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`Lyme disease': ancient engine
of an unrecognized
borreliosis pandemic?q
W. T. Harvey, P. Salvato
Diversified Medical Practices, Houston, Texas, USA
Summary Unexpectedly we have found large numbers of chronically ill Borrelia burgdorferi PCR- and
seropositive patients in Houston, Texas, a zoonotically `non-endemic' area. In order to understand this finding prior
to sufficient data availability, we chose to examine critically currently accepted but troublesome `Lyme disease'
concepts. Our method was to analyze each foundation `Lyme disease' premise within the context of available
medical and veterinary literature, then to reconstruct the disease model consistent with the preponderance of that
data. We find the present conceptualization of the illness seriously truncated, with a high likelihood of two distinct
but connected forms of human B. burgdorferi infection. The yet-unrecognized form appears to have a broader
clinical presentation, wider geographic distribution, and vastly greater prevalence. We conclude that `Lyme
disease' currently acknowledges only its zoonosis arm and is a limited conceptualization of a far more
pervasive and unrecognized infection state that must be considered a global epidemic.
� 2003 Elsevier Science Ltd. All rights reserved.
INTRODUCTION
`No part of the aim of normal science is to call forth new
sorts of phenomena; indeed those that will not fit the
box are not seen at all'. Thomas Kuhn: The Structure of
Scientific Revolutions (1).
In 2000, Paul Ewald advanced the hypothesis that
evolutionary biology principles, if followed faithfully,
predict that infection likely underpins many current illnesses
without known etiology, perhaps via a single
agent (2). Here we present evidence that may identify
one such agent.
Twenty-six months ago, our practice began to test
chronically ill patients with multi-system presentation
for Borrelia burgdorferi (Bb) infection. Our criteria further
included suspicion of protracted infection and inability
to otherwise find a diagnosis. About a third of
initial tests were positive via CDC Western blot criteria
or serum/urine PCR; however, repeat testing eventually
revealed that most are positive. We had not expected
these results, as we are in Southeastern Texas, a `nonendemic'
region. (The prevalence of Borrelia-infected
ticks in Texas is about 1-2%.) (3-5).
Concurrently, we recognized a striking similarity in
symptoms and signs of test-positive individuals to other
untested patients of ours. Most fit within the presentation
criteria of `late, disseminated Lyme disease' but with
some prominent differences. We began antibiotic treatment
of all test-positive patients, and most, regardless of
presentation, began noticeable improvement within 3 to
6 months.
Since no history of erythema migrans (EM) rash or
illness following tick bite was reported by these patients,
and most had been ill for many years with similarly ill
family members, we set out to understand what we were
confronting. Our experience did not match the CDC case
definition or the epidemiological evidence for late `Lyme
742
qWe have no competing financial interests and have used no grants in
creating this paper.
Received 16 July 2002
Accepted 11 November 2002
Correspondence to: W.T. Harvey MD, MS, MPH, 3826 Princeton Park Court,
Houston, TX 77058, USA. Pager number 713-990-8791,
Phone: 281-461-9866 or Cell: 281-451-8556; Fax: 1-713-961-3085;
E-mail: [email protected]
disease'. To resolve this conundrum, we concluded that
our best initial strategy was to derive our own conclusions
by careful assessment of all available relevant data.
METHOD
We began by examining the present conceptualization of
`Lyme disease' for comprehensiveness and accuracy. We
chose the US Centers for Disease Control and Prevention
(CDC) `surveillance case definition' of `Lyme disease' as
the current standard model of human Bb infection. We
next isolated what we believed to be the linchpin premises
supporting that model, examining each against
available pertinent National Library of Medicine (NLM)
medical and veterinary Bb data. Each premise was addressed
independently with relevant data categorized
and summed. We then derived a modified illness model
of human Bb infection by combining the reassessed
premises. Finally, we examined this newly-derived illness
model within the context of current medical nosology
and the realities of contemporary clinical medicine for
plausible fit and superior predictability potential.
FINDINGS
Semantics: `Lyme disease' examined
The origin and conceptualization of `Lyme disease'
`Lyme disease' is the label given to a human illness first
recognized in Old Lyme, CN in 1975 (6). The initial cases
resulted from a zoonosis present in local vertebrate reservoirs/
hosts and transferred incidentally to humans via
an arthropod vector, Ixodes scapularis (6-10). The responsible
agent was later identified as B. burgdorferi,
a spirochetal bacterium, with human disease considered
to result exclusively from the genospecies cluster
B. burgdorferi sensu lato (Bbsl ). (7,11). Globally, the
species presently within this cluster include B. burgdorferi
sensu stricto (Bbss), B. afzelii, B. garinii, B. lonestari,
and possibly B. valaisiana (12,13).
As the knowledge base expanded internationally in
the subsequent 26 years, the zoonosis-only conceptualization
of `Lyme disease' persisted with emphasis on
acute and early stages. The exclusive focus on zoonosis
resulted in a major portion of resources being concentrated
on reservoir and vector prevalence (14). The 1975
conceptual model reached `standard-of-care' status little
changed with publication of the CDC `case classification'
in 1997 (15).
`Lyme disease' as defined by the CDC: the prevailing
view
The CDC initially published case definitions for Public
Health Surveillance in October, 1990. For the first time,
uniform criteria were available to be used in case reporting
that included `Lyme disease' (16). The full CDC
criteria for `Lyme disease' were published in the May,
1997 MMWR (CDC Morbidity and Mortality Weekly
Report) for surveillance purposes and included clinical
description, laboratory diagnostic criteria, confirmed
case classification, and relevant definition of terms (15).
We refer the reader to the referenced MMWR for the
complete surveillance criteria, all contained under the
title: `Lyme Disease (Revised 9/96) clinical description'.
More extensive descriptions of the illness presentation,
course, epidemiology, and diagnosis may be found in
subsequent CDC sources (17,18). We included these in
our synthesis of the most comprehensive current conceptualization
of `Lyme disease', but considered the
1997 `surveillance case definition' as authoritative.
The foundation premises of the `Lyme disease'
model
Following are what we consider to be the foundation
premises used to create and support the present internationally
endorsed conceptualization (model) of `Lyme
disease' believed to represent all human Bb-induced illness.
(All illness models incorporate a set of premises
derived from numerous observations, assumptions and
definitions by inductive reasoning. Collectively, the
premises deductively create a conceptual framework
that constitutes the model. The model is then used deductively
to derive diagnosis and treatment.) We state
each premise separately, then compare to the available
published data. (We reviewed 951 peer-reviewed papers
and 13 books to cover what we deemed the relevant
literature.) A re-summarization completes the process.
Assessment of these 13 premises constitutes the body of
our argument.
Before examining the premises which we believe
support the concept of `Lyme disease', we stress that our
use of this label will be limited to its presently defined
conceptual boundaries. The CDC defines `Lyme disease',
exclusively as a zoonotic illness. Congenital and gestational
transfer cases have been disregarded for reasons
not evident to us. This limited perspective is the first
important illness-model error that will further compound
as we examine its premises.
The 13 premises are grouped into five general areas:
Initial Clinical Presentation (1-3), Testing/Confirmation
(4-5), Pathogen Transfer, (6-9), Course and Outcome
(10-11), and Distribution and History (12-13).
Premise 1: The erythema migrans rash consistently
heralds initial B. burgdorferi infection
In most early and many recent studies, the presence of
an EM rash is presumed to consistently verify initial
`Lyme disease' 743
� 2003 Elsevier Science Ltd. All rights reserved. Medical Hypotheses (2003) 60(5), 742-759
human inoculation of Bbsl via tick (17). This assumption
is, in fact, the foundation of many important conclusions
reached about `Lyme disease' despite numerous papers
that acknowledge secondary EM lesions occur (15,17).
Available data do not support the EM rash to be dependable
for diagnosis. The EM rash may follow initial
tick inoculation (primary), or it may occur months to
years later (secondary) (19-28). The rash also frequently
fails to appear following tick inoculation (26). It is not
known to be a marker in gestational or congenital
Bbsl transfer (13). Baranton's recent data show that
some Lyme-derived Bbsl variants do not cause EM
lesions (29).
Premise 2: Borrelia burgdorferi infection is sub-clinical in
some infected humans with assumed benign outcome
Copious data support that B. burgdorferi infection can
be `sub-clinical' and thus unnoticed in infected individuals
(20,30-54) and animals (55,56). The average
symptomatic/asymptomatic ratio (S/A) in these studies
from endemic areas, primarily using serology for diagnosis,
is close to 1:1, much as Steere first noted in 1986
(57). The S/A ratio in `non-endemic' areas may be similar
or higher (58). Notably, no recent `Lyme disease' study
referenced by the CDC considers the asymptomatic state
to be significant (17,18).
The question of whether sub-clinical cases activate or
fail to activate at some future date is intriguing. Lack of
sufficiently prolonged longitudinal follow-up in available
studies fails to provide an answer. Baranton's recent
data, however, show differing pathogenicity among Bbsl
species, lending support to the reality of some prolonged
innocuous sub-clinical infections although study design
limits insight into ultimate outcome (59). When prolonged
longitudinal outcome has been considered, several
studies do support reactivation among patients
(31,33,36,37,41,43,49,53,57,60).
Premise 3: Arthritis is a primary late musculoskeletal `Lyme'
infection sequela, where `late' in CDC parlance is vague
Objective joint swelling is a `late Lyme disease' symptom
criterion (15). This frequently-documented standard,
however, was derived primarily from data limited to
patients meeting strict `Lyme disease' requirements, necessitating
vector inoculation for inclusion and recent
enough for high antibody levels (6,61-69). False-seronegative
individuals would have necessarily been rejected,
possibly including those with low antibody levels
and those infected by sexual, congenital or gestational
routes. Further, we find no concise or consistent definition
of `late' in published `Lyme disease' definition criteria,
obfuscating the time when arthritis might be
expected to appear (17,18).
