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Probable late lyme disease: A variant manifestation of untreated Borrelia burgdorferi infection


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Lyme disease, a bacterial infection with the tick-borne spirochete Borrelia burgdorferi, can cause early and late manifestations. The category of probable Lyme disease was recently added to the CDC surveillance case definition to describe patients with serologic evidence of exposure and physician-diagnosed disease in the absence of objective signs. We present a retrospective case series of 13 untreated patients with persistent symptoms of greater than 12 weeks duration who meet these criteria and suggest a label of 'probable late Lyme disease' for this presentation. The sample for this analysis draws from a retrospective chart review of consecutive, adult patients presenting between August 2002 and August 2007 to the author (JA), an infectious disease specialist. Patients were included in the analysis if their current illness had lasted greater than or equal to 12 weeks duration at the time of evaluation. Probable late Lyme patients with positive IgG serology but no history of previous physician-documented Lyme disease or appropriate Lyme treatment were found to represent 6% of our heterogeneous sample presenting with ≥ 12 weeks of symptom duration. Patients experienced a range of symptoms including fatigue, widespread pain, and cognitive complaints. Approximately one-third of this subset reported a patient-observed rash at illness onset, with a similar proportion having been exposed to non-recommended antibiotics or glucocorticosteroid treatment for their initial disease. A clinically significant response to antibiotics treatment was noted in the majority of patients with probable late Lyme disease, although post-treatment symptom recurrence was common. We suggest that patients with probable late Lyme disease share features with both confirmed late Lyme disease and post-treatment Lyme disease syndrome. Physicians should consider the recent inclusion of probable Lyme disease in the CDC Lyme disease surveillance criteria when evaluating patients, especially in patients with a history suggestive of misdiagnosed or inadequately treated early Lyme disease. Further studies are warranted to delineate later manifestations of Lyme disease and to quantify treatment benefit in this population.
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R E S E A R C H A R T I C L E Open Access
Probable late lyme disease: a variant
manifestation of untreated Borrelia burgdorferi
John N Aucott
, Ari Seifter
and Alison W Rebman
Background: Lyme disease, a bacterial infection with the tick-borne spirochete Borrelia burgdorferi, can cause early
and late manifestations. The category of probable Lyme disease was recently added to the CDC surveillance case
definition to describe patients with serologic evidence of exposure and physician-diagnosed disease in the absence
of objective signs. We present a retrospective case series of 13 untreated patients with persistent symptoms of
greater than 12 weeks duration who meet these criteria and suggest a label of probable late Lyme diseasefor this
Methods: The sample for this analysis draws from a retrospective chart review of consecutive, adult patients
presenting between August 2002 and August 2007 to the author (JA), an infectious disease specialist. Patients were
included in the analysis if their current illness had lasted greater than or equal to 12 weeks duration at the time of
Results: Probable late Lyme patients with positive IgG serology but no history of previous physician-documented
Lyme disease or appropriate Lyme treatment were found to represent 6% of our heterogeneous sample presenting
with 12 weeks of symptom duration. Patients experienced a range of symptoms including fatigue, widespread
pain, and cognitive complaints. Approximately one-third of this subset reported a patient-observed rash at illness
onset, with a similar proportion having been exposed to non-recommended antibiotics or glucocorticosteroid
treatment for their initial disease. A clinically significant response to antibiotics treatment was noted in the majority
of patients with probable late Lyme disease, although post-treatment symptom recurrence was common.
Conclusions: We suggest that patients with probable late Lyme disease share features with both confirmed late
Lyme disease and post-treatment Lyme disease syndrome. Physicians should consider the recent inclusion of
probable Lyme disease in the CDC Lyme disease surveillance criteria when evaluating patients, especially in patients
with a history suggestive of misdiagnosed or inadequately treated early Lyme disease. Further studies are warranted
to delineate later manifestations of Lyme disease and to quantify treatment benefit in this population.
Lyme disease, caused by infection with the tick-borne
spirochete Borrelia burgdorferi, is the most common
vector-borne disease in North America. In highly en-
demic regions of the United States, the annual incidence
of infection may be as high as 13% with a cumulative
prevalence as high as 715% [1,2]. In the majority of
cases, the diagnosis of confirmed early Lyme disease is
based on identification of the hallmark erythema
migrans (EM) rash, which may occur in isolation or in
conjunction with viral-like symptoms such as fever, mal-
aise, fatigue, and generalized achiness [3].
However, in up to 16% of early Lyme cases, patients
do not present with a rash and the primary symptoms of
their acute illness are viral-like [4]. Historically, surveil-
lance criteria requiring a high degree of specificity have
excluded patients with only viral-like or subjective
patient-reported symptoms in case definitions for Lyme
disease [5]. In 2008, however, the Centers for Disease
* Correspondence:
Equal contributors
Department of Medicine, Division of General Internal Medicine, Johns
Hopkins University School of Medicine, Baltimore, MD, USA
Full list of author information is available at the end of the article
© 2012 Aucott et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Aucott et al. BMC Infectious Diseases 2012, 12:173
Control (CDC) surveillance criteria for Lyme disease
were modified to include patients with solely subjective
symptoms and a positive confirmatory serology as prob-
able Lyme disease [6]. Based on the revised surveillance
case definition, more than 30,000 new confirmed or
probable cases of Lyme disease were reported in 2009
[7], though studies have shown that the actual number
of cases may exceed reported cases by a factor of 6 to 12
in endemic areas [8,9].
If left untreated, Lyme disease may progress to later
stages involving the musculoskeletal, neurologic, or car-
diovascular systems. The diagnosis of these late stages of
Lyme disease is based on clinical diagnosis with sero-
logic confirmation using CDC surveillance criteria [10].
The CDC case definition for confirmed late Lyme dis-
ease relies on signs of specific organ damage such as in-
flammatory arthritis with synovitis and joint effusion, or
objective neurologic disease, all confirmed by a positive
IgG immunoblot (western blot) for antibodies to B. burg-
dorferi [6]. However, an initial longitudinal observation of
untreated Lyme disease patients suggested that a signifi-
cant number (18%) of late Lyme cases may only exhibit
symptoms such as fatigue, arthralgias or myalgias, without
development of classic physical signs of late Lyme arthritis
or neurologic disease [11]. The patient phenotype of IgG
seropositivity and musculoskeletal pain, fatigue, and/or
cognitive dysfunction without signs of organ inflammation
or dysfunction corresponds with a late manifestation of
the current surveillance category of probable Lyme dis-
ease. When present, this phenotype can be termed prob-
able late Lyme disease.
The specific presentation of probable late Lyme dis-
ease, including untreated patients with a history of sub-
jective symptoms and a positive IgG immunoblot, differs
in two important ways from those meeting criteria for
post-treatment Lyme disease syndrome (PTLDS), a dis-
ease category recently added to the Infectious Disease
Society of America (IDSA) guidelines [10]. First, patients
with probable late Lyme have no history of a prior phys-
ician diagnosis of objective findings consistent with early
or late Lyme disease, a requirement for patients with
PTLDS. Second, patients with probable late Lyme have
not been previously treated with an antibiotic regimen
recommended for Lyme disease, also a requirement for
PTLDS. Since patients with probable late Lyme disease
have serologic evidence of remote exposure to B. burg-
dorferi, they represent a distinct subset among patients
with other chronic presentations that are often categor-
ized as medically unexplainedsymptoms or syndromes
such as chronic fatigue syndrome or fibromyalgia.
