
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=10&strInstance=3#References10>  11
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=11&strInstance=3#References11>  12
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=12&strInstance=2#References12>  13
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=13&strInstance=4#References13>
The administration of placebo and treatment with a regimen of parenteral
ceftriaxone for 30 days, followed by oral doxycycline for 60 days, had
similar effects on the patients' health-related quality of life. This
antibiotic-treatment regimen was selected because of the in vitro and in
vivo activity of both of these antibiotics against B. burgdorferi and
because they are effective for the treatment of neuroborreliosis. 1
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=1&strInstance=2#References1>  Experience with other chronic
infectious diseases caused by persistent bacteria (e.g., syphilis,
tuberculosis, and helicobacter infection) suggests that it is unlikely that
more prolonged antibiotic therapy or a different combination of antibiotics
would result in greater improvement than was observed in this study.
Although we used both conventional and hypertonic culture mediums to isolate
B. burgdorferi in base-line samples of cerebrospinal fluid and blood and
used PCR to detect B. burgdorferi DNA in base-line samples of blood and
cerebrospinal fluid as well as samples of blood collected during treatment,
we did not find evidence of persistent infection with B. burgdorferi in
these patients. There was no evidence of B. burgdorferi in a total of more
than 700 different blood and cerebrospinal fluid samples from the 129
patients in these studies.
The placebo groups in these studies provide a view of the natural history of
symptoms among patients with chronic Lyme disease after treatment. During
the six-month evaluation period, we observed improvement in health status in
36 percent of patients, worsening health status in 39 percent, and no
significant change in 25 percent. A similar relation between the
administration of placebo and health-related quality of life has been
reported previously among patients with other rheumatologic diseases that do
not appear to be related to persistent infection. For example, a randomized,
placebo-controlled trial in patients with mild-to-moderate rheumatoid
arthritis found an improved clinical response after 48 weeks of placebo
treatment in 39 to 41 percent of patients, as compared with 54 to 56 percent
of patients treated with minocycline. 27
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02&strNumber=27&strInstance=1#References27>
In summary, patients with chronic musculoskeletal pain, neurocognitive
symptoms, or both that persist after antibiotic treatment for
well-documented Lyme disease have considerable impairment in their
health-related quality of life. The patients enrolled in these studies did
not have evidence of persistent infection by B. burgdorferi, as judged on
the basis of the available microbiologic and molecular methods of detection.
There were no significant differences between clinical responses of patients
who received intravenous and oral antibiotics for 90 days and those of
patients who received placebo.
Figure 1. Change or Lack of Change from Base Line in the Health-Related
Quality of Life as Measured by the Medical Outcomes Study 36-Item Short-Form
General Health Study (SF-36).
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>
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[ Return to Text
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e.asp?strXMLFilename=20010712/01071202&%09%09strDate=%09%097%2F12%2F2001&str
Art=02#FigureRefInstance1>  ]

Figure 1. Change or Lack of Change from Base Line in the Health-Related
Quality of Life as Measured by the Medical Outcomes Study 36-Item Short-Form
General Health Study (SF-36).
Results are shown for the overall outcome (Panel A, all patients; Panel D,
seropositive patients; Panel G, seronegative patients); the physical
component (Panel B, all patients; Panel E, seropositive patients; Panel H,
seronegative patients); and the mental component (Panel C, all patients;
Panel F, seropositive patients; Panel I, seronegative patients). The scores
of patients in the antibiotic group are compared with those of patients in
the placebo group at the end of intravenous treatment (day 30), at the end
of oral treatment (day 90), and 3 months after the completion of treatment
(day 180). Statistical tests comparing the scores in the antibiotic group
with those in the placebo group showed no statistically significant
difference at any of the time points.



Table 1. Base-Line Characteristics of the Patients.
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Art=02#TableRefInstance1>  ]

Table 1. Base-Line Characteristics of the Patients.



Table 2. Clinical Responses at 180 Days.
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Art=02#TableRefInstance1>  ]

Table 2. Clinical Responses at 180 Days.