In our `non-endemic' region, we have rarely seen
rheumatic joint presentation in our 455 seropositive or
PCR positive patients. Many have migratory and intermittent
arthralgias, however, and most have been ill far
longer than one year. We find no data to support our
clinical experience, however, likely because our patients
fall outside the `Lyme disease' inclusion criteria.
Premise 4: Humans with late stage `Lyme disease'
show high antibody levels and high numbers of Western
blot test bands
The data support this position when applied strictly to
presently defined `Lyme disease' (17,70). These data do
not address non-zoonotic transfer cases. An exhaustive
review addressing `Lyme disease' antibody data may be
found in a recent work by Gardner (13). IgG and IgM
response curves are reproducible within reasonably
consistent ranges (8,71-74). Of note, however, referenced
patients were studied only a limited number of
months following initial vector inoculation, most less
than a year (25,72,75-78).
We found no study characterizing immune reactivity
to Bbsl in untreated patients from non-endemic regions
and where symptoms have been present for one year to
decades. Consistently, most serious studies have examined
and tested only patients from limited geographic
areas where high tick infection rate and acute human
disease coincide. The immune reaction of infected patients
not meeting `Lyme disease' criteria have fallen
outside rigorous scrutiny.
Gardner and others have shown conclusively that a
group of Bbsl-infected humans was not inoculated
transdermally but rather acquired their disease congenitally
or gestationally (13,79-81). How might their
antibody picture appear? Gardner's exhaustive review
of antibody production following gestational Bbsl
transfer is instructive. In her Table 11-8, 72% of neonates
with tissue-verified borreliosis did not produce
antibodies in sufficient quantity to be seropositive (13).
Review of normal human fetal and neonatal antibody
production in general reveals as well lagging IgG and
IgM antibody levels to age one year (graph data, P46)
(82). Beyond one to three years, we find no clarifying
data.
Premise 5: Serologic testing to verify spirochete viability
in late `Lyme disease' cases is reliable
Numerous potential problems confound conclusions
from the available in-vivo serology data (37,83-86).
Terms such as `symptomatic' are typically defined
within the case definition of early (We assume much
less than one year after inoculation) `Lyme disease'. The
presumed presence of B. burgdorferi in the human host
744 Harvey and Salvato
Medical Hypotheses (2003) 60(5), 742-759 � 2003 Elsevier Science Ltd. All rights reserved.
is dependent on a strong history of vector inoculation
and the subsequent (early) pattern of antibody response.
Other requirements imposed for `proof of infection'
include endemic area residence, length of tick
attachment, or recent memory of EM-like rash. High
background seropositivity in `non-endemic' areas is
dismissed as `false' without adequate proof. Studies are
also insufficiently longitudinal. The extensive data
linking serologic outcome with spirochete presence in
the host limit this connection to relatively early `Lyme
disease' and thus exclude late and all non-zoonotic
patients.
Once Bbsl disseminates in the host, other immunerelated
factors apply that have not been sufficiently addressed
in the `Dearborn criteria' defining seropositivity
(87). Pleomorphism, variable antigen presentation, immune
avoidance, individual immune variance, host-derived
enzyme cloaking, immune complex sequestration,
and antibody inaccessibility to spirochete-privileged
sites argue against sustained or consistent immune response
(88-92). Recent findings by Wang and Hilton
suggest the presence or absence of Bb antibody production
is associated with unique individual HLA specificities
of the Class II (93). Eighteen of 44 (41%)
variously symptomatic patients were found seronegative
where infection was verified by PCR to Osp A in cerebrospinal
fluid or mononuclear cells.
Other data support serology test uncertainty: (1)
Seronegativity does not prove absence of a viable Bb
infection (45,90,93), which is consistent with the
principle that negative findings cannot be used to
prove lack of positivity. (2) Antibodies may exist minimally
or rarely in very late Bbsl-infected humans (90).
(3) Culture and histological methods have been used
extensively by veterinarians, and provide substantial
data supporting the inaccuracy and insensitivity of serology
in identifying living B. burgdorferi in non-human
subjects (51,52,60,94-98). (4) By ``similarity'', the
presence of antibodies to T. pallidum generally means
the presence of spirochetes (99). An evolutionary biology
perspective is further to the point. Any persistent
pathogen (relevant if Bbsl survives into late illness)
must effectively escape the immune system. An example
is Chlamydia pneumoniae infection where antibodies
appear only when the agent is causing active
pneumonia, yet the organism persists primarily unnoticed
and undetected (2).
Bbsl prevalence data are rife with a mixture of
asymptomatic seropositive as well as symptomatic seronegative
findings (43-45,49,53,65,90,100-107). Many
presumptions have been used to rationalize this data.
Curiously, none have considered the possibility that the
subject pools may include a high number of intra-human
transfer cases.
In summary, the preponderance of available data cast
serious doubt on the validity of current serology criteria
for diagnosing viable human Bb infection.
Premise 6: The presumed US human `Lyme disease'
agent is limited to one species of Bbsl: B. burgdorferi
sensu stricto (Bbss)
Until very recently, the presumed sole United States (US)
human `Lyme disease' agent is the species Bbss. The
preponderance of available data, based on the assumption
that all B. burgdorferi human infection is zoonotic,
supports this assumption (29,59). James has now published
evidence, however, that Borrelia lonestari infects
humans in the US via the vector Amblyomma americanum
(12). Borrelia valaisiana has also been found to
infect humans in two US cases (13).
Bbss was the first species to be identified shortly
after discovery of the disease in the Northeastern US.
Because the illness was immediately assumed solely a
zoonosis, this assumption resulted in the tendency to
look for other possible species and strains less among
ill humans than in vectors and animal reservoirs. Such
a `self-fulfilling' assumption built into the `Lyme disease'
model may have helped assure that the only
species identified until recently would be the prevailing
regional endemic zoonotic species. Our Houston
clinical experience of numerous patients with Acrodermatits
chronicum atrophicans (ACA), typically found
in Borrelia afzelii, support the likelihood that other
Borrelia genospecies cause human disease within the
US.
Premise 7: `Lyme disease' is exclusively a vector-borne
(primarily arthropod) illness
To date, the vector considered primary for transmission
of Bbsl to humans is the arthropod (17) likely related to
its role in the initial 1975 recognition of `Lyme disease'
in humans (6). Many arthropod species have been found
infected with Bbsl and causal transfer established (13).
The tick has been studied in North America exhaustively,
having the characteristics of a highly effective
vector: long life, vertebrate blood meal feeding, and
bacterial transovarial passage (13). Its role in `Lyme disease'
is assured, because it is the vector in what is considered
exclusively a zoonosis.
Data are available, however, that expand the possible
diversity of Borrelia vectors worldwide beyond the arthropod.
Other possible carriers include the flea
(108,109), mosquito (110-112), fly (111), and mite (113).
Related enzootic cycles have been only rarely examined,
although some data link non-arthropod vectors with
animal hosts (110,112-114). We suggest that early,
`Lyme disease' 745
� 2003 Elsevier Science Ltd. All rights reserved. Medical Hypotheses (2003) 60(5), 742-759
sustained myopic focus on the arthropod as sole vector
in the spread of `Lyme disease' within the zoonosis
context likely delayed early consideration of other enzootic
cycles as well as non-zoonotic Bbsl transfer directly
between humans.
We propose the human may well be the most likely
`vector' for Bbsl transfer to other humans. The label
`Lyme disease' has become, by convention, a semantic
boundary that excludes consideration that an infectious
agent responsible for a zoonosis may also exist independently
as a non-zoonosis. CDC-defining criteria do
not address human congenital transfer and in at least
one reference deny without proof that sexual transfer
occurs (17). This mindset assures that Bbsl cases falling
outside `Lyme disease' criteria have not been considered
in most research, nor reported to local health agencies.
Premise 8: Congenital (vertical) transmission between
humans does not occur
The CDC position on intra-human Bbsl transmission is
that `Lyme disease bacteria are not transmitted from
person-to-person' (17). Current human and veterinary
data make this position indefensible (79,80).
Schlesinger and MacDonald reported the first human
congenital transfer cases of Bbsl. Gardner provided the
initial and now most recent exhaustive review of available
human gestational transfer cases (13,81). Her
credible supporting studies utilized histological, PCR, or
culture identification of Bb in both mother and newborn
or aborted fetus. She reviewed 263 Bbsl-infected cases
and summarized the birth outcomes. If mothers are
untreated, Gardner notes the high percentage of negative
pregnancy outcomes along with symptomatic, as
well as seemingly asymptomatic, neonates. Indirect data
supports the possibility of human congenital B. burgdorferi
transfer (95,96,115), including similarity to other
spirochetal diseases such as Treponema pallidum
(116-118).
Contrary data suggest that congenital human
(24,119-122) and congenital animal (123-126) transfer
does not occur. Use of the `Lyme disease' model for
these studies (with inclusion criteria of EM rash, tick
attachment history, or endemic region residence) necessarily
excludes congenital transfer, which obviates
their conclusions (15). Most of the human data were
based on simple surveys of birth outcome, without satisfactory
proof of spirochetal absence (likely a current
impossibility). The contrary veterinary data appear
credible and employ a search for spirochetes by culture
or histological methods. These data support animal
species that exhibit congenital transference and those
that may not, which suggested species-specific transfer
differences.