The existence of probable late Lyme disease, mani-
festing only as subjective symptoms with a concur-
rent positive IgG immunoblot serology, has remained
controversial. This patient presentation was described in
a recent review categorizing the spectrum of patients la-
belled as having chronic Lyme disease[12]. The
authors suggest that IgG seropositive patients with
symptoms but no signs of illness have at most equivocal
evidence for infection with B. burgdorferi and that any
benefit from treatment would be unlikely[12]. Patients
with probable late Lyme disease share clinical pheno-
types which overlap with patients who have PTLDS,
fibromyalgia, chronic fatigue syndrome, and those whose
symptoms remain medically unexplained after extensive
medical evaluation. Thus, many have argued against
serologic screening for Lyme disease among patients
whose symptoms of fatigue, widespread pain, and sub-
jective cognitive dysfunction exist in the absence of
physical findings or laboratory abnormalities [2,12].
Patients with probable late Lyme disease, or those un-
treated patients with a positive IgG serologic test for
Lyme disease and otherwise unexplained symptoms, rep-
resent an interesting subset of patients who have not
been clinically characterized in the modern Lyme disease
literature. This article offers a description of a sample of
such patients, within the context of the wider spectrum
of late and chronic Lyme patients seen for evaluation in
community-based clinical practice.
Patients and setting
The sample for this analysis draws from a chart review
of consecutive, adult patients age 18 and above referred
for evaluation of possible Lyme disease between August
2002 and August 2007 to the author (JA), an infectious
disease trained internist. The practice is located in a
Lyme-endemic suburban community of a medium sized
Mid-Atlantic city. Patients had either been self or phys-
ician referred for consultation and in some cases had
already been treated with antibiotics for Lyme disease
prior to their evaluation.
At the time of medical evaluation, a complete history
was taken for all patients and a physical exam was per-
formed. All objective physical exam findings and subject-
ive symptoms were documented and any relevant
medical records were reviewed. All records of acute and
convalescent ELISA and immunoblot serologies from
commercial laboratories utilizing CDC interpretive cri-
teria were documented [13]. Immunoblot results were
included even if a simultaneous ELISA was not docu-
mented in the records. Extensive evaluation for alterna-
tive diagnoses was initiated if the medical history,
physical exam, or laboratory findings were suggestive of
such. Patients self-reported prior diagnoses of their
current illness as well as any antibiotic or glucocorticos-
teroid use following disease onset. Charts were later
abstracted and relevant clinical information was entered
into a database. The database was used to identify
Aucott et al. BMC Infectious Diseases 2012, 12:173 Page 2 of 10
patients with probable late Lyme disease; these charts
were individually reviewed to obtain further information
on the patients presenting symptoms and their subse-
quent treatment response.
Definition of cases
Patients were included in the analysis if their current ill-
ness had lasted greater than or equal to 12 weeks dur-
ation at the time of evaluation. This subset was then
characterized as meeting criteria for one of five disease
categories, corresponding to those identified by Feder
et al. [12]. Final group determination was reviewed by a
clinician (JA) to ensure accuracy.
a) Confirmed late Lyme disease. CDC guidelines for
diagnosis of confirmed late Lyme arthritis, carditis,
or neurologic disease, including the presence of
objective signs involving the joints, the heart, or the
central or peripheral nervous system, were
stringently applied [6].
b) Other, non-Lyme diagnoses. Patients diagnosed with
an alternative, non-Lyme diagnosis which explained
their presenting symptoms were identified in this
c) Probable late Lyme disease. Patients in this group
were defined by a positive IgG serologic test and a
history of self reported subjective symptoms
including some combination of fatigue, non-
inflammatory musculoskeletal pain, and cognitive
symptoms. Patients with a history of either a
physician-documented EM rash or other objective
finding suggestive of Lyme disease were excluded.
Patients were also excluded from this category if
evidence was found that they had been treated with
a recommended antibiotic regimen for early Lyme
disease. However, patients with non-recommended
antibiotic, duration of antibiotic therapy less than
7 days, and glucocorticoid exposure for presumed
alternate diagnoses were included.
d) PTLDS. Patients meeting all criteria for the IDSA
proposed definition of PTLDS were included in this
group [10]. Patients meeting a less stringent
definition with a history of physician-documented
Lyme disease and current fatigue, musculoskeletal
pain or neurocognitive dysfunction but failing to
meet supplementary inclusion or exclusion criteria
relating to the timing of symptom onset or the
presence of minor depression were also included,
but are identified and presented separately.
e) No specific diagnosis. The remaining patients who
did not meet criteria for any of the above categories
were characterized as a final group with medically
unexplained symptoms and with no specific
Clinical characteristics of probable late lyme disease
Demographic and clinical characteristics of patients
meeting criteria for probable late Lyme were then
determined. Illness duration was defined from initial
patient-reported date of onset of subjective symptoms
coinciding with the present illness. Charts were also
reviewed for symptoms reported; symptoms were con-
sidered present as part of the current illness if men-
tioned in the medical record after date of illness onset.
While group criteria excluded those with a history of
physician-documented EM, patients with self-observed
rashes either not observed by a physician, or thought
not to be EM, were included. Antibiotics considered
Figure 1 Categorization of patients presenting for evaluation of Lyme disease with symptoms 12 weeks duration (n = 235).
Aucott et al. BMC Infectious Diseases 2012, 12:173 Page 3 of 10
non-recommended or of insufficient duration for treat-
ment of Lyme disease included all members of the quin-
olone class of antibiotics, first generation cephalosporins,
and five-day courses of azithromycin [10].
Tests for group differences were performed using chi-
square or Kruskal-Wallis tests, as appropriate. Results with
a two-sided p < 0.05 were considered statistically significant.
This chart review was approved by the Institutional Review
Board of the Johns Hopkins University School of Medicine.
Disease classification
A total of 235 patients with symptoms greater than
12 weeks were seen for evaluation (Figure 1). Of these,
35 (15%) had alternative, non-Lyme diagnoses which
explained their presenting signs and symptoms. An add-
itional 128 (54%) could not be assigned a specific diag-
nosis or category using the current CDC surveillance
criteria for Lyme disease and had medically unexplained
Among the remaining patients, 36 (15%) had a history
of prior, physician-documented and treated early Lyme
disease with persistent or recurrent symptoms. Nine of
these (25%) met the proposed IDSA case definition of
PTLDS, while the remaining 27 (75%) had persistent
symptoms after treatment of Lyme disease but failed to
meet supplementary inclusion or exclusion criteria in
the IDSA case definition. The most common reasons for
exclusion were the presence of an exclusionary comor-
bid condition which preceded illness onset (12/27, 44%),
a symptom duration of less than 6 months (7/27, 26%),
and a greater than six month duration between exposure
and subjective illness onset (7/27, 26%, mean time to
onset of illness 3.5 years, range 2.1-5.5 years).
Twenty-three patients (10%) met criteria for con-
firmed late Lyme disease, with the majority presenting
with objective oligoarthritis, primarily of the knee,
rather than neurologic abnormalities. The remaining 13
patients (6%) met the definition of probable late Lyme
disease with patient-reported symptoms and positive
IgG immunoblot, but without a history of previously
physician-documented Lyme disease or prior appro-
priate treatment. Probable late Lyme accounted for
12% of those with medically explained symptoms and
a specific Lyme or non-Lyme related diagnosis.
Probable late lyme disease
Table 1 presents demographic and clinical characteristics
of the 13 patients with probable late Lyme disease in
comparison to patients with other Lyme disease and
non-Lyme disease related diagnoses. The median age at
illness onset was 61 in patients with probable late Lyme
disease. The majority of the patients in the overall sam-
ple, with exception of those with confirmed late Lyme
arthritis, presented with some combination of fatigue,
generalized musculoskeletal pain, and cognitive com-
plaints. By definition, patients with probable late Lyme
disease had no history of physician documented or trea-
ted EM rash and no objective clinical signs associated
with late Lyme disease. However, 38% recalled a rash
consistent with EM at illness onset not documented or
diagnosed by a physician. In some cases the rash was felt
by the patient or physician to be atypical for Lyme dis-
ease because of the lack of the classic bulls eyeappear-
ance or because the rash did not meet the minimum
5 cm size in the CDC surveillance criteria (Figure 2,
patient #1 Table 2). This proportion of prior patient-
documented rash in the absence of physician diagnosed
erythema migrans was higher in the probable late Lyme
disease group when compared to the other four disease
groups (4% late Lyme, 3% PTLDS, 14% other diagnoses,
26% no specific diagnosis, p = 0.002).
