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

Abstract

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
infection
John N Aucott
1*
, Ari Seifter
2†
and Alison W Rebman
2
Abstract
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 disease’for this
presentation.
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
evaluation.
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.
Background
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 1–3% with a cumulative
prevalence as high as 7–15% [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: jaucott2@jhmi.edu
†
Equal contributors
1
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 (http://creativecommons.org/licenses/by/2.0), 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
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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 unexplained”symptoms 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.
Methods
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
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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
group.
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
diagnosis.
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).
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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.
Results
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
symptoms.
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 “bull’s eye”appear-
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
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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.
Discussion
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 disease”and 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
(n=23)
Probable Late
(n=13)
PLS (n=36) Other diagnosis
(n=35)
No specific diagnosis
(n=128)
Demographics
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)
Symptoms
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%)
Signs
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%)
Serology
% 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%)
Treatment
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
bursitis.
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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 ‘probable’Lyme 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 patients’symptoms 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 patient’s 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
History
Presenting
Symptom/signs
Duration
Symptoms
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;
Headache
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
Improved.
Relapsed
6 Unknown Memory loss
w/normal CSF
dysthesias
6 months Doxycycline 12 weeks No improvement.
7 Viral symptoms with
rash Rx with 5 day
Zithromax
Arthralgia; Fatigue 6 months Doxycycline
3 weeks
80% improved.
Relapsed
8 Unknown Leg myalgia 12 months Doxycycline 12 weeks No clinically significant
improvement
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,
Edema
7 months Doxycycline 3 weeks Complete response.
Relapsed
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
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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).
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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
alone”in 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 (0.1–0.01% 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
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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 “syndrome”diagnosis 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.
Conclusions
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.
Consent
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
journal.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
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.
Acknowledgements
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
1
Department of Medicine, Division of General Internal Medicine, Johns
Hopkins University School of Medicine, Baltimore, MD, USA.
2
The Lyme
Disease Research Foundation of Maryland, Lutherville, MD, USA.
Received: 13 June 2011 Accepted: 28 July 2012
Published: 1 August 2012
References
1. Alpert B, Esin J, Sivak SL, Wormser GP: Incidence and prevalence of Lyme
disease in a suburban Westchester County community. N Y State J Med
1992, 92(1):5–8.
2. Tugwell P, Dennis DT, Weinstein A, Wells G, Shea B, Nichol G, Hayward R,
Lightfoot R, Baker P, Steere AC: Laboratory evaluation in the diagnosis of
Lyme disease. Ann Intern Med 1997, 127(12):1109–1123.
3. Wormser GP: Clinical practice. Early Lyme disease. N Engl J Med 2006,
354(26):2794–2801.
4. Steere AC, Dhar A, Hernandez J, Fischer PA, Sikand VK, Schoen RT,
Nowakowski J, McHugh G, Persing DH: Systemic symptoms without
Aucott et al. BMC Infectious Diseases 2012, 12:173 Page 9 of 10
http://www.biomedcentral.com/1471-2334/12/173

erythema migrans as the presenting picture of early Lyme disease. Am J
Med 2003, 114(1):58–62.
5. Bacon RM, Kugeler KJ, Mead PS: Surveillance for Lyme disease–United
States, 1992–2006. MMWR Surveill Summ 2008, 57(10):1–9.
6. Centers for Disease Control and Prevention: Lyme Disease (Borrelia
burgdorferi) 2011 Case Definition. Borrelia burgdorferi; 2011. http://www.cdc.
gov/osels/ph_surveillance/nndss/casedef/lyme_disease_current.htm.
7. Reported Lyme disease Cases by State, 1996–2009; [http://www.cdc.gov/
lyme/stats/charstables/reportedcases_statelocality.html]
8. Meek JI, Roberts CL, Smith EV Jr: Cartter ML: Underreporting of Lyme
disease by Connecticut physicians, 1992. J Public Health Manag Pract
1996, 2(4):61–65.
9. Coyle BS, Strickland GT, Liang YY, Pena C, McCarter R, Israel E: The public health
impact of Lyme disease in Maryland. JInfectDis1996, 173(5):1260–1262.
10. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS,
Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler JS,
Nadelman RB: The clinical assessment, treatment, and prevention of lyme
disease, human granulocytic anaplasmosis, and babesiosis: clinical
practice guidelines by the Infectious Diseases Society of America. Clin
Infect Dis 2006, 43(9):1089–1134.
11. Steere AC, Schoen RT, Taylor E: The clinical evolution of Lyme arthritis.
Ann Intern Med 1987, 107(5):725–731.
12. Feder HM Jr: Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser GP,
Ad Hoc International Lyme Disease Group, Agger WA, Artsob H, Auwaerter
P, Dumler JS, Bakken JS, Bockenstedt LK, Green J, Dattwyler RJ, Munoz J,
Nadelman RB, Schwartz I, Draper T, McSweegan E, Halperin JJ, Klempner
MS, Krause PJ, Mead P, Morshed M, Porwancher R, Radolf JD, Smith RP,Jr,
Sood S, Weinstein A, Wong SJ, Zemel L: A critical appraisal of "chronic
Lyme disease". N Engl J Med 2007, 357(14):1422–1430.
13. Anonymous Case definitions for infectious conditions under public health
surveillance: Centers for Disease Control and Prevention. MMWR Recomm
Rep 1997, 46(10):1–55.
14. Schoen RT: A case revealing the natural history of untreated Lyme disease.:
Nat Rev Rheumatol.
15. Aucott J, Morrison C, Munoz B, Rowe PC, Schwarzwalder A, West SK:
Diagnostic challenges of early Lyme disease: lessons from a community
case series. BMC Infect Dis 2009, 9:79.
16. Nowakowski J, McKenna D, Nadelman RB, Cooper D, Bittker S, Holmgren D,
Pavia C, Johnson RC, Wormser GP: Failure of treatment with cephalexin
for Lyme disease. Arch Fam Med 2000, 9(6):563–567.
17. Steere AC, Angelis SM: Therapy for Lyme arthritis: strategies for the treatment
of antibiotic-refractory arthritis. Arthritis Rheum 2006, 54(10):3079–3086.
18. Embers ME, Barthold SW, Borda JT, Bowers L, Doyle L, Hodzic E, Jacobs MB,
Hasenkampf NR, Martin DS, Narasimhan S, Phillippi-Falkenstein KM, Purcell
JE, Ratterree MS, Philipp MT: Persistence of Borrelia burgdorferi in rhesus
macaques following antibiotic treatment of disseminated infection. PLoS
One 2012, 7(1):e29914.
19. Wormser GP, Nadelman RB, Schwartz I: The amber theory of Lyme
arthritis: initial description and clinical implications. Clin Rheumatol 2012.
20. Aguero-Rosenfeld ME, Nowakowski J, Bittker S, Cooper D, Nadelman RB,
Wormser GP: Evolution of the serologic response to Borrelia burgdorferi
in treated patients with culture-confirmed erythema migrans. J Clin
Microbiol 1996, 34(1):1–9.
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