Not unexpectedly, we find no serious or credible epidemiological
studies that have attempted to identify the
true rate of human congenital Bbsl transfer. The only
method we have of estimating congenital human Bb
transfer is by other intra-human illnesses. Transfer rates
of Cytomegalovirus and Toxoplasmosis range from 14%
to 59% (127). The congenital transfer rate of Treponema
pallidum has been reported as high as 68% in one cohort
of treated infected mothers (116).
There is evidence to support the possibility that Bb
may present clinically differently in congenitally infected
versus vector-inoculated humans, and a review of similar
chronic trans-placental diseases in humans is instructive
(82,127). Common in congenital infection are
`silent' transfer, differential neonate illness presentation,
and a negative effect on later immune competence. The
general principles of neonate immune function, adult
immune function, and transplacental transfer of pathogens
provide further insight into the relationship between
trans-placental agents and a new and developing
immune system (13). This information collectively suggests
that silent or atypical birth presentation may be
common, possibly resulting in delayed or complete lack
of recognition of the transfer.
Premise 9: Sexual (horizontal) transfer between humans
does not occur
The CDC position on sexual intra-human Bbsl transmission
is that it does not occur (17).
We find no study that addresses sexual transmission
of Bb among humans; conversely, we find no study
supporting that it does not occur. Inferential data, however,
suggest the possibility of human sexual transfer.
The data come from sound veterinary studies
(96,98,115), the finding of Bb in human semen and
breast milk (128,129), and by similarity to Treponema
pallidum where sexual transfer is abundantly documented
(117,130,131).
Our clinical experience strongly suggests that predictable,
possibly inevitable Bbsl transfer between sexually
active couples occurs. The preponderance of
infected spouses we have tested to date also exhibit
positive serology or PCR for Bbsl presence.
Premise 10: `Lyme disease' is not considered a
persistent infection, implying self-limited outcome
Most CDC-referenced studies support this assumption.
There is insufficient or no follow up after initial diagnosis
or treatment in these studies, however, to support this
position. Extensive use of unsupported presumptions is
troubling as well. The latter include labeling patients
with persisting or recurring disease characteristics as
`reinfected' without serology or tissue evidence, or pre-
746 Harvey and Salvato
Medical Hypotheses (2003) 60(5), 742-759 � 2003 Elsevier Science Ltd. All rights reserved.
suming lack of infection because subsequent positive
antibody tests do not meet `Lyme disease' inclusion
criteria (patients were not from `endemic' areas, etc.)
(17,18).
Substantial data support the probability that human
Bbsl infection can persist indefinitely. This state may
obtain even when treatment is provided according to
`standard guidelines' (52,90,132-135). The supporting
rationale for persistence is summarized as follows: (1)
Latency and relapse are widely observed Bb phenomena
(43,89,94,100,136,137). (2) Symptoms frequently reemerge
following therapy (89,94,100,137). (3) Many
mechanisms of potential survivability have been found
in the highly complex and adaptable Bb organism (138-
141). (4) An inert survival state is implied by the lengthy
time to grow viable spirochetes from EM incubated
cultures (43,142). (5) Animal models support extensive
survival of Bb in tissue despite lack of detectable presence
in body fluids (51,52). (6) Cyst forms have been
found in-vivo to transfer infection directly without reversion
to spirochete form, suggesting a possible alternative
mechanism for silent transfer (143). (7) Recent
T. pallidum data unexpectedly support prolonged
human spirochetal infection despite use of standard
treatment protocols (144).
Premise 11: Long-term `Lyme disease' sequelae
are autoimmune-induced or the result of past infection
damage
This premise is a corollary of premise 10, where longterm
infection sequelae are used to rationalize lack of
infection persistence. Very few `Lyme disease' CDC-referenced
studies conclude that long-term sequelae are a
result of chronic infection (17,18). Several hypotheses,
nevertheless, have been advanced to address the nature
of `late' sequelae. Autoimmune effect is one proposed
mechanism derived from indirect evidence (145-147).
Another is anatomic damage assumed induced by Bbsl in
earlier infection (148). Both positions are hypothetical
and use unsupported assumptions.
On the other hand, substantial data suggest that late
sequelae are the result of persistent infection (see Premise
3). We believe this large number of published
studies supporting that a high probability of persistent
Bbsl infection casts doubt on the above two mechanisms
as primary determinants of pathology. They may, we
believe, be included within the context of persistence
as potential contributory mechanisms of ongoing
pathology.
A search for other clinical outcomes of prolonged Bb
infection in published data yields no clear answer. The
CDC position in 2001 is limited to a few sentences: `Infrequently,
Lyme disease morbidity may be severe,
chronic, and disabling. An ill-defined post-Lyme disease
syndrome occurs in some persons following treatment
for Lyme disease. Lyme disease is rarely, if ever, fatal.'
(17). Most published research avoids comment on longterm
sequelae (149).
Because of the present dearth of relevant data, we
propose use of another perspective to address the
question of sequelae from late active Borrelia infection.
Late effects differing from early effects is used as a rationale
that, because of this difference, support that active
infection no longer exists. Examination of other
persistent infections contradicts this argument. Many
infections often present with dissimilar acute and late
effects. Examples are Chicken Pox later appearing as
`Shingles', and `strep throat' manifesting eventually as
Rheumatic Fever. Some chronic infections have no acute
phase. An example is the virus HHV-8 later manifesting
as Kaposi's Sarcoma. Thus, there exists the possibility in
late Bbsl infection of not recognizing the presentation.
Asymptomatic patients with late infection may also
be easily overlooked, and assumed non-infected (20,30-
54). Further, ill patients presenting with disseminated
symptoms without meeting defined `Lyme disease' endemicity
criteria are also at serious risk of not being
considered Bbsl infected.
Premise 12: Lyme disease is geographically constrained
to areas of high zoonosis prevalence, mostly in North
America and Eurasia
Gardner has comprehensively summarized international
`Lyme disease' distribution data (13). The resulting map
concentrates illness primarily into a Northern Hemisphere
temperate zone belt covering most of Europe and
the United States. Expectedly, maps of zoonotic endemicity
overlie the illness maps faithfully. We conclude a
high likelihood that `Lyme disease' is constrained to
areas of high zoonotic endemicity simply because endemic
area occurrence is an inclusion criterion. This
illustrates the circularity of creating a predicted disease
outcome by limiting its definition.
An extensive search of published literature reveals
that distribution of human borreliosis may be much
broader than described, practically is essentially globally
disseminated. Bbsl presence in humans, other vertebrate
reservoirs or both, have been reported from over thirty
countries on six continents and several islands
(5,22,54,55,58,110-112,114,150-179). Failure to document
the full geographic extent of the organism may
stem from simple lack of public health resources in most
countries or lack of recognition of the disease in humans.
We find no credible studies of human Bbsl infection
prevalence conducted outside `endemic' zoonotic
regions.
`Lyme disease' 747
� 2003 Elsevier Science Ltd. All rights reserved. Medical Hypotheses (2003) 60(5), 742-759
Premise 13: `Lyme disease' is a contemporary human
illness
Bbsl was first acknowledged as a human pathogen in the
US medical literature from 1982 to 1983 (7-9,11). The
limited historical data that address earlier human infection
do so indirectly by examining reservoir (Peromyscus,
Massachusetts, 1894) or vector (Ixodes ricinus, Germany,
1884) infection using museum DNA evidence(163,180),
or disease categorizations based on skin manifestations
of unknown etiology (26,30,172,181-185).
Data from outside the `Lyme disease' zoonosis model
vaguely suggest the possibility that Bbsl is not a recent
pathogen in nature, including human infection. Isolated
papers examining Bb dissemination address such possibilities
as: (1) The birth of the pathogen as a transkingdom
mutation from African Swine Fever virus (186).
(2) European `Lyme disease' gradient rising from West to
East (22). (3) Extensive presence of Borrelia garinii and
afzelii in Eurasia (13). (4) Extensive presence of the spirochete
(Garinii and Afzelii only) in Northeast Asia
(Vladivostok) in a common Ixodid vector providing opportunity
for Siberian-Alaska land bridge transfer
10,000-30,000 BC (187). (5) A recent hypothesis that
Bbsl may be the protective agent of juvenile and adult
arthritis in Louisiana Tchefuncte Indians between 500
BC and 300 AD (187,188). (6) Documented human
presence in central and southern South America. (7) Bb
sensu stricto main genospecies in North America (18). (8)
Evidence for spread of Bb sensu stricto from the Western
hemisphere to Europe after 1492 (189). Together, we
suggest these data hint at a possible but unexamined
circum-global dissemination of the pathogen over many
human generations.
We believe the global occurrence of B. burgdorferi
and its many strains provides the strongest evidence to
support the likelihood that Bbsl has been present in nature
and in humans for centuries to millennia. Protracted
existence of the spirochete, if validated, would provide
strong support for broad intra-human spread that began
some indefinite time following early vector-to-human
transfer.
Re-synthesis of premises by `preponderance of data'
weighting
`Lyme disease' was the label initially given to the illness
conceptualization (disease model) of human Bb infection.
The model congealed about 20 years ago as a
zoonosis principally from locally available information.
Subsequent worldwide data appear to have been gathered
within the contextual boundaries of this initially
conceived model. We find that the preponderance of this
data support the conclusion that the zoonotic model
was, and remains, incomplete, and includes only a portion
of all B. burgdorferi infected humans. The data
suggest there may exist a much larger unrecognized
pool of Bbsl-infected individuals sustained by persistent
intra-human transfer that we provisionally call `Epidemic
Borreliosis'. A summary comparing these two populations
is shown in Table 1.