Following illness onset, a significant number of all
patients had been exposed to glucocorticosteroids, anti-
biotics not recommended for the treatment of Lyme dis-
ease or of less than 10 days duration, or both. There
were no significant differences across groups in the pro-
portions exposed to ineffective antibiotics or steroids.
While male and female patients were approximately
equally represented in the probable late Lyme group, the
distribution was more variable across groups. Figure 3
shows the percentage male across all five groups, with
women slightly under-represented in the first and third
groups and over-represented in the second, fourth, and
fifth groups. The group distribution was found to be dif-
ferent by sex at trend level of p = 0.06. When compared
across the three Lyme-related disease groups (late, prob-
able late, and PTLDS), percent male was not found to be
significantly different by group, nor was it significantly
different when compared across the two remaining non-
Lyme-related groups (other diagnoses and no specific
diagnoses). However, when treated as two composite
variables, a significantly higher proportion male was
found in the Lyme-related group compared to the non-
Lyme-related group (p = 0.006). Age at illness onset was
also found to be significantly higher in the Lyme-related
group compared to the non-Lyme related group (PTLDS
p < 0.001).
Figure 4 presents box plots of the number of positive
IgG bands present on serologies obtained from patients in
each of the five disease groups. By definition, patients with
probable late Lyme disease were strongly IgG immunoblot
positive by CDC criteria (greater than 5 bands present).
PTLDS patients presented with a wide range of number of
IgG bands present, whereas those in the final two groups
all presented with negative IgG results.
Table 2 shows the specific symptoms and response to
therapy of the 13 patients with probable late Lyme
Aucott et al. BMC Infectious Diseases 2012, 12:173 Page 4 of 10
disease. Twelve of the 13 patients were treated after the
diagnosis of probable late Lyme disease, 8/12 by their re-
ferring physician prior to patient evaluation. Of those
treated, 75 percent reported what was considered to be
clinically significant improvement following antibiotic
treatment for probable late Lyme disease. However, 4/9
(44%) of patients who were seen in follow up after treat-
ment had relapse of some or all of their initial pre-
treatment symptoms.
This article presents a sample of untreated patients with
a history of persistent, subjective symptoms and IgG
antibodies to B. burgdorferi, a group which has not been
well-described. Patients with this presentation make up
an unknown proportion of all patients presenting for
evaluation of Lyme disease to a general practitioner or
medical subspecialist. In our experience, this group
accounted for 6% of all patients with symptoms greater
than 12 weeks who presented for evaluation of Lyme
disease in an endemic region, and 36% of patients with
confirmed or probable late Lyme disease.
Patients with this clinical presentation have been consid-
ered to be most similar to other subsets of patients with
the nonspecific label of chronic Lyme diseaseand thus
thought not to have evidence of active, untreated infection
with B. burgdorferi [12]. As a result, the etiology of their
symptoms and any recommendations for treatment
Table 1 Demographic and clinical characteristics of patients included in this retrospective chart review*
Characteristics Confirmed Late
Probable Late
PLS (n=36) Other diagnosis
No specific diagnosis
Age at illness onset 49.1 (44.9-65.3) 56.6 (50-67) 46.6 (35.5-52.5) 55.4 (36.5-61.6) 42.2 (32.1-53.0)
Male Sex 14/23 (61%) 6/13 (46%) 19/36 (53%) 14/35 (40%) 43/128 (34%)
Illness duration (weeks) 52 (9-130) 63 (52-152) 127 (30-270) 52 (25-216) 78 (40-204)
Widespread musculoskeletal pain 2/23 (9%) 11/13 (85%) 36/36 (100%) 17/35 (49%) 112/128 (88%)
Fatigue 0/23 (0%) 8/13 (62%) 32/36 (89%) 15/35 (43%) 96/128 (75%)
Cognitive complaints 0/23 (0%) 6/13 (46%) 19/36 (53%) 8/35 (23%) 67/128 (52%)
Patient reported rash in absence
of physician diagnosis of EM
1/23 (4%) 5/13 (38%) 1/36 (3%) 5/35 (14%) 33/128 (26%)
Physician documented EM 1/23 (4%) 0/13 (0%) 26/36 (72%) 4/35 (11%) 1/128 (1%)
Other physician documented
objective findings
21/23 (91%) 0/13 (0%) 9/36 (25%) 2/35 (6%) 11/128 (9%)
% ELISA positive ( >.9) 17/18 (94%) 11/11 (100%) 18/28 (64%) 6/23 (26%) 6/104 (6%)
Median ELISA among those (+) 3.5 2.0 1.8 1.75 1.4
% IgM immunoblot (+) 14/22 (64%) 2/11 (18%) 14/31 (45%) 4/28 (14%) 32/109 (29%)
Non-recommended antibiotic 8/23 (35%) 4/13 (31%) 14/36 (39%) 6/35 (17%) 43/128 (34%)
Steroid 3/23 (13%) 2/13 (15%) 9/36 (25%) 5/35 (14%) 19/128 (15%)
*no. (%) for dichotomous variables and median (IQR) for continuous variables.
Figure 2 Untreated skin lesion in patient number 1. Because of
the small size, lack of enlargement and lack of symptoms the
lesion was not felt to be consistent with erythema migrans. The
patient noted onset of symptoms 10 weeks later with olecranon
Aucott et al. BMC Infectious Diseases 2012, 12:173 Page 5 of 10
remain controversial. However, this group of narrowly
defined patients with ongoing symptoms and a positive
IgG immuno serology would meet CDC surveillance cri-
teria for probableLyme disease. In the clinical context of
months of ongoing symptoms, lack of an alternative diag-
nosis, lack of prior antibiotic therapy, and a positive IgG
immunoblot blot serology, we propose that this group of
patients has untreated, probable late Lyme disease.
A comparison of probable late Lyme and confirmed
late Lyme patients in our sample show some similarities.
Patients in both groups have significant immunoblot re-
activity on IgG immunoblot blot analysis, exceeding the
highly specific CDC criteria 5 band cut-off for positivity.
This pattern strongly supports the exposure of both
groups to B. burgdorferi and is consistent with a diagno-
sis of late, untreated infection. The finding of a positive
serology by itself is not diagnostic of active, untreated
infection in probable late Lyme disease, as it is also
present in the convalescent phase of resolved Lyme dis-
ease in the estimated 40% of individuals who are never
treated during the acute phase and never develop late
manifestations of Lyme disease. However in the context
of otherwise unexplained symptoms it is a reasonable
hypothesis that the patientssymptoms are a result of
previously untreated infection with B. burgdorferi.By
definition, probable late Lyme disease is characterized by
patient-reported symptoms rather than objective phys-
ical exam signs of disease, distinguishing this group from
those with untreated late Lyme arthritis or neurologic
disease. However, the type and chronicity of symptoms
in the probable group are very similar to a subset of
those patients described in an early observational series
of untreated Lyme disease in which 18% of patients
developed periarticular or musculoskeletal pain for as
long as 6 years, but never developed objective joint ab-
normalities [11]. In the same study, other patient-
reported symptoms including fatigue (41%), headache
(16%), myalgias (9%), and abdominal pain (9%) were also
found in addition to objective signs of Lyme arthritis.