Source Information

From New England Medical Center and Tufts University School of Medicine,
Boston (M.S.K., L.T.H., C.H.S., G.M.J., R.P. T., J.M.); Yale–New Haven
Hospital, New Haven, Conn. (J.E., D.W.), New York Medical College, Valhalla
(D.N., L.L., A.W.); and Quality Metric, Lincoln, R.I. (M.K.). Address
reprint requests to Dr. Klempner at the Department of Medicine, Boston
University School of Medicine, 715 Albany St., Boston, MA 02118, or at
[log in to unmask] <mailto:[log in to unmask]> .
Supported by grants (N01-AI-65308 and M01 RR000054) from the National
Institutes of Health. Roche provided the ceftriaxone for the study, and
Pfizer provided the doxycycline.
We are indebted to Philip J. Baker, Ph.D., Steven P. Heyse, M.D., Marilyn
Tuttleman, M.S., Dennis Dixon, Ph.D., and Mark Van Raden, Ph.D., of the
National Institute of Allergy and Infectious Diseases Lyme Disease Program;
to Barbara E. Murray, M.D., Robert Edelman, M.D., Frank G. Miller, Ph.D.,
Donald Rosenstein, M.D., and Barbara Tilley, Ph.D., of the data and safety
monitoring board; to John E. Edwards, Jr., M.D., Carl Brenner, J. Stephen
Dumler, M.D., Fred A. Gill, M.D., Phyllis Mervine, Justin Radolf, M.D., and
Gregory Owens, Ph.D., of the Scientific Advisory Committee; and to the
following persons who provided helpful services: Rich Noring, Bilaal
McCloud, Bo Lin, Ph.D., Richard Kaplan, Ph.D., David Weld, Roger
D'Entremont, Kitty Mullen, Chris Covington, Vincent DiPaola, Paul Drouilhet,
David Fletcher, Jerrold Gold, Thomas Hirsch, Clyde Kessel, Keith Krewson,
Laura Lattanzio, Rebecca Leland, Shawn Lyden, William Macleod, Roy Matthews,
Peter Morton, Dave Murray, Jim Platz, John Sample, Elliott Schiffman,
Michael Shabazian, Jason Stone, John Taylor, Bradford Von Weise, Frank
Weldon, Larry Camerlin, Raymond Partridge, M.D., Marianna Wilson, M.S., John
Consoletti, Pharm.D., Cindy Mason, R.N., David Thorpe, Pharm.D., Cindy
Moore, R.N., June Novio, R.N., Eileen Regan, R.N., Andy Dousa, Pharm.D., Don
Morrison, Pharm.D., Laura Cavagna, Pharm.D., Linda Griffith, Pharm.D., Sean
Corbett, Pharm.D., Scott Reid, Pharm.D., Fran Bickert, R.N., John Opolski,
R.N., Karen Tooker, R.N., Mark Wolff, Ph.D., Phyllis Barr, Ph.D., Anna
Lornell, M.D., Phil Molloy, M.D., Karen Forschner, Dennis Hoak, M.D., David
N. Mesches, M.D., Tim Lepore, M.D., Robina Folland, Robert Lopez, Bai
Margolin, Crystal Sylvester, George Perides, Ph.D., Allen Steere, M.D.,
Ellen Jamieson, Jim Grayson, Timothy Brauns, Lilla Rogers, Jenn Finn, R.N.,
Pamela Norton, R.N., Karen Mazzotta, Anh Nguyen, M.D., Eric Logigian, M.D.,
William Brown, M.D., Anne Donohoe, Sandy Doveikis, Karen Fenicchia, R.N.,
Hua Wang, R.N., Nancy Zajac, R.N., Jamie Evanowski, David Carlson, Jason
Hoitt, Carol Bauscher, L.P.N., Teryi Deshefy-Longhi, R.N., M.S., Carl Henn,
Dee Dee Moss, Glynnis Fisher, Janet Mattson, Rosemary Hammil, Beth Horrigan,
William Blackwelder, M.D., Frank Cavileri, M.D., John Nowakowski, M.D.,
Morris Dannon, M.D., Brij Mohan Singh Ahluwalia, M.D., Gary Wormser, M.D.,
Rhea Dornbush, Ph.D., Catherine Crea, Maria Aguero-Rosenfeld, M.D., Alan
Gerber, M.D., Michael Tenner, M.D., Maureen Grix, Ph.D., Lois Zentmaier,
Denise Cooper, Susan Bittker, Sheila Hughes, R.N., Junius Edlow, Tim
McGarty, Jeffrey Bandola, M.D., Andrew Artenstein, M.D., Nancy Clark, R.N.,
Jerry Fingerut, M.D., Robert Schoen, M.D., Donna D'Euginio, R.N., Linda
Bockenstedt, M.D., Alexia Bellperron, Brad Herskowitz, M.D., George
Rickerson, M.D., LeBraun Paige, M.D., Volker Knappertz, M.D., Kimberly
Stoddard, Ph.D., Ann Sweeney, R.N., Michael Westerveldt, Ph.D., Maureen
Tacey, Thomas Rush, M.D., Jill Auerbach, Betty Gross, Manuel DaSilva, M.D.,
Arthur Rabson, M.D., Brian Fallon, M.D., Linda Tanner, Richard Horowitz,
M.D., Edmond Yunis, M.D., Paul Alexander, R.N., and Ann Marie McClean, R.N.

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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.