Clinical diagnosis of long-infected patients has been
inconsistent and puzzling, specifically regarding the
signs of EM rash and arthritis. The erythema migrans
rash, initially considered the herald lesion for infection,
actually occurs both sporadically in initial inoculation
and later as secondary lesions. Its absence alone is thus
of no value in rejecting a diagnosis, although its presence
alerts to the probability of infection. A symptomatic
state may be present or absent in the initial presentation,
where absence of symptoms can mask the presence of a
non-pathogenic strain. Arthritic joints are considered
common in disseminated zoonotic Bbsl, but paradoxically,
only intermittent and migratory joint pain is described
in very late borreliosis.
Laboratory tests are presently reliable for supporting a
diagnosis of recent vector-transferred `Lyme disease' but
seem highly unreliable if the transfer was zoonotic more
than a year earlier, or was congenital. In these cases
where antibodies are likely sparse, serology is valid only
when positive. Negative results are necessarily inconclusive
and may be seriously misleading, regardless of
symptoms. The argument supporting `false positive' serology,
when based on zoonosis criteria, is invalid if Bbsl
infection is widespread from prolonged intra-human
transfer.
The pathogen responsible for `Lyme disease' is a
limited subset of the genospecies B. burgdorferi. Until
recently, only one human pathogen had been identified
in the continental United States: B. burgdorferi sensu
stricto (Bbss). The exclusive position of this species likely
arose from limiting the early search for vectors to the
geographic region where `Lyme disease' was initially
discovered. Given the global diversity of species such as
Borrelia afzelii and garinii, the reality of intra-human
transfer, and the probability of prolonged infection, we
expect extensive regional diversity of Bbsl species in
humans both in endemic and non-endemic regions of
the earth. We propose that anticipating other species will
improve identification by broadening the carriers tested
to humans as well as zoonotic vectors and reservoirs.
Transfer of Bbsl to humans occurs via both zoonotic
vectors (`Lyme disease') and other humans. Congenital
transfer is fact. Animal data support that sexual transfer
can occur, and other data suggest its possibility. `Lyme
disease' reservoirs and vectors may be even more globally
widespread than currently modeled, increasing the
probability of broader and historically longer inoculation
of Bbsl into the human population. The finding of Bbsl in
748 Harvey and Salvato
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virtually all countries where it is sought also implies
more uniform global distribution of the infection in
humans. We expect regionally endemic `Lyme disease'
cases now to be far fewer than intra-human disease cases
(Epidemic Borreliosis), and that many of the latter are
unrecognized principally due to mislabeling.
Regardless of initial transfer route, human infection
with pathogenic Bbsl may persist for life. Symptoms and
signs may vary from sub-clinical to extensive and
severe, including cycling between these states
(33,77,190,191). Clinical sequelae from prolonged
infection appear likely and may be cumulative with
various mechanisms operant. An unknown number of
sub-clinical cases may remain undetected for life, regardless
of whether latency persists or unrecognized
activation occurs. If lifetime persistence is the rule, then
all living, untreated patients infected at any time during
their lives remain infected.
The preponderance of all reviewed data suggest that
B. burgdorferi may have been present in both natural
reservoirs as well as in humans via intra-human transfer
for centuries or millennia. We propose that this concept,
if verified, predicts a much larger current population
of congenitally and possibly sexually infected
individuals worldwide than infected via zoonotic vectors.
In summary, we propose a significantly modified
human Bbsl infection illness model that incorporates
`Lyme disease' only as one engine feeding a larger reservoir
of chronic, Borrelia-infected humans (Fig. 1). We
believe zoonosis was the likely source of initial human
disease, and continues to contribute newly infected
cases. We further propose that vertical and horizontal
intra-human transmission over generations has likely
had a non-linear amplifying effect on human prevalence.
If true, this transmission mechanism now significantly
exceeds the contribution of new cases from zoonotic
vectors, and has reached pandemic proportion on all
continents where humans reside. These conclusions
strongly support our clinical experience.
Table 1 Comparison of proposed illness characteristics
`Lyme disease'a Epidemic Borreliosisb
What is the initial disease presentation?
Erythema Migrans (EM) rash Frequent but inconsistent Secondary; occasional
Symptoms present if `early' None to flu-like In neonates: none to fatal
Symptoms present if `late' None to multi-organ None to multi-organ
Joint symptoms if `late' Arthritis Arthralgiasc
Cardiac signs if `late' High-degree block Arrhythmias, T-waves unstablec
Typical illness length at initial presentation <1 year <2 years
How is the infection diagnosed?
Number of Bb species One (region-specific) Many (non region-specific)
Serum antibody levels High and constant Low or occasional
Accuracy of serology Accurate High number of false negatives
Relationship of serology to region of diagnosis Direct None
Usefulness of EM rash Alerts to recent inoculation Announces infection presence
Usefulness of arthritis Suggests `late' infection stage Suggests zoonosis transfer
How is the disease conferred to humans?
By Zoonotic Vector? Yes No
Congenitally? No Yes (proven)
Sexually No Yes (not studied)
Regional? Yes: endemic areas No: anywhere
What is the disease course & outcome?
Self-limited? Defined as likely No; likely lifelong infection
Latent? Yes Yes
Activate or reactivate? No by assumption Yes
Considered long-term sequelae Autoimmunity/residual damage Infection persistence/(mechanisms
not elucidated)
Asymptomatic seropositive patient infection status Considered infected only
if from endemic region
Infected regardless of region of residence
What other epidemiological factors pertain?
Primary worldwide vector Arthropod Human
Bbsl presence in human population (time) Not addressed Millennia
Distribution in humans Confined to endemic areas Worldwide, diffuse
a `Lyme disease' - All human cases of human Borrelia burgdorferi infection within the defined limits of the CDC case definition (15).
b Epidemic borreliosis - all human Borrelia burgdorferi infection cases outside the CDC case definition of `Lyme disease'. Includes Zoonosis
vector-transferred infections more than one year old and all congenital, gestational and sexual intra-human transferred infections whether
symptomatic or asymptomatic.
c Author's clinical experience.
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CONCLUSIONS
We propose there are at least two similar and unified, but
distinct forms of human B. burgdorferi infection: `Lyme
disease', and `Epidemic Borreliosis' (disease spread
directly between humans). Late (more than one year old)
zoonotic disease may overlap both forms.
`Lyme disease' is the only presently acknowledged Bb
illness form, conceptualized as a zoonotic disease where
intra-human transfer is considered rare. As defined,
`Lyme disease' is primarily located in limited geographic
areas, is clinically recognized relatively early after inoculation,
and the reported case numbers are small. Human
infection in this model is considered accidental and
`self-limited'.
We propose the existence of a much larger `non-
Lyme' pool of B. burgdorferi-infected humans with a
clinical presentation of extraordinary variability, global
geographic distribution, and far greater prevalence.
Transfer is intra-human (congenital and almost certainly
sexual) and is initially silent or unrecognized. If not
successfully treated, infection is life-long, and latency,
late activation, and reactivation are common. Zoonotic
cases more than one year old may present similarly. We
label this larger pool `Epidemic Borreliosis'.
Combining both the `Lyme' and `non-Lyme' concepts
results in a significantly altered model of human B.
burgdorferi infection. Zoonotic borreliosis is fact and is
the milieu within which the complete human disease
has existed, perhaps for millennia. Zoonotic transfer was
likely the initial route of human inoculation and continues
with regularity into the larger pool of infected
humans in zoonotically endemic regions. We believe
that human endemicity is virtually ubiquitous wherever
humans live worldwide and has now reached pandemic
proportion. Overlap of these two groups occurs where
competent infected vectors exist, but we believe the
numbers of `non-Lyme' cases predominate significantly
even here. Infection prevalence has not likely reached
numerical stability, since the amplifying effect of congenital
transfer, coupled with the current global population
expansion, suggests the probability of continuing
prevalence rise.
We propose that `Lyme disease' is a limited conceptualization
of a far more pervasive Borrelia infection
state that is now an unrecognized global epidemic.
DISCUSSION
Our proposed model further challenges many aspects of
medical science now believed to be true. Not only does it
consign `Lyme disease' to a minor role in B. burgdorferi
infection prevalence but supports the idea that a zoonosis
can initiate what can later become a vastly more
extensive intra-human infectious disease. As a medical
model, we find this revised concept works with exceptional
success. Until now, the current model has seriously
limited our capacity to diagnose and treat many
Fig. 1 Revised model of Human Epidemic Borreliosis.
750 Harvey and Salvato
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patients. In our patient population, the revised model
provides a rational mechanism that far better explains
our experience. It effectively resolves the conflicting
viewpoints held by clinicians and academicians about
what has been labeled `chronic Lyme disease' and is now
allowing us to resolve or minimize illness in most of
these patients.
Unexpectedly, the revised model has provided us
much more. Most of our patients arrive with a diagnosis
from diverse specialty areas but unsuccessfully treated.
Use of this reframed model provides rational insight into
many of these cases. It provides a successful diagnosis
and treatment strategy that, when applied, resolved many
patients' symptoms, thus suggesting to us that B. burgdorferi
may underpin these illnesses as cofactor or origin.