These early descriptions suggest that the distinction
between subjective, patient-reported symptoms and ob-
jective signs of late Lyme disease may not be absolute.
For example, patient-reported symptoms of musculo-
skeletal pain may precede the onset of objective syno-
vitis. In addition, the physical finding of joint swelling
may be intermittent, so that on any given physician
evaluation the only evidence of late Lyme disease may
be the patients report of symptoms [14].
Further, in probable late Lyme disease, the lack of
physician-documented signs of early disease, including
Table 2 Specific symptoms and responses to therapy of the 13 patients with probable late Lyme disease
Patient Exposure
Treatment Outcome
1 Non-diagnostic
skin lesion not treated.
(See figure 2)
Arthralgias, neck stiffness,
fatigue; Olecranon bursitis
12 months Doxycycline
4 weeks
All symptoms resolved.
No Relapse
2 Unknown Arthralgias: hip;
5 years Doxycycline
7 weeks
80% Improved.
No relapse
3 Tick bite with
cellulitis Rx with cephalexin
Arthralgias: jaw, arm;
Fatigue, memory problems
3 months Amoxicillin
4 weeks
95% improved.
No relapse
4 Unknown Back pain 18 months Unknown Unknown
5 Spider bite, Rx
with erythromycin
Arthralgias, Poor memory;
Night sweats
15 months Ceftriaxone 3 weeks;
Amoxicillin 4 weeks
6 Unknown Memory loss
w/normal CSF
6 months Doxycycline 12 weeks No improvement.
7 Viral symptoms with
rash Rx with 5 day
Arthralgia; Fatigue 6 months Doxycycline
3 weeks
80% improved.
8 Unknown Leg myalgia 12 months Doxycycline 12 weeks No clinically significant
9 Unknown Arthralgias; Olecranon bursitis 12 months Doxycycline 6 weeks Marked improvement
10 Remote untreated EM
25 years prior
Memory loss 12 months Doxycycline 4 weeks No improvement
11 Viral like illness Arthralgias; Olecranon bursitis,
7 months Doxycycline 3 weeks Complete response.
12 Round rash, no treatment Arthralgias 30 months Doxycycline 4 weeks Improvement. Relapsed
13 Unknown Fatigue, arthralgias, vertigo 18 months Doxycycline 8 weeks 50% improved.
No relapse
Aucott et al. BMC Infectious Diseases 2012, 12:173 Page 6 of 10
Figure 4 Box plots of the number of reactive IgG bands on commercially available serologic tests for antibodies to Borrelia burgdorferi
by disease group (n = 235).
Figure 3 Percent male in each disease group (n = 235).
Aucott et al. BMC Infectious Diseases 2012, 12:173 Page 7 of 10
EM, is not unexpected and does not necessarily negate
the possibility for development of late infection. It is
known that during the acute phase of infection, EM may
not occur, may not be seen, or may be misdiagnosed,
allowing patients to progress to later stages of disease
[15,16]. Series of patients with late Lyme arthritis report
a history of EM in 23% of patients and flu-like illness
alonein 16% of patients that preceded their diagnosis
of late Lyme arthritis [17]. Interestingly, approximately
one third of patients in our series with probable late
Lyme disease reported a history of a rash at illness onset
that was never physician-documented or treated.
Until the causal relationship of symptoms to infection
in probable late Lyme disease can be proven pathologic-
ally, the practicing physician must weigh the relative risk
and benefit of antibiotic treatment in this group of
patients. The finding that 8/12 patients with probable
late Lyme eventually received antibiotic treatments for
Lyme disease prior to their subsequent referral for evalu-
ation demonstrates that current community practice is
often to treat these patients. The treatment approach to
this group of patients has not been clearly outlined in
the medical literature, with one recent review suggesting
that any benefit from treatment would be unlikely [12].
The result that 75% of probable late Lyme patients
reported clinically significant improvement with appro-
priate Lyme disease treatment is consistent with treat-
ment outcomes in confirmed late Lyme arthritis, in
which 90% of patients respond to one or more courses
of antibiotic therapy. 10% of patients with definite late
Lyme disease do not completely respond to antibiotics
and are described as having antibiotic-refractory late
Lyme arthritis. The pathophysiology of this syndrome is
not well understood, although proposed to be an auto-
immune based process [17], the role of ongoing bacterial
infection in the process remains under investigation
[18,19]. The long term outcomes of patients with per-
sistent symptoms after antibiotic treatment of probable
late Lyme disease are unclear. In our small case series 4/
9 (44%) of patients had relapse of symptoms after their
initial antibiotic therapy suggesting that a subset of
patients with probable late Lyme disease will go on to
develop PTLDS. Future studies are needed to assess ef-
fective treatment modalities in a controlled fashion.
Our sample of probable late Lyme disease also showed
some differences and some similarities when compared to
patients with PTLDS. Patients with probable late Lyme
disease had similar rates of patient reported symptoms of
pain, fatigue, and cognitive complaints as those patients
with PTLDS. In contrast to those with PTLDS, our group
of probable late Lyme patients had not been previously
diagnosed with Lyme disease, nor had they been previ-
ously treated with antibiotics for Lyme disease. The higher
rates of IgG seroreactivity in patients with probable late
Lyme disease is also in contrast to patients with PTLDS,
who all have a history of physician-documented early
Lyme disease and variable serologic reactivity. The lower
rate of seroreactivity among those with PTLDS is likely
explained by exposure to early, effective antibiotics during
acute infection, which is known to potentially blunt sero-
logic response to infection with B. burgdorferi [20]. It is
also in contrast to patients with other, non-Lyme diagno-
ses and those with medically unexplained symptoms, all of
whom lacked IgG immunoblot seropositivity at a level to
meet the CDC surveillance criteria for Lyme disease. Until
a gold standard with high sensitivity for exposure to B.
burgdorferi becomes available the percentage of patients
with medically unexplained symptoms that are due to ex-
posure to B. burgdorferi infection will remain unknown.
Because of the limitations of serology in documenting
prior exposure to B. burgdorferi with early antibiotic treat-
ment Lyme disease, the case definition for PTLDS is clin-
ically based. In an attempt to increase specificity the
definition may lose sensitivity by excluding patients with
onset of symptoms greater than 6 months after the anti-
biotic treatment or by excluding those with common pre-
existing conditions such as mild depression. As many
patients with no specific diagnosis and medically unex-
plained symptoms had poorly documented past medical
histories, we cannot rule out that some may have had
unrecognized or undocumented early Lyme disease that
was treated, resulting in unrecognized PTLDS.
The observed demographic differences found across
disease groups in our sample also warrant further re-
search. The younger, female predominance in the medic-
ally unexplained group may reflect the inclusion of
patients with syndromes such as fibromyalgia and
chronic fatigue syndrome, which are known to have a fe-
male predominance. However, the possibility remains
unexplored that certain group inclusion or exclusion cri-
teria, or other factors such as patterns of interaction
with the health care system, may be associated with spe-
cific demographic characteristics.
Previous recommendations have stated that the pre-
test probability for Lyme disease in patients without a
history of objective manifestations is too low to justify
testing and treatment [2]. Recommendations for Lyme
disease testing in patients without objective physical
findings have been based on assumptions that the in-
cidence of disease in this population is low and not
significantly higher than in the general population of
a low-moderately endemic region (0.10.01% pre-test
probability estimates). Our results suggest that the pre-
test probability may be significantly higher than these
estimates in patients with symptoms being evaluated in
a Lyme endemic area; closer to the 6% assumption
which has been used for patients with fibromyalgia-like
symptoms from a very high incidence region. This
Aucott et al. BMC Infectious Diseases 2012, 12:173 Page 8 of 10
assumption of higher disease prevalence leads to a post-
test probability of approximately 25%, more than twice
what has been reported in previous analyses [2]. Among
those with probable late Lyme disease, a patient-
reported history of rash suggests that the pre-test prob-
ability of Lyme disease (and thus the predictive value of
a positive serologic result in certain selected patients
with very significant histories) may be even higher. We
suggest that in patients from Lyme endemic regions, the
possible diagnosis of probable late Lyme disease is rea-
sonable to consider in the setting of an unexplained ill-
ness and a history highly suggestive of Lyme disease
exposure. These patients may benefit from testing for
IgG antibodies to confirm exposure to B. burgdorferi
and to suggest the possibility of late untreated infection.
