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Prolonged antibiotic therapy in PCR confirmed
persistent Lyme disease
Wolfgang Klemann, MD, PhD
Bernt-Dieter Huismans, MD, PhD
Stephan Heyl, MD, PhD
Abstract: We examined a sample of 90 individuals that had previously received a
course of appropriate antibiotics for Lyme disease without experiencing full
resolution of their symptoms and had evidence of persistent infection documented
by PCR analysis.
Mean duration of symptoms was 9.5 years (range 1 - 40 years). The treatment
was adapted to the individual case according to clinical response. Long term
antibiotic therapy was initiated and patients were treated continuously for at least 6
months, in some cases several years of intermittent therapy was administered.
About 38,8% of the patients experienced full remission of symptoms while about
56,7% reported a significant improvement, 5,6% of patients were deemed
refractory to therapy. Therapeutic modalities are discussed in detail.
Key words: persistent Lyme disease, Borrelia PCR, long term antibiotic treatment,
lyme serology, Borrelia DNA
Key issues:
·
All study patients were Borrelia- DNA positive
·
Commonly reported symptoms included fatigue, muscolo- sceletal and
neuro-psychiatric complaints
·
Only about 42% of patients had a history of an erythema migrans
·
Serologic testing is fairly insensitive in late disseminated lyme disease
·
Antibiotic treatment must be tailored to the individual clinical response in
late disseminated lyme disease
·
The majority of patients benefited from long term antibiotic treatment
·
Recurrence of symptoms was common during treatment
·
Long term antibiotic therapy was generally well tolerated
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Introduction
Lyme disease was first described as an independent entity by Allen C. Steere et.
al. [1] in 1977. Since then we have learned that this complex illness is the result of
an infectious process, that not only affects the skin and joints but can potentially
disseminate systemically. Although 30 years have passed since the discovery of
the disease, the available data on therapy still has to be considered sparse. In a
review article published in 2006 D. Hassler summarized the available data on the
treatment of lyme disease and commented on the paucicity of evidence [2]. Only a
few controlled studies and some in vitro observations are available. Nevertheless
certain standards have been established and have made their way into treatment
guidelines. Two currently available guidelines are widely accepted, one is
published by the Infectious Diseases Society of America (IDSA) [3], the other by
the International Lyme and Associated Diseases Society (ILADS) [4]. The two
guidelines propose strikingly different approaches for the treatment of late stage
Lyme disease.
Previous studies usually included patients that were diagnosed with Lyme
borreliosis based on clinical and serologic findings most of which were in an early
stage of the disease [5,6]. These serological criteria were introduced primarily for
epidemiologic purposes reasons and lack sensitivity [4,7] for clinical use. It is
doubtful whether results obtained from these studies can be generalized and
applied to other cases of lyme disease. Articles that document cases diagnosed by
detection of borrelial DNA have, to our knowledge, been limited to case reports
and case series [8,9]. For this article we have gathered a large number of patients
that were diagnosed with late stage lyme disease based on clinical and
serological findings as well as direct evidence of the causative microorganism by
using polymerase chain reaction (PCR). We provide long term follow up on the
clinical course and treatment of these patients and evaluate the efficacy of
prolonged courses (range 6-60 months) of antibiotics in these patients.
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Patients
Patients sought medical attention between 1998 and 2007
because of persistent
symptoms despite a presumably adequate course of antibiotics for Lyme disease.
To be included in this analysis the patients had to have demonstrable Borrelia
DNA (PCR method) in a skin sample in conjunction with the presence of clinical
signs and symptoms consistent with Lyme disease.