We wondered if all of these `atypical' Borrelia-infected
patients might give us a clue to the true magnitude
of the infection prevalence. A large number of
clinically-similar (to late Bbsl infection) medical conditions
with unknown etiology exist within the inclusive
medical framework. Aaron, reviewing evidence from
unexplained medical conditions (chronic fatigue syndrome,
fibromyalgia, the irritable bowel syndrome,
multiple chemical sensitivities, temporomandibular disorder,
tension headache, interstitial cystitis, and the
post-concussion syndrome), found substantial clinical
overlap (192). Clauw likewise found similar clinical
overlap among several of these illness categories, as
have others, that include Gulf War Syndrome variants,
overtraining syndromes, and numerous `functional somatic
syndromes' (193-197). A single paper by Pachner
and Steere written in 1985 provides a credible rationale
for most of the neurological symptoms and signs described
in these illnesses as well as in human Bbsl
infection (198). Later papers describe a persistent, infection-
based inflammation that may provide the fundamental
pathology mechanism (106,145,199-215).
These `orphan' illnesses that constitute most of our
(now) Borrelia-positive Houston patients sum to at least
a double-digit prevalence in the United States even if we
consider only four of these `chronic syndromes'. Estimates
of case-definition fibromyalgia include 2-4%
(193,216,217), chronic fatigue syndrome, 0.42% (218),
Gulf War syndrome, 4% (219) and multiple chemical
sensitivities, 2-5% (220). Vague model boundary limits
in these similar `syndromes' coupled to illness labels
where no prevalence data is available make this information
unquestionably imprecise. However, when
combined with the unknown but finite prevalences of
the many other illness categories mentioned above including
unknown overlap, however they hint that the
combined number is not small.
We wondered whether our proposed model could
generate such numbers as the infection rates reported by
the CDC support a much lower prevalence (18). When
the CDC data are examined using our derived assumptions,
however, and a `zoonosis-only' prevalence is
generated, the outcome is 0.6% (Appendix A).
We next generated a crude estimate of the expected
background prevalence of `Lyme disease' in non-endemic
regions using the assumptions of Masters (221).
The resulting point prevalence is 2% once system stability
has been reached. If congenital transfer is added
and assumed ongoing for 1000 years, which we think
not unreasonable, the point prevalence in 2000 AD becomes
6.5%. If sexual transfer is further added with the
same assumptions at a 50% transfer rate, the combined
point prevalence becomes 15.5%. Details of this exercise
are found in Appendix B.
Another combined prevalence estimate based only on
symptoms was generated by one of us in 1993 from an
annual medical history form. 2683 employees of a Department
of Energy plant were queried regarding 30
common symptoms and signs of late Bb infection. Endemicity
and EM or tick bite criteria were excluded.
12.8% of the employees met similar symptom criteria.
(Appendix C: unpublished data).
These unexpected numbers of possible Bbsl-infected
patients hidden for decades by mislabeling, fit comfortably
within our proposed model and are then not difficult
to explain. We propose that where data were not
initially available, temporary hypothetical bridges, although
dissimilar, were necessarily created by early investigators
to fill their model framework gaps. Our
proposed model now fills in most such gaps for all these
illnesses. It also revises framework elements of other
illnesses we had considered unassailable parts of the
standard medical paradigm.
We believe failure to recognize the breadth of this
infection is readily explainable by inadvertent research
errors: (1) most data have been derived only from zoonotically
endemic areas, (2) `validation' rested on inadequate
serologic diagnostic methodology, and (3)
controls, when used, were useless since half those infected
are `sub-clinical'. Clearly, discovery of the illness
in an area of high zoonotic endemicity contributed to
early and continuing clinical myopia but was the necessary
first step in its recognition.
Other factors contribute to clinical recognition failure.
Silent transfer, latency, late activation, and recurrent
activation likely combine to create a setting resistant to
standard epidemiological detection methods. The pathogen's
extreme complexity is another probable contributor.
Its adaptability, pleomorphism, genetic diversity,
and differential tissue tropism create extraordinary
symptom variability. Likewise, activation of numerous
latent viruses and opportunistic bacteria from immune
depression in late disease may further expand illness
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complexity. Such varied presentation is not likely to
have previously been considered to have a single infectious
etiology, thus which excludes Bbsl from most differential
diagnoses.
We propose that zoonotic transfer combined with
human transfer on a global scale for centuries can indeed
result in double-digit prevalence.These numbers
applied to our model hint at the highly improbable: that
the prevalence of all humans infected with Bbsl could
constitute an even larger percentage of the population
by including the sub-clinical cases mostly excluded from
epidemiological surveys to date.
The technological solution that can validate our proposed
model is a more sensitive and specific laboratory
test likely not based on serum antibody presence. We do
not offer a specific solution but propose that detection of
the organism itself or unique biochemical markers altered
by the infection are required. Because of unpredictable
latency and inability to use controls, use of Koch's postulate
or sophisticated epidemiological methods are no
longer adequate in cases such as this and have likely
reached the historical limits of their usefulness here (2).
Despite the need for dramatically improved detection
methods, there exists even now an instrument capable
of recognizing the scope of this illness: the astute clinician
willing to carry what Carl Sagan called the `burden
of skepticism' (222). This perspective is an essential
medical tool, as the `system' within which the clinician
works requires reframing prevailing cognitive paradigms
before unfamiliar ideas can be `seen' at all (222,223).
(The history of medicine, in fact, is built on examples of
mindset that delayed recognition or evolution of most
illness concepts (224).)
We believe that reliance on familiar models is ultimately
the principal reason that what we here term `Epidemic
Borreliosis' remains hidden from the view of
science. Our purpose in publishing this newly proposed
model is to encourage skepticism by investigators as well
as clinicians: to consider the possibility that `Lyme disease'
is an inadequate conceptualization of all human Bb
infection. We are confident that once considered, others
will `see' what we are finding in clinical practice (223).
We thus propose that `Lyme disease' is only the herald
encounter with a human infectious disease of currently
inconceivable proportion. We anticipate that if
our model is validated and the proposed high prevalence
of B. burgdorferi in humans is verified, the conceptual
framework of this and many other human diseases will
be radically altered.
RECOMMENDATIONS
Our recommendations are based on verifying or disproving
the disease model we present here and are derived
from the gaps remaining in the data we have
reviewed.
The initial task must be to identify all humans infected
with B. burgdorferi. This likely requires first understanding
antibody status in late (beyond 18 months)
infections and the pathophysiological mechanisms
linking Bbsl presence and human disease. Commercial
tests to reliably detect living Bbsl in humans as well as
reservoirs and vectors must then follow to reveal the
agent's true worldwide prevalence. Extensive effort will
be required to prove or disprove persistence, and to
determine all disease entities associated with Bbsl infection:
whether cause-and-effect, co-factor, or unrelated.
Finally, the full extent of epidemiological science must
be applied to determine the scope and efficiency of human
congenital transfer and to investigate sexual Bbsl
transfer. Answers will guide development of preventive
strategies.
Concurrently, treatment modalities and schedules to
eradicate B. burgdorferi from all patients regardless of
infection route or duration, must be created. If our
experience holds, this will be a difficult task, and will
require serious and rapid commitment from all nations.
APPENDIX A. DERIVED `LYME DISEASE'
PREVALENCE USING CDC INFECTION RATES
The number of `Lyme disease' cases reported by the
CDC appears unreasonably small compared to our estimates.
Within the defined parameters of the current
`Lyme disease' model employed by state and federal
public health agencies, 16,273 cases were reported
(more likely underreported) in the US in 1999 (0.06% of
the population) (17). However, assuming lifetime prevalence
and no treatment, the 1992-1997 crude mean annual
incidence of 5.1 reported cases/100,000 persons/
year roughly corresponds to a prevalence of 1,070,000
infections over the 75-year period, 1925-2000 AD (18).
This number, likely an underestimate of true prevalence,
is nevertheless 0.6% of the period population mean
(1963). This suggests that a 2% true zoonotic-only stable
Bb human prevalence may not be unreasonable in the
US and, we propose, globally.
APPENDIX B. ESTIMATING THE FULL
PREVALENCE OF HUMAN Bbsl INFECTION
We used a simple exercise to estimate the possible human
Bbsl prevalence. Employing complex statistical
methods was of no value because insufficient data exists
to use precision. We sought only a `ballpark' number to
make the point that the possibility of unexpectedly high
prevalence exists.
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(1) Assumption 1: Transfer is via Zoonotic vector only.
* Assume: zoonotic transfer only, one tick bite per decade
per human (221), 1% of ticks infected (5), 50%
chance of tick-to-human transfer, and prevalence stability.
* Point prevalence1/48 tick bites/lifetime1% of ticks
infected50% chance of infection if bitten1/2 (average
human at midlife)1/4PP1/48 (TIR) (CI)/21/42%.
* This exercise predicts that 2% of humans are infected
with Bb in Texas. We propose this number approximates
the worldwide background prevalence of humans
infected via zoonosis vector transfer regardless
of region endemicity.
(2) Assumption 2: If congenital transfer is combined with
vector transfer for at least one millennium.
* Assume: 2% of the population in 1000 AD was infected
via zoonosis only, the prevalence and infection
rate are stable, congenital transfer rate is 50%, full
population turnover per 100 years, male/female ratio
is 1:1, and no congenital transfer occurs before 1000
AD.
* Then 2% of all mothers after 1000 AD are already infected
at conception.
* At a 50% transfer rate, 1% of all female newborns will
be infected congenitally by 1100 AD.
* These 1% newborn females (1/2% of population) mature
and join the 2% infected via zoonotic vectors
1/42.5% Infected mothers at 50% transfer rate by
3-4 generations (assume 100 years).
* In the subsequent 100 years after 1000 AD, 2% of
population already infected by tick + 1/2% infected
congenitally by 1100 AD.
* Every succeeding 100 years, 1/2% more humans
will be infected (ignore compounding for simplicity
and conservatism): Point Prevalence1/42%+ 1/2%
�y  100�=�100� 1/4 2% � 1=2%�900=100�.