There are several important limitations to this study
and future research is warranted. First, the retrospective
nature of the data relied largely on patient self-report as
well as on serologic results from several commercial la-
boratories and past medical records from several phys-
ician offices. Because of this, results of testing for other
tick-borne infections such as babesiosis, anaplasmosis,
ehrlichiosis, bartonellosis, and rickettsiosis. were gener-
ally not available and were not included in this report.
The insensitivity of serology for the early diagnosis of
Lyme disease and for documenting remote exposure to
B. burgdorferi infection may have led to unintended mis-
classification of an unknown number of cases currently
defined as medically unexplained and led to an under-
estimation of the true numbers of cases of Lyme disease
or PTLDS. Extrapolation of our findings in patients will
probable Late Lyme disease to the much larger number
of patients with syndromediagnosis such as fibromyal-
gia, chronic fatigue syndrome, and medically unex-
plained symptoms with be the focus for future
investigations when better biomarkers for Lyme disease
and B.burgdorferi exposure becomes available.
In addition, the possibility of sex based differences in
performance of serologic tests for Lyme disease may fur-
ther complicate the ability to establish exposure to B.
burgdorferi and to make the accurate diagnosis of Lyme
disease. The opportunity exists for recall or other biases,
particularly among patients eager to label previously unex-
plained symptoms. While the retrospective nature of the
data is not ideal, we would argue that the opportunity for
prospective studies capturing this subset of patients is
challenging. Finally, because of the small sample size in
our case series, additional studies with larger sample sizes
are needed to see if our findings are replicable.
In conclusion, untreated patients with persistent, unex-
plained symptoms and serologic evidence of prior expos-
ure to B. burgdorferi represent an interesting subset of
patients presenting for evaluation of Lyme disease to a
community based Lyme disease referral practice. These
patients with probable late Lyme disease have a combin-
ation of patient reported symptoms such as fatigue,
widespread pain, and cognitive complaints but lack the
classic objective findings of joint synovitis or large fiber
neuropathy that defines definite late Lyme disease. Some
of these patients may have a history suspicious for previ-
ously unrecognized early Lyme disease with EM, which
highlights the importance of careful physician histories
in endemic regions. The predictive value of a positive
serologic result in this subset of patients may not be as
low as previously thought. Physicians should consider
the recent inclusion of probable Lyme disease in the
CDC Lyme disease surveillance criteria when evaluating
patients, especially those with a history consistent with
misdiagnosed or inappropriately treated early Lyme dis-
ease. Further studies are needed to more precisely define
the clinical spectrum, ideal treatment, and long-term
outcomes of patients with probable late Lyme disease.
Written informed consent was obtained from the patient
shown in Figure 2 for publication of this manuscript and
any accompanying images. A copy of the written consent
is available for review by the Series Editor of this
Competing interests
The authors declare that they have no competing interests.
JA conceived of the study, participated in its design and coordination and
helped draft the manuscript. AS assisted with the data analysis and helped
draft the manuscript. AR participated in the study design, performed the
statistical analysis and helped draft the manuscript. All authors read and
approved the final manuscript.
This research was funded by the Lyme Disease Research Foundation of
Maryland. The authors would like to thank Lauren A. Crowder, MPH for her
significant editorial and data analysis contributions to this manuscript.
Author details
Department of Medicine, Division of General Internal Medicine, Johns
Hopkins University School of Medicine, Baltimore, MD, USA.
The Lyme
Disease Research Foundation of Maryland, Lutherville, MD, USA.
Received: 13 June 2011 Accepted: 28 July 2012
Published: 1 August 2012
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... The putative association between these disorders and LD has remained contentious, and indeed the surveillance case definition established by the Centers for Disease Control and Prevention in the 1990s restricted LD to classic objective presentations such as EM or joint effusion. With the addition of a "possible late Lyme disease" case category in 2008 that does not require objective clinical abnormalities, and instead encompasses subjective symptoms such as fatigue and widespread musculoskeletal pain accompanied by reactive IgG serology, syndromic Lyme disease presentations have been described [20]. Although one definition of CLD identifies unresolved Borrelia infection as the etiologic agent of longstanding illness [21], the concept has incited controversy, and a dominant clinical narrative maintains that chronic Lyme symptoms are falsely attributed to tick-borne pathogens [22]. ...
... Seroreactive results among patients with subjective symptoms were largely dismissed as false-positive findings, and antibiotic intervention was not recommended as the risk-benefit calculation was not favourable [83]. The CDC case definition at the time supported this perspective, although it has since evolved, and original treatment recommendations have been challenged by the observation that some late "syndromic" diseases proximal to Borrelia exposure appear to respond to antimicrobial intervention, albeit with a high relapse rate [20]. However, the significance of Borrelia in FMS specifically remains unclear in the literature. ...
... Conversely, concerns persist that positive laboratory findings in the context of atypical or subjective disease manifestations are unreliable [87]. IgG seropositivity in conjunction with non-specific symptoms like myalgia, brain fog, and fatigue that do not satisfy objective criteria for late Lyme may be classified as probable late Lyme disease [20] or chronic Lyme disease [21], yet the utility of testing individuals who lack objective clinical findings has been challenged [88]. Indeed, current clinical practice guidelines issued by the Infectious Diseases Society of America (IDSA) recommend against testing for Borrelia seroreactivity in patients with MS, amylotrophic lateral sclerosis (ALS), Parkinson's disease, dementia, or psychiatric and behavioural disorders [75]. ...
Full-text available
Lyme disease, caused by vector-borne Borrelia bacteria, can present with diverse multi-system symptoms that resemble other conditions. The objective of this study was to evaluate disease presentations and Borrelia seroreactivity in individuals experiencing a spectrum of chronic and complex illnesses. We recruited 157 participants from Eastern Canada who reported one or more diagnoses of Lyme disease, neurological, rheumatic, autoimmune, inflammatory, gastrointestinal, or cardiovascular illnesses, or were asymptomatic and presumed healthy. Intake categories were used to classify participants based on their perceived proximity to Lyme disease, distinguishing between those with a disclosed history of Borrelia infection, those with lookalike conditions (e.g. fibromyalgia syndrome), and those with unrelated ailments (e.g. intestinal polyps). Participants completed three questionnaires, the SF-36 v1, SIQR, and HMQ, to capture symptoms and functional burden, and provided blood serum for analysis at an accredited diagnostic lab. Two-tiered IgG and IgM serological assessments (whole cell ELISA and Western blot) were performed in a blinded fashion on all samples. The pattern of symptoms and functional burden were similarly profound in the presumptive Lyme and Lyme-like disease categories. Borrelia seroprevalence across the study cohort was 10% for each of IgG and IgM, and occurred within and beyond the Lyme disease intake category. Western blot positivity in the absence of reactive ELISA was also substantial. Fibromyalgia was the most common individual diagnostic tag disclosed by two-tier IgG-positive participants who did not report a history of Lyme disease. Within the IgG seropositive cohort, the presence of antibodies against the 31 kDa Outer Surface Protein A (OspA) was associated with significantly better health outcomes. Previously, this marker has been linked to treatment-refractory Lyme arthritis. Overall, our findings support prior observations of phenotypic overlap between Lyme and other diseases. Seropositivity associated with non-specific symptoms and functional impairment warrants further mechanistic investigation and therapeutic optimization.