Patient characteristics:
·
Borrelia DNA detected in skin biopsies of all patients
·
Despite adequate course of antibiotics in the past ongoing symptoms and
signs most typical for Lyme Disease
·
36,66% (33/90) of patients were male, 63,33% (57/90) were female
·
All age groups present, mean age 49, range 7- 88 years
·
42,22% (38/90) recalled skin rash consistent with erythema migrans
·
Increased LFTs in 19% of patients
·
Mean duration of illness 9,5 years (range 1-40 years) as shown in figure 1
0
5
10
15
20
25
30
35
40
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11
20
30
11
3
10
0
13
12
16
32
5
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19
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20
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15
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27
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109
5
25
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20
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5
211
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20
40
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1
35
18
109
12
2122
445
40
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54
7
1
5
88
11
12
34
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98
342
Years
Patients
Figure 1: Duration in years from onset of symptoms until first
administration of antibiotics (Only data from 76/90 patients was available)
The most commonly reported symptoms were fatigue, musculoskeletal and
neuropsychiatric complaints (see figure 2). This observation is similar to that
found in the current literature. [10, 11]. The severity of the symptoms ranged
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from relatively mild to disabling. Most patients had already seen many
specialists about their persistent complaints.
To be included in the study the patients had to have skin manifestations, in most
cases clinically diagnosed acrodermatitis chronica atrophicans or recurrent
erythema migrans as a manifestation of disseminated disease.
0
10
20
30
40
50
60
70
80
90
100 95,55
94,44
88,88
60
56,66
46,66
42,22
32,22
28,88
1*
2*
3*
4*
5*
6*
7*
8*
9*
Percent
Figure 2: The frequency of clinical symptoms and findings. 1*.
Neuropsychiatric, 2 *. Musculo- skeletal 3 *. Fatigue, 4 *. Gastrointestinal
[10], 5 *. Eye manifestations, 6 *. Cardiac, 7 *. History of Erythema migrans
8 *. Hypertension, 9 *. Thyroid disease
Many of the patients had serologic evidence of coinfections (e.g. Chlamydia spp.,
Mycoplasma spp., Yersinia enterocolitica or others) or non- infectious
comorbidities. We evaluated 42/ 90 patients for coinfections. 80,6% (25/31) were
positive for Chlamydia spp., 78,3 % (18/23) for Mycoplasma spp. and 77,8% for
Yersinia (7/9). The seroprevalence of these infections was considerably higher
among our sample than the seroprevalence reported among the general
population [12, 13, 14]. The reasons for this surprising finding are unclear,
although one could speculate that our patient sample was more prone to infection
than the general population because of their persistent Lyme disease. Treatment
was considered in cases of detectable IgM/ IgA response. Coinfected patients
tended to have more severe disease and often needed combination therapy.
Serologic testing by ELISA and Western blot was performed on all patients.
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Surprisingly, only 57% of patients had a positive Borrelia serology, even though
all had PCR confirmed disease. The serologic findings of our sample are shown in
figure 3. The IgG western blot exhibited the highest degree of sensitivity (58%).
Only 43,52% (37/85) of patients had both a positive ELISA test and a positive
Western blot, while in 10,85% (9/85) the positive ELISA result was not confirmed
by the Western blot. In 24,70% (21/85) of cases the ELISA test remained negative
despite a positive Western blot, even though, to be useful as a screening tool, the
ELISA test should theoretically exhibit higher sensitivity. These results question
the often recommended two- tiered testing approach [3, 4, 7], since some patients
with a negative ELISA test will still have a strongly positive Western blot.
The lack of sensitivity of serologic testing for lyme disease has been described [8,
9, 15, 16] and commercially available kits are not standardized and produce
dramatically different results in some cases.
0
10
20
30
40
50
60
46,66
12,22
54,54
14,12
Elisa-IgG
Elisa-IgM
W-Blot-IgG
W-Blot-IgM
Percent
Figure 3: Positive serological findings in study patients
Detection of borrelial DNA in skin biopsies
Author of this section: ZeckLab, Labor für Klinische Diagnostik und Prüfung, Dr.
Gabriele Liebisch/Prof. Dr. Arndt Liebisch
Up´n Kampe 3, D-30938 Burgwedel,
Tel.: 0049-5139-892447
Fax : -892448
www.Zecklab.de
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