* Human point prevalence now1/42%+ 4.5%1/46.5%
(from 1000 to 2000 AD).
(3) Assumption 3: If Vector, congenital and sexual transfer
are combined for at least one millennium.
* Assume: Use above assumptions. Add: fathers infect
new mothers at a 50% rate, begin in 1000 AD. 2% infected
fathers infect 1% more mothers1/43%.
* In 1100 AD all humans born to 2.5% + 1% infected
mothers (2% infected fathers infect 98% uninfected
mothers at 50% sexual transfer rate).
* Assume 50% rate in congenital transfer continues.
* Using the information in (2), infected humans
1/42%+ 1.5% �y  100�=�100�.
* Point prevalence now1/42%+ 13.5%1/415.5% (from
1000 to 2000 AD).
This exercise has been invoked to demonstrate the
possibility that if intra-human transfer is established as
common, the numbers of humans presently infected
with Bbsl may significantly exceed the number of humans
infected via zoonotic transfer. The difference is in
the stability of the transfer system. Zoonotic systems
reach some stability if populations are relatively stable
over the short term and exposure remains close to constant.
In recent years, the human population has risen
rapidly, but so has urbanization with diminished outdoor
work and leisure activity. Overall, in the 20th
century, we estimate human-vector contact has remained
relatively constant. Prior to the 20th century,
human-vector contact was more extensive, making our
estimates conservative.
Although made possible initially by vector infection,
intra-human infection prevalence rises with the passage
of time. The latter will rise in absolute numbers as the
population size increases. This exercise assumes that
human zoonosis infections remain relatively stable.
When intra-human transfer occurs extensively, however,
prevalence rise can approach geometric progression.
Thus, the importance of time in estimating
differences in the two types of transmission.
APPENDIX C. OCCUPATIONAL MEDICAL
HISTORY SURVEY
In 1993, one of us, while Medical Director of a US Department
of Energy facility in a non-endemic state, attempted
to estimate the prevalence of chronically ill
employees with symptoms similar to late, disseminated
Lyme disease. A computerized medical history form was
crafted for the required annual medical examination, in
which 2683 actively working employees participated.
Randomly interwoven in the Review of Systems portion
of the questionnaire were 30 questions characteristic of
the illness. `Inclusion' criteria were: 50% of the questions
had to be answered in the affirmative, with five
questions determined most important: frequent headaches,
persistent muscle pain, persistent activity limitation,
intermittent and/or migratory joint pain, and any
recurrent unexplained neurological symptom such as
seizure, vertigo, or focal special-sense phenomenon
(e.g., tinnitus or photophobia). There was no follow-on
testing for borreliosis.
Active employees (343 (12.8%)) were found to meet our
criteria for diagnosis. A random review of 35 (10%)
charts selected from this group revealed symptoms had
been present from less than a year to nearly 30 years (the
full length of employment). A much broader degree of
morbidity than in the inclusion criteria was found, with
six employees near termination for number of lost
workdays due to illness. None of the 35 records revealed
a prior diagnosis that might account for the full symptom
complex, although the fiscal resources expended on
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imaging, electronic tests (e.g., EMG, EEG, and EKG), and
repeated outpatient visits was considerable. None had
been tested for B. burgdorferi by any test method.
REFERENCES
1. Kuhn T. In: The Structure of Scientific Revolutions,
3rd edn. Chicago, IL: The University of Chicago Press,
1996: 212.
2. Ewald P. In: Plague Time: How Stealth Infections Cause
Cancers, Heart Disease, and Other Deadly Ailments. New
York, NY: The Free Press, 2000: 282.
3. Texas zoonosis diseases. Internet web site ed: Texas
department of Health, Zoonosis Control Division, 2000.
[Cited 2001 Oct 15]. Available from URL: http:// www.tdh.state.tx.us/phpep/dpn/issues/dpn59n10.pdf.
4. Rawlings J. A., Fournier P. V., Teltow G. J. Isolation of
Borrelia spirochetes from patients in Texas. J Clin Microbiol
1987; 25(7): 1148-1150.
5. Rawlings J. A., Teltow G. J. Prevalence of Borrelia
(Spirochaetaceae) spirochetes in Texas ticks. J Med Entomol
1994: 297-301.
6. Steere A. C. et al.Lymearthritis: an epidemic of oligoarticular
arthritis in children and adults in three connecticut
communities. Arthritis Rheum 1977; 20(1): 7-17.
7. Burgdorfer W. et al. Lyme disease-a tick-borne
spirochetosis. Science 1982; 216(4552): 1317-1319.
8. Steere A. C. et al. The spirochetal etiology of Lyme disease.
N Engl J Med 1983; 308(13): 733-740.
9. Burgdorfer W. Discovery of the Lyme disease spirochete
and its relation to tick vectors. Yale J Biol Med 1984; 57(4):
515-520.
10. Davis J. P. et al. Lyme disease in Wisconsin: epidemiologic,
clinical, serologic, and entomologic findings. Yale J Biol
Med 1984; 57(4): 685-696.
11. Burgdorfer W. et al. Erythema chronicum migrans - a
tickborne spirochetosis. Acta Trop 1983; 40(1): 79-83.
12. James A. M. et al. Borrelia lonestari Infection after a bite by
an Amblyomma americanum Tick. J Infect Dis 2001;
183(12): 1810-1814.
13. Gardner T. Chapter 11: Lyme disease. In: J. Remington,
J. Klein (eds). Infectious Diseases of the Fetus and Newborn
Infant. Philadelphia, PA: W.B. Saunders Company, 2001:
519-641.
14. Barbour A. G., Fish D. The biological and social
phenomenon of Lyme disease. Science 1993; 260(5114):
1610-1616.
15. Case definitions for infectious conditions under public
health surveillance. Centers for Disease Control and
Prevention. MMWR Morb Mortal Wkly Rep 1997;
46(RR-10): 1-55.
16. Wharton M. et al. Case definitions for public health
surveillance. MMWR Morb Mortal Wkly Rep 1990;
39(RR-13): 1-43.
17. Lyme Disease. Internet web site ed: CDC Division of
Vector-borne Infectious Diseases, 2001. [Cited 2001 Dec
6]. Available from URL: http//www.cdc.gov.ncidod/clvbid/
lyme/index.htm.
18. Surveillance for Lyme Disease - United States, 1992-1998.
Morb Mortal Wkly Rep 2000; 49(SS03)): 1-11.
19. Billings A. N., Rawlings J. A., Walker D. H. Tick-borne
diseases in Texas: a10-year retrospective examination of
cases. Tex Med 1998; 94(12): 66-76.
20. Chary-Valckenaere I. et al. Diagnosis of Lyme disease.
Current difficulties and prospects. Rev Rhum Engl Ed 1995;
62(4): 271-280.
21. Christen H. J. Lyme neuroborreliosis in children. Ann Med
1996; 28(3): 235-240.
22. Cimmino M. et al. European Lyme borreliosis clinical
spectrum. Zentralbl Bakteriol 1998; 287(3): 248-252.
23. Hejka A. G. et al. The pathologist's view of Lyme disease.
Wis Med J 1989; 88(11): 17-20.
24. Hercogova J. et al. Early-stage lyme borreliosis during
pregnancy: treatment in 15 women with erythema
migrans. Cesk Gynekol 1993; 58(5): 229-232.
25. Lesniak O. M., Belikov E. S. The classification of Lyme
borreliosis (Lyme disease. Ter Arkh 1995; 67(11): 49-51.
26. Malane M. S. et al. Diagnosis of Lyme disease based on
dermatologic manifestations. Ann Intern Med 1991; 114(6):
490-498.
27. Maraspin V. et al. Erythema migrans in pregnancy. Wien
Klin Wochenschr 1999; 111(22-23): 933-940.
28. Schmidt R. et al. Prevalence of erythema migrans
borreliosis in blood donors. Infusionstherapie 1989; 16(6):
248-251.
29. Baranton G. et al. Distinct levels of genetic diversity of
Borrelia burgdorferi are associated with different
aspects of pathogenicity. Res Microbiol 2001; 152(2):
149-156.
30. Asbrink E., Brehmer-Andersson E., Hovmark A.
Acrodermatitis chronica atrophicans - a spirochetosis.
Clinical and histopathological picture based on 32
patients; course and relationship to erythema chronicum
migrans Afzelius. Am J Dermatopathol 1986; 8(3):
209-219.
31. Christian C. L. Management of asymptomatic Borrelia
burgdorferi infection (see comments. Arthritis Rheum 1992;
35(11): 1395.
32. Coyle P. K. et al. Detection of Borrelia burgdorferi-specific
antigen in antibody-negative cerebrospinal fluid in
neurologic Lyme disease. Neurology 1995; 45(11):
2010-2015.
33. Coyle P. K. et al. Borrelia burgdorferi reactivity in patients
with severe persistent fatigue who are from a region in
which Lyme disease is endemic. Clin Infect Dis 1994;
18(Suppl. 1): S24-S27.
34. Dournon E. Lyme disease: biological diagnosis and
treatment. Rev Prat 1989; 39(15): 1300-1303.
35. Fahrer H. et al. Prevalence of Lyme borreliosis in a Swiss
population at risk. Schweiz Med Wochenschr 1988; 118(2):
65-69.
36. Fahrer H. et al. Longterm survey (7 years) in a population at
risk for Lyme borreliosis: what happens to the seropositive
individuals? Eur J Epidemiol 1998; 14(2): 117-123.
37. Fahrer H. et al. The prevalence and incidence of clinical
and asymptomatic Lyme borreliosis in a population at risk.