... For example, patients with intermittent bouts of late Lyme arthritis continued to have such symptoms present during the intervening intervals (10). Occasionally, symptoms without physical exam, laboratory, or other so-called "objective" findings remain the major or only manifestations of untreated Lyme disease infection (11). The use of direct tests such as culture, polymerase chain reaction (PCR) or antigen detection for B. burgdorferi to aid clinicians in diagnosis is extremely limited, and B. burgdorferi cannot be cultured in non-research settings. ...
... Similarly, there does not appear to be a significant difference by gender among those who meet a highly-specific definition for persistent symptoms in the research setting (59,60). However, it has been noted that when less specific definitions are used, as may be applied in clinical practice, the ratio of patients is instead majority female (11,61). When diagnosed and treated promptly, children appear less likely than adults to report persistent symptoms following Lyme disease (22,(62)(63)(64) Among adults, it is not clear if age represents a significant risk factor. ...
... Notably, PTLD is a mechanistically neutral research definition and the term "post-treatment" refers to the patient's status of having been previously treated with appropriate antibiotics. In our experience, patients who meet this case definition are not uncommon in a Lyme disease referral practice in an endemic area, and represent ∼15% of patients referred for evaluation (11,60). ...
Full-text available
It has long been observed in clinical practice that a subset of patients with Lyme disease report a constellation of symptoms such as fatigue, cognitive difficulties, and musculoskeletal pain, which may last for a significant period of time. These symptoms, which can range from mild to severe, have been reported throughout the literature in both prospective and population-based studies in Lyme disease endemic regions. The etiology of these symptoms is unknown, however several illness-causing mechanisms have been hypothesized, including microbial persistence, host immune dysregulation through inflammatory or secondary autoimmune pathways, or altered neural networks, as in central sensitization. Evaluation and characterization of persistent symptoms in Lyme disease is complicated by potential independent, repeat exposures to B. burgdorferi, as well as the potential for co-morbid diseases with overlapping symptom profiles. Antibody testing for B. burgdorferi is an insensitive measure after treatment, and no other FDA-approved tests currently exist. As such, diagnosis presents a complex challenge for physicians, while the lived experience for patients is one marked by uncertainty and often illness invalidation. Currently, there are no FDA-approved pharmaceutical therapies, and the safety and efficacy of off-label and/or complementary therapies have not been well studied and are not agreed-upon within the medical community. Post-treatment Lyme disease represents a narrow, defined, mechanistically-neutral subset of this larger, more heterogeneous group of patients, and is a useful definition in research settings as an initial subgroup of study. The aim of this paper is to review the current literature on the diagnosis, etiology, risk factors, and treatment of patients with persistent symptoms in the context of Lyme disease. The meaning and relevance of existing patient subgroups will be discussed, as will future research priorities, including the need to develop illness biomarkers, elucidate the biologic mechanisms of disease, and drive improvements in therapeutic options.
... However, establishing a clear link between pathogen diversity and pathogenicity requires the use of model systems, particularly for identifying specific virulence loci. In addition, molecular studies of serological progression help to identify the breadth of potential Lyme disease manifestations [7] and the variable accuracy of diagnostic tests [8]. This is especially important for B. burgdorferi sensu stricto, which can have wide-ranging effects in the human body due to an immunological cascade from initial infection to late-onset symptoms. ...
Global emergence of vector-borne and zoonotic diseases presents a rapidly growing ‘wicked’ problem. We outline the need for a transdisciplinary research program that is grounded in ecological and evolutionary theory but integrates fundamentally with research perspectives spanning the health, social, and natural sciences.
... While not an attractive sample type for routine diagnostics because of the need for an invasive biopsy, molecular testing of EM skin biopsy specimens could be used during the development of a routine test that utilizes a less invasive sample type, such as whole blood, by aiding in determining true-positive results and true-negative results. Direct detection of nucleic acid in the skin may be especially useful for aiding in diagnoses of small lesions that may not reach the specific case definition of 5 cm and may therefore be missed (50) or of atypical lesions that may be confused with other diagnoses in consultative dermatology or infectious diseases practices (51). PCR/ESI-MS and other direct detection approaches can help identify a larger group of patients to decrease misdiagnosis and delayed treatment. ...
Full-text available
Lyme disease is a tick-borne infection caused by the bacteria Borrelia burgdorferi . Current diagnosis of early Lyme disease relies heavily on clinical criteria, including the presence of an erythema migrans rash. The sensitivity of current gold-standard diagnostic tests relies upon antibody formation, which is typically delayed and thus of limited utility in early infection. We conducted a study of blood and skin biopsy specimens from 57 patients with a clinical diagnosis of erythema migrans. Samples collected at the time of diagnosis were analyzed using an ultra-sensitive, PCR-based assay employing an isothermal amplification step and multiple primers. In 75.4% of patients, we directly detected one or more B. burgdorferi genotypes in the skin. Two-tier testing showed that 20 (46.5%) of those found to be PCR positive remained serologically negative at both acute and convalescent time points. Multiple genotypes were found in 3 (8%) of those where a specific genotype could be identified. The 13 participants who lacked PCR and serologic evidence for exposure to B. burgdorferi could be differentiated as a group from PCR positive participants by their levels of several immune markers as well as by clinical descriptors such as their number of acute symptoms and the pattern of their erythema migrans rash. These results suggest that within a Mid-Atlantic cohort, patient subgroups can be identified using PCR-based direct detection approaches. This may be particularly useful in future research such as vaccine trials and public health surveillance of tick-borne disease patterns.
... The most commonly observed symptoms of the patients in this study included back pain, dizziness, fatigue, muscle pain, and weakness in the extremities. This finding corresponds with those in other studies; fatigue, joint pain, difficulty in focusing, muscle pain, and memory were rated among the most common and/or severe [16,38,40,[45][46][47][48]. After calculating the change in number of patients with each symptom before and after treatment, it was found that the majority of symptoms improved in most of the symptom categories. ...
Full-text available
Lyme disease is a vector-borne illness caused by Borrelia spp. bacterium spread by ticks to humans and other mammals. Despite being prevalent in many regions of the world, there remains considerable uncertainty surrounding many aspects of the disease, and consensus on the most appropriate and effective means of treating the illness remains to be achieved. Recommendations published by the Infectious Diseases Society of America (IDSA) and the International Lyme and Associated Diseases Society (ILADS), the primary guidelines followed by health care professionals treating Lyme disease, diverge in many of their key recommendations, including treatment duration. Given this lack of consensus, surprisingly little research has been conducted on patient outcomes following different treatment approaches. In this study, patient outcomes were evaluated from a cohort of 210 Canadian Lyme disease patients seeking treatment at one US Lyme disease clinic following a treatment regimen conforming to the ILADS treatment guidelines. It was found that the majority of Lyme disease patients at the clinic responded positively to treatment and a significant (p < 0.05) decrease in symptoms was observed over time. This study, along with related studies, may help to guide physicians to provide their patients with the most effective care.
... In traditional reservoir hosts like the white-footed mouse, Bb infection most often manifests as a persistent, asymptomatic infection [15,153], whereas inbred laboratory models such as the C3H/He background suffer debilitating tissue pathologies [154], as discussed in Section 3.1. Longstanding infection has been described both in untreated model organisms and humans [155]. The interactions with the host immune system and other cells and tissues of the body are therefore thought to be key determinants driving the outcome. ...