J Infect Dis 1991; 163(2): 305-310.
38. Feder H. M., Jr et al. Prospective assessment of Lyme
disease in a school-aged population in Connecticut. J Infect
Dis 1995; 171(5): 1371-1374.
39. Hanrahan J. P. et al. Incidence and cumulative frequency of
endemic Lyme disease in a community. J Infect Dis 1984;
150(4): 489-496.
40. Karch H. et al. Demonstration of Borrelia burgdorferi DNA
in urine samples from healthy humans whose sera contain
B. burgdorferi-specific antibodies. J Clin Microbiol 1994;
32(9): 2312-2314.
754 Harvey and Salvato
Medical Hypotheses (2003) 60(5), 742-759 � 2003 Elsevier Science Ltd. All rights reserved.
41. Kubo N. et al. Questionnaire surveys of cases of tick bite
and Lyme borreliosis in hunters in Hokkaido with
reference to detection of anti-Borrelia burgdorferi
antibody. Intern Med 1992; 31(10): 1163-1168.
42. Kuiper H. et al. Evaluation of central nervous system
involvement in Lyme borreliosis patients with a solitary
erythema migrans lesion. Eur J Clin Microbiol Infect Dis
1994; 13(5): 379-387.
43. MacDonald A. B., Berger B. W., Schwan T. G. Clinical
implications of delayed growth of the Lyme borreliosis
spirochete, Borrelia burgdorferi. Acta Trop 1990; 48(2): 89-
94.
44. Mautner V. F. et al. Epidemiology of Borrelia burgdorferi
infection. Relation of the prevalence rate on determination
by serologic procedures. Nervenarzt 1990; 61(2): 94-97.
45. Nohlmans M. K. et al. Prevalence of Lyme borreliosis in
The Netherlands. Ned Tijdschr Geneeskd 1991; 135(48):
2288-2292.
46. Pfister H. W. et al. Latent Lyme neuroborreliosis: presence
of Borrelia burgdorferi in the cerebrospinal fluid without
concurrent inflammatory signs. Neurology 1989; 39(8):
1118-1120.
47. Schmid G. P. et al. Failure to detect endotoxin in sera from
patients with Lyme disease. J Infect Dis 1984; 150(4): 616.
48. Schmutzhard E. et al. Infections following tickbites.
Tick-borne encephalitis and Lyme borreliosis - a
prospective epidemiological study from Tyrol. Infection
1988; 16(5): 269-272.
49. Smith H. V., Gray J. S., McKenzie G. A Lyme borreliosis
human serosurvey of asymptomatic adults in Ireland.
Zentralbl Bakteriol 1991; 275(3): 382-389.
50. Smith J. L., Israel C. W. Spirochetes in the aqueous
humor in seronegative ocular syphilis. Persistence after
penicillin therapy. Arch Ophthalmol 1967; 77(4):
474-477.
51. Straubinger R. K. PCR-based quantification of Borrelia
burgdorferi organisms in canine tissues over a 500-day
postinfection period. J Clin Microbiol 2000; 38(6):
2191-2199.
52. Straubinger R. K. et al. Status of Borrelia burgdorferi
infection after antibiotic treatment and the effects of
corticosteroids: an experimental study. J Infect Dis 2000;
181(3): 1069-1081.
53. Weder B. et al. Chronic progressive neurological
involvement in Borrelia burgdorferi infection. J Neurol
1987; 234(1): 40-43.
54. Yoshinari N. H. et al. Outline of Lyme borreliosis in
Brazil. Rev Hosp Clin Fac Med Sao Paulo 1997; 52(2):
111-117.
55. Gylfe et al. Isolation of Lyme disease Borrelia from puffins
(Fratercula arctica) and seabird ticks (Ixodes uriae) on the
Faeroe Islands. J Clin Microbiol 1999; 37(4): 890-896.
56. Lane R. S. et al. Risk factors for Lyme disease in a small rural
community in northern California. Am J Epidemiol 1992;
136(11): 1358-1368.
57. Steere A. C. et al. Longitudinal assessment of the clinical
and epidemiological features of Lyme disease in a defined
population. J Infect Dis 1986; 154(2): 295-300.
58. Hoshinari N. H. et al. Epidemiological study of Lyme
disease in Brazil. Rev Hosp Clin Fac Med Sao Paulo 1992;
47(2): 71-75.
59. Baranton G. Alphanumeric List of Borrelia burgdorferi
sensu Lato Strains. Paris, France: Pasteur Institute,
Molecular Biology and Medicine Unit, 2001.
60. Straubinger R. et al. Two-lessons from the canine model of
Lyme disease: migration of Borrelia burgdorferi in tissues
and persistence after antibiotic treatment. J Spirochetal
Tick-Borne Dis 1997; 4(1/2).
61. Goebel K. M., Krause A., Neurath F. Acquired transient
autoimmune reactions in Lyme arthritis: correlation
between rheumatoid factor and disease activity. Scand J
Rheumatol 1988; 75(Suppl.): 314-317.
62. Albert S. et al. Lyme arthritis in a 12-year-old patient after a
latency period of 5 years. Infection 1999; 27(4-5):
286-288.
63. Bussen S., Steck T. Manifestation of Lyme arthritis in the
puerperal period. Z Geburtshilfe Perinatol 1994; 198(4):
150-152.
64. Flisiak R., Wiercinska-Drapalo A., Prokopowicz D.
Immunologic reaction in patients with arthritis in the
course of borreliosis with Lyme disease. Przegl Epidemiol
1996; 50(3): 253-257.
65. Priem S. et al. Detection of Borrelia burgdorferi by
polymerase chain reaction in synovial membrane, but not
in synovial fluid from patients with persisting Lyme
arthritis after antibiotic therapy. Ann Rheum Dis 1998;
57(2): 118-121.
66. Sigal L. H. Musculoskeletal manifestations of Lyme
arthritis. Rheum Dis Clin North Am 1998; 24(2):
323-351.
67. Steere A. C., Hardin J. A., Malawista S. E. Erythema
chronicum migrans and Lyme arthritis:
cryoimmunoglobulins and clinical activity of skin and
joints. Science 1977; 196(4294): 1121-1122.
68. Steere A. C. Lyme arthritis: the joint lesions in Lyme
borreliosis in the USA. Ter Arkh 1995; 67(11): 43-45.
69. Weyand C. M., Goronzy J. J. Immune responses to Borrelia
burgdorferi in patients with reactive arthritis. Arthritis
Rheum 1989; 32(9): 1057-1064.
70. Recommendations for test performance and interpretation
from the Second National Conference on Serologic
Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep
1995: 590-591.
71. Craft J. E. et al. Antigens of Borrelia burgdorferi recognized
during Lyme disease. Appearance of a new
immunoglobulin M response and expansion of the
immunoglobulin G response late in the illness. J Clin Invest
1986; 78(4): 934-939.
72. Ostrov B. E., Athreya B. H. Lyme disease. Difficulties in
diagnosis and management. Pediatr Clin North Am 1991;
38(3): 535-553.
73. Fung B. P. et al. Humoral immune response to outer
surface protein C of Borrelia burgdorferi in Lyme disease:
role of the immunoglobulin M response in the
serodiagnosis of early infection. Infect Immun 1994; 62(8):
3213-3221.
74. Padula S. J. et al. Use of recombinant OspC from Borrelia
burgdorferi for serodiagnosis of early Lyme disease. J Clin
Microbiol 1994; 32(7): 1733-1738.
75. Petrovic M. et al. Lyme borreliosis - a review of the late
stages and treatment of four cases. Acta Clin Belg 1998;
53(3): 178-183.
76. Rahn D. W., Felz M. W. Lyme disease update. Current
approach to early, disseminated, and late disease. Postgrad
Med 1998; 103(5): 51-54, , 57-9, 63-4 passim.
77. Schmid G. P. Epidemiology and clinical similarities of
human spirochetal diseases. Rev Infect Dis 1989; 11(Suppl.
6): S1460-S1469.
`Lyme disease' 755
� 2003 Elsevier Science Ltd. All rights reserved. Medical Hypotheses (2003) 60(5), 742-759
78. Zhong W., Oschmann P., Wellensiek H. J. Detection and
preliminary characterization of circulating immune
complexes in patients with Lyme disease. Med Microbiol
Immunol (Berl) 1997; 186(2-3): 153-158.
79. MacDonald A. B. Human fetal borreliosis, toxemia of
pregnancy, and fetal death. Zentralbl Bakteriol Mikrobiol
Hyg [A] 1986; 263(1-2): 189-200.
80. Schlesinger P. A. et al. Maternal-fetal transmission of the
Lyme disease spirochete, Borrelia burgdorferi. Ann Intern
Med 1985; 103(1): 67-68.
81. Gardner T. Chapter 11: Lyme disease. In: J. S. Remington,
J. O. Klein (eds). Infectious Diseases of the Fetus and
Newborn Infant. New York, NY: W.B. Saunders Company,
1995: 1373.
82. Lewis D. B., Wilson C. B. Chapter 2: Developmental
immunology and role of host defenses in neonatal
susceptibility to infection. In: J. S. Remington, J. O. Klein
(eds). Infectious Diseases of the Fetus and Newborn Infant.
New York, NY: W.B. Saunders Company, 1995:
1373.
83. Wormser G. P., Aguero-Rosenfeld M. E., Nadelman R. B.
Lyme disease serology: problems and opportunities. JAMA
1999; 282(1): 79-80.
84. Wilske B., Fingerle V. Diagnosis of Lyme borreliosis. How
to corroborate suspected borreliosis. MMW Fortschr Med
2000; 142(15): 28-31.