Full-text available
Lyme disease is a complex tick-borne zoonosis that poses an escalating public health threat in several parts of the world, despite sophisticated healthcare infrastructure and decades of effort to address the problem. Concepts like the true burden of the illness, from incidence rates to longstanding consequences of infection, and optimal case management, also remain shrouded in controversy. At the heart of this multidisciplinary issue are the causative spirochetal pathogens belonging to the Borrelia Lyme complex. Their unusual physiology and versatile lifestyle have challenged microbiologists, and may also hold the key to unlocking mysteries of the disease. The goal of this review is therefore to integrate established and emerging concepts of Borrelia biology and pathogenesis, and position them in the broader context of biomedical research and clinical practice. We begin by considering the conventions around diagnosing and characterizing Lyme disease that have served as a conceptual framework for the discipline. We then explore virulence from the perspective of both host (genetic and environmental predispositions) and pathogen (serotypes, dissemination, and immune modulation), as well as considering antimicrobial strategies (lab methodology, resistance, persistence, and clinical application), and borrelial adaptations of hypothesized medical significance (phenotypic plasticity or pleomorphy).
Untreated Lyme disease (infection with the bacteria B. burgdorferi sensu lato) progresses over time through three clinical stages that can present with skin, cardiac, nervous system, and musculoskeletal manifestations. Diagnosing Lyme disease can be challenging, as the initial characteristic skin lesion, erythema migrans, is highly variable, and may present as a single or multiple lesions. Erythema migrans is also not always visible. Patients may initially present with non-specific symptoms such as fever, fatigue, and malaise. All non-erythema migrans manifestations require a positive two-tier serology to confirm the diagnosis. The majority of second stage early disseminated cases are neurologic in nature and may present with any combination of cranial nerve palsy, radiculoneuritis, and meningitis, whereas the majority of late disseminated cases are musculoskeletal in nature. Persistent symptoms may occur after treatment of any stage of Lyme disease, and may be due to a number of potential mechanisms still under study.
Most patients with Lyme disease will fully recover with recommended antibiotic therapy. However, some patients report persisting nonspecific symptoms after treatment, referred to as posttreatment Lyme disease symptoms (PTLDs) or syndrome (PTLDS), depending on the degree to which the individual's symptoms impact their quality of life. PTLDs occur in a portion of patients diagnosed with chronic Lyme disease (CLD), a controversial term describing different patient populations, diagnosed based on unvalidated tests and criteria. Practitioners should review the evidence for the Lyme disease diagnosis and not overlook unrelated conditions. Current evidence shows that prolonged antibiotic therapy provides little benefit and carries significant risk. Further research to elucidate the mechanisms underlying persistent symptoms after Lyme disease and to understand CLD is needed.
Lyme borreliosis is the most common vector-borne disease in the United States, where most infections are caused by Borrelia burgdorferi sensu stricto (s.s.) and transmitted by Ixodes scapularis. Both the geographic locations and the number of infections have steadily increased. Variations within Lyme borrelia, together with differences in the host response and time to antibiotic treatment, play a role in the diversity of disease manifestations and/or in their severity. Compared with Europe, early Lyme borreliosis presenting with erythema migrans in the United States is associated with more symptomatic disease and untreated infection is particularly linked with arthritis. Progress has been made toward new approaches for Lyme borreliosis laboratory diagnosis, including simplification of the current algorithm, opening the door for the development of point-of-care tests. Recommendations for the treatment of Lyme borreliosis are similar between the United States and European guidelines, with small differences regarding the use of phenoxymethylpenicillin, antibiotic treatment of pregnant women, and postexposure chemoprophylaxis. The majority of recognized coinfections in the United States involve two of the three most common pathogens, B. burgdorferi, Anaplasma phagocytophilum, and Babesia microti, but I. scapularis can also transmit B. mayonii, B. miyamotoi, Ehrlichia muris eauclairensis, and the deer tick virus subtype of Powassan virus. The controversial issue of chronic Lyme disease is a growing problem in both the United States and Europe, which will need well-designed approaches to investigate this heterogeneous group of patients and set up the groundwork for more effective treatment strategies for patients.KeywordsLyme diseaseLyme borreliosis Borrelia burgdorferi Borreliella burgdorferi United StatesEurope
Riassunto La borreliosi di Lyme è dovuta, nella grande maggioranza dei casi, all’infezione da una delle tre specie Borrelia burgdorferi, Borrelia garinii e Borrelia afzelii, che sono trasmesse dai morsi di zecche del genere Ixodes. Altri agenti infettivi, a volte trasmessi anch’essi da queste zecche, causano danni neurologici solo eccezionalmente. La borreliosi di Lyme è, il più delle volte, limitata a un eritema migrante, ma, più raramente, può colpire le articolazioni, il sistema nervoso o il cuore. La neuroborreliosi interessa circa 450 pazienti ospedalizzati all’anno in Francia. Le presentazioni più frequenti sono la meningoradiculite e una lesione dei nervi faciali. Molto più raramente, la neuroborreliosi può manifestarsi come meningite, encefalite, mielite, vasculite o polineuropatia. La diagnosi si basa generalmente sull’associazione di una sintomatologia suggestiva, di un’ipercellulorachia e di una sintesi intratecale di anticorpi anti-Borrelia. La sierologia può essere falsamente negativa nelle neuroborreliosi precoci o restare positiva nel caso di antica infezione guarita. Il trattamento fa ora ricorso alla doxiciclina o al ceftriaxone per 14-21 giorni. Nonostante le polemiche mediatiche, a oggi non ci sono prove scientifiche della superiorità di altri metodi diagnostici né della persistenza di un’infezione clinicamente significativa dopo un trattamento appropriato. Sono comunque possibili sequele neurologiche.
Full-text available
The persistence of symptoms in Lyme disease patients following antibiotic therapy, and their causes, continue to be a matter of intense controversy. The studies presented here explore antibiotic efficacy using nonhuman primates. Rhesus macaques were infected with B. burgdorferi and a portion received aggressive antibiotic therapy 4-6 months later. Multiple methods were utilized for detection of residual organisms, including the feeding of lab-reared ticks on monkeys (xenodiagnosis), culture, immunofluorescence and PCR. Antibody responses to the B. burgdorferi-specific C6 diagnostic peptide were measured longitudinally and declined in all treated animals. B. burgdorferi antigen, DNA and RNA were detected in the tissues of treated animals. Finally, small numbers of intact spirochetes were recovered by xenodiagnosis from treated monkeys. These results demonstrate that B. burgdorferi can withstand antibiotic treatment, administered post-dissemination, in a primate host. Though B. burgdorferi is not known to possess resistance mechanisms and is susceptible to the standard antibiotics (doxycycline, ceftriaxone) in vitro, it appears to become tolerant post-dissemination in the primate host. This finding raises important questions about the pathogenicity of antibiotic-tolerant persisters and whether or not they can contribute to symptoms post-treatment.
Full-text available
Lyme disease, the most common vector-borne infection in North America, is increasingly reported. When the characteristic rash, erythema migrans, is not recognized and treated, delayed manifestations of disseminated infection may occur. The accuracy of diagnosis and treatment of early Lyme disease in the community is unknown. A retrospective, consecutive case series of 165 patients presenting for possible early Lyme disease between August 1, 2002 and August 1, 2007 to a community-based Lyme referral practice in Maryland. All patients had acute symptoms of less than or equal to 12 weeks duration. Patients were categorized according to the Centers for Disease Control and Prevention criteria and data were collected on presenting history, physical findings, laboratory serology, prior diagnoses and prior treatments. The majority (61%) of patients in this case series were diagnosed with early Lyme disease. Of those diagnosed with early Lyme disease, 13% did not present with erythema migrans; of those not presenting with a rash, 54% had been previously misdiagnosed. Among those with a rash, the diagnosis of erythema migrans was initially missed in 23% of patients whose rash was subsequently confirmed. Of all patients previously misdiagnosed, 41% had received initial antibiotics likely to be ineffective against Lyme disease. For community physicians practicing in high-risk geographic areas, the diagnosis of Lyme disease remains a challenge. Failure to recognize erythema migrans or alternatively, viral-like presentations without a rash, can lead to missed or delayed diagnosis of Lyme disease, ineffective antibiotic treatment, and the potential for late manifestations.
Purpose: To provide a quantitative and qualitative evaluation of the predictive value of the laboratory diagnosis of Lyme disease and to use the resultant data to formulate guidelines for clinical diagnosis. Data Sources: A MEDLINE search of English-language articles or articles with English-language abstracts published from 1982 to 1996. Data Extraction: Sensitivity, specificity, and likelihood ratios were calculated, and a random-effects model was used to combine the proportions from the eligible studies. Prespecified criteria were used to determine which studies were eligible for analysis. Data Synthesis: Laboratory testing in general is not clinically useful if the pretest probability of Lyme disease is less than 0.20 or greater than 0.80. When the pretest probability is 0.20 to 0.80, sequential testing with enzyme-linked immunosorbent assay and Western blot is the most accurate method for ruling in or ruling out the possibility of Lyme disease. Conclusions: Laboratory testing is recommended only in patients whose pretest probability of Lyme disease is 0.20 to 0.80. If the pretest probability is less than 0.20, testing will result in more false-positive results than true-positive results; a negative test result in this situation effectively rules out the disease.
Lyme arthritis differs in many respects from other bacterial causes of arthritis. Based on an observation made for a patient with Lyme arthritis, we propose that the pathogenesis of joint swelling in Lyme arthritis is due to the introduction into the joint space of non-viable spirochetes or more likely spirochetal debris enmeshed in a host-derived fibrinous or collagenous matrix. This "amber" hypothesis can account for the clinical and laboratory features of Lyme arthritis and is amenable to experimental validation. Validation would directly impact the clinical management of patients with Lyme arthritis.
Maize (Zea mays L.) is susceptible to infection by Fusarium verticillioides through autoinfection and alloinfection, resulting in diseases and contamination of maize kernels with the fumonisin mycotoxins. Attempts at controlling this fungus are currently being done with biocontrol agents such as bacteria, and this includes bacterial endophytes, such as Bacillus mojavensis . In addition to producing fumonisins, which are phytotoxic and mycotoxic, F. verticillioides also produces fusaric acid, which acts both as a phytotoxin and as an antibiotic. The question now is Can B. mojavensis reduce lesion development in maize during the alloinfection process, simulated by internode injection of the fungus? Mutant strains of B. mojavensis that tolerate fusaric acid were used in a growth room study to determine the development of stalk lesions, indicative of maize seedling blight, by co-inoculations with a wild-type strain of F. verticillioides and with non-fusaric acid producing mutants of F. verticillioides. Lesions were measured on 14-day-old maize stalks consisting of treatment groups inoculated with and without mutants and wild-type strains of bacteria and fungi. The results indicate that the fusaric-acid-tolerant B. mojavensis mutant reduced stalk lesions, suggesting an in planta role for this substance as an antibiotic. Further, lesion development occurred in maize infected with F. verticillioides mutants that do not produce fusaric acid, indicating a role for other phytotoxins, such as the fumonisins. Thus, additional pathological components should be examined before strains of B. mojavensis can be identified as being effective as a biocontrol agent, particularly for the control of seedling disease of maize.
A 71-year-old woman presented to a rheumatologist with what she believed to be a 2-year history of Lyme disease, progressing from erythema migrans to Lyme arthritis. History, physical examination and serologic testing confirmed the diagnosis of Lyme disease. Lyme disease. The patient refused antibiotic therapy during the first 2 years of her illness. During the next 2 years, she consulted a rheumatologist, but declined antibiotic therapy. She continued to have recurrent episodes of arthritis, following which she was successfully treated with doxycycline, given initially for 2 weeks, with a second, 4-week cycle administered 2 months later. This case illustrates the natural history of untreated Lyme disease, which is rarely observed in most patients since diagnosis almost always leads to successful antibiotic treatment. Furthermore, this case also demonstrates that infection with Borrelia burgdorferi can persist for years in untreated patients; however, antibiotic therapy is still likely to be effective, despite long-term infection.
Lyme disease is a multisystem disease that occurs in North America, Europe, and Asia. In the United States, the etiologic agent is Borrelia burgdorferi sensu stricto, a spirochete transmitted to humans by infected Ixodes scapularis and I. pacificus ticks. The majority of patients with Lyme disease develop a characteristic rash, erythema migrans (EM), accompanied by symptoms of fever, malaise, fatigue, headache, myalgia, or arthralgia. Other manifestations of infection can include arthritis, carditis, and neurologic deficits. Lyme disease can be treated successfully with standard antibiotic regimens. 1992--2006. U.S. health departments report cases of Lyme disease voluntarily to CDC as part of the National Notifiable Disease Surveillance System. Variables collected include patient age, sex, race, county and state of residence, date of illness onset, and reported signs and symptoms. During 1992--2006, a total of 248,074 cases of Lyme disease were reported to CDC by health departments in the 50 states, the District of Columbia, and U.S. territories; the annual count increased 101%, from 9,908 cases in 1992 to 19,931 cases in 2006. During this 15-year period, 93% of cases were reported from 10 states (Connecticut, Delaware, Massachusetts, Maryland, Minnesota, New Jersey, New York, Pennsylvania, Rhode Island, and Wisconsin). Incidence was highest among children aged 5--14 years, and 53% of all reported cases occurred among males. More than 65% of patients with EM had illness onset in June and July, compared with 37% of patients with arthritis. Lyme disease is the most commonly reported vectorborne illness in the United States. The geographic distribution of cases is highly focused, with the majority of reported cases occurring in the northeastern and north-central states. During 1992--2006, the number of reported cases more than doubled. A disproportionate increasing trend was observed in children and in young males compared with other demographic groups. The results presented in this report underscore the continued emergence of Lyme disease and the need for tick avoidance and early treatment interventions. Public health practitioners can use the data presented in this report to target prevention campaigns to populations with increasing incidence (i.e., children and young males).
This study was designed to determine the incidence and prevalence of Lyme disease in a section of Chappaqua, NY, a residential community in which Lyme disease is epidemic, and to identify risk factors for this disease. On the basis of clinical history and baseline serologic testing, the overall prevalence of Lyme disease for 114 persons entering the study was 8.8%. The incidence during the 5-month study period of May through September 1989 was 2.6%; all three incident cases had erythema migrans (EM). Hours outdoors per week in play or exercise correlated with the occurrence of Lyme disease.
To determine the clinical evolution of Lyme arthritis, 55 patients who did not receive antibiotic therapy for erythema chronicum migrans were followed longitudinally for a mean duration of 6 years. Of the 55 patients, 11 (20%) had no subsequent manifestations of Lyme disease. From 1 day to 8 weeks after disease onset, 10 of the patients (18%) began to have brief episodes of joint, periarticular, or musculoskeletal pain for as long as 6 years, but they never developed objective joint abnormalities. From 4 days to 2 years after disease onset, 28 (51%) had one episode or began to have intermittent attacks of frank arthritis, primarily in large joints; a few had polyarticular movement. The total number of these patients who continued to have recurrences decreased by 10% to 20% each year. The remaining 6 patients (11%) developed chronic synovitis later in the illness; of these, 2 (4%) had erosions, and 1 (2%), permanent joint disability. The spectrum of Lyme arthritis ranges from subjective joint pain, to intermittent attacks of arthritis, to chronic erosive disease.