85. Kaiser R. False-negative serology in patients with
neuroborreliosis and the value of employing of different
borrelial strains in serological assays. J Med Microbiol
2000; 49(10): 911-915.
86. Banyas G. T. Difficulties with Lyme serology. J Am Optom
Assoc 1992; 63(2): 135-139.
87. Guidelines for laboratory evaluation in the diagnosis of
Lyme disease. American College of Physicians. Ann Intern
Med 1997; 127(12): 1106-1108.
88. Lawrence C. et al. Seronegative chronic relapsing
neuroborreliosis (see comments). Eur Neurol 1995; 35(2):
113-117.
89. Sigal L. H. Persisting complaints attributed to chronic
Lyme disease: possible mechanisms and implications
for management. Am J Med 1994; 96(4): 365-374.
90. Preac-Mursic V. et al. Survival of Borrelia burgdorferi in
antibiotically treated patients with Lyme borreliosis.
Infection 1989; 17(6): 355-359.
91. Nordstrand A., Barbour A. G., Bergstrom S. Borrelia
pathogenesis research in the post-genomic and
post-vaccine era. Curr Opin Microbiol 2000; 3(1): 86-92.
92. Schutzer S. E. et al. Sequestration of antibody to Borrelia
burgdorferi in immune complexes in seronegative Lyme
disease. Lancet 1990; 335(8685): 312-315.
93. Wang P. Hilton, Contribution of HLA alleles in the
regulation of antibody production in Lyme disease. Front
Biosci 2001; 6: B10-B16.
94. Straubinger R. K. et al. Clinical manifestations,
pathogenesis, and effect of antibiotic treatment on Lyme
borreliosis in dogs. Wien Klin Wochenschr 1998; 110(24):
874-881.
95. Burgess E. C., Windberg L. A. Borrelia sp. infection in
coyotes, black-tailed jack rabbits and desert cottontails in
southern Texas. J Wildl Dis 1989; 25(1): 47-51.
96. Burgess E. C., Wachal M. D., Cleven T. D. Borrelia
burgdorferi infection in dairy cows, rodents, and birds from
four Wisconsin dairy farms. Vet Microbiol 1993; 35(1-2):
61-77.
97. Burgess E. C. Borrelia burgdorferi infection in Wisconsin
horses and cows. Ann NY Acad Sci 1988; 539: 235-243.
98. Liebstein M. M., Khan M. I., Bushmich S. L. Evidence for in
utero transmission of Borrelia burgdorferi from naturally
infected cows. J Spirochetal Tick-Borne Dis 1998; 5(4):
54-62.
99. Ghinsberg R. C., Nitzan Y. Is syphilis an incurable disease.
Med Hypotheses 1992; 39(1): 35-40.
100. Logigian E. L., Kaplan R. F., Steere A. C. Chronic neurologic
manifestations of Lyme disease (see comments). N Engl J
Med 1990; 323(21): 1438-1444.
101. Jelic S., Filipovic-Ljeskovic I. Positive serology for Lyme
disease borrelias in primary cutaneous B-cell lymphoma: a
study in 22 patients; is it a fortuitous finding. Hematol
Oncol 1999; 17(3): 107-116.
102. Ma B. et al. Serodiagnosis of Lyme borreliosis by western
immunoblot: reactivity of various significant antibodies
against Borrelia burgdorferi. J Clin Microbiol 1992; 30(2):
370-376.
103. Ma Y., Weis J. J. Borrelia burgdorferi outer surface
lipoproteins OspA and OspB possess B-cell mitogenic and
cytokine-stimulatory properties. Infect Immun 1993; 61(9):
3843-3853.
104. Plorer A. et al. Effects of adequate versus inadequate
treatment of cutaneous manifestations of Lyme borreliosis
on the incidence of late complications and late serologic
status. J Invest Dermatol 1993; 100(2): 103-109.
105. Preac-Mursic V. et al. First isolation of Borrelia burgdorferi
from an iris biopsy. J Clin Neuroophthalmol 1993; 13(3):
155-161 (Discussion 162).
106. Sigal L. H. Lyme disease: a review of aspects of its
immunology and immunopathogenesis. Annu Rev
Immunol 1997; 15: 63-92.
107. Honegr K. et al. In process citation. Epidemiol Mikrobiol
Immunol 2001; 50(1): 10-16.
108. Teltow G. J., Fournier P. V., Rawlings J. A. Isolation of
Borrelia burgdorferi from arthropods collected in Texas.
Am J Trop Med Hyg 1991; 44(5): 469-474.
109. Hubalek Z., Halouzka J., Juricova Z. Investigation of
haematophagous arthropods for borreliae - summarized
data 1988-1996. Folia Parasitol 1998; 45(1): 67-72.
110. Halouzka J. P. D., Hubalek Z. Isolation of the spirochete
Borrelia afzelii from the mosquito Aedes vexans in the
Czech Republic. Med Vet Entomol 1998; 12(1):
103-105.
111. Magnarelli L. A., Anderson J. F. Ticks and biting insects
infected with the etiologic agent of Lyme disease,
Borrelia burgdorferi. J Clin Microbiol 1988; 26(8):
1482-1486.
112. Hubalek Z., Halouzka J. Distribution of Borrelia burgdorferi
sensu lato genomic groups in Europe, a review. Eur J
Epidemiol 1997; 13(8): 951-957.
113. Pokorny P. Incidence of the spirochete Borrelia burgdorferi
in arthropods (Arthropoda) and antibodies in vertebrates
(Vertebrata). Cesk Epidemiol Mikrobiol Immunol 1989;
38(1): 52-60.
114. Badalian L. O. et al. The neurological syndromes in Lyme
disease in children. Zh Nevropatol Psikhiatr Im S S
Korsakova 1994; 94(3): 3-6.
115. Gustafson J. M. et al. Intrauterine transmission of Borrelia
burgdorferi in dogs. Am J Vet Res 1993; 54(6): 882-890.
116. McFarlin B. L. et al. Epidemic syphilis: maternal factors
associated with congenital infection. Am J Obstet Gynecol
1994; 170(2): 535-540.
756 Harvey and Salvato
Medical Hypotheses (2003) 60(5), 742-759 � 2003 Elsevier Science Ltd. All rights reserved.
117. Hederstedt B. et al. IgM-antibodies against T. pallidum
detected in sera from mothers of stillborn babies in
Mozambique by the solid-phase haemadsorption
assay (SPHA). Int J STD AIDS 1992; 3(5):
347-349.
118. Schwartz D. A. et al. Pathology of the umbilical cord in
congenital syphilis: analysis of 25 specimens using
histochemistry and immunofluorescent antibody to
Treponema pallidum. Hum Pathol 1995; 26(7):
784-791.
119. Gerber M. A., Zalneraitis E. L. Childhood neurologic
disorders and Lyme disease during pregnancy. Pediatr
Neurol 1994; 11(1): 41-43.
120. Nadal D. et al. Infants born to mothers with antibodies
against Borrelia burgdorferi at delivery. Eur J Pediatr 1989;
148(5): 426-427.
121. Strobino B. A. et al. Lyme disease and pregnancy outcome:
a prospective study of two thousand prenatal patients. Am J
Obstet Gynecol 1993; 169(2 Pt 1): 367-374.
122. Strobino B., Abid S., Gewitz M. Maternal Lyme disease and
congenital heart disease: a case-control study in an
endemic area. Am J Obstet Gynecol 1999; 180(3 Pt 1):
711-716.
123. Mather T. N., Telford S. R. d., Adler G. H. Absence of
transplacental transmission of Lyme disease spirochetes
from reservoir mice (Peromyscus leucopus) to their
offspring. J Infect Dis 1991; 164(3): 564-567.
124. Mather T. N., Fish D., Coughlin R. T. Competence of dogs
as reservoirs for Lyme disease spirochetes (Borrelia
burgdorferi). J Am Vet Med Assoc 1994; 205(2): 186-188.
125. Moody K. D., Barthold S. W. Relative infectivity of Borrelia
burgdorferi in Lewis rats by various routes of inoculation.
Am J Trop Med Hyg 1991; 44(2): 135-139.
126. Silver R. M. et al. Fetal outcome in murine Lyme disease.
Infect Immun 1995; 63(1): 66-72.
127. Klein J. O., Remington J. S. Chapter 1: Current Concepts of
Infections of the Fetus and Newborn Infant. In J. S. a. K.
Remington, J. O. (eds) Infectious Diseases of the Fetus and
Newborn Infant. New York, NY: W.B. Saunders Company,
1995: 1373.
128. Kumi-Diaka J., Harris O. Viability of Borrelia burgdorferi in
stored semen. Br Vet J 1995; 151(2): 221-224.
129. Schmidt B. L. et al. Detection of Borrelia burgdorferi DNA
by polymerase chain reaction in the urine and breast milk
of patients with Lyme borreliosis. Diagn Microbiol Infect
Dis 1995; 21(3): 121-128.
130. MacDonald A. B. Gestational Lyme borreliosis.
Implications for the fetus. Rheum Dis Clin North Am 1989;
15(4): 657-677.
131. Bromberg K., Rawstron S., Tannis G. Diagnosis of
congenital syphilis by combining Treponema pallidumspecific
IgM detection with immunofluorescent antigen
detection for T. pallidum. J Infect Dis 1993; 168(1): 238-
242.
132. Bayer M. E., Zhang L., Bayer M. H. Borrelia burgdorferi
DNA in the urine of treated patients with chronic Lyme
disease symptoms. A PCR study of 97 cases. Infection
1996; 24(5): 347-353.
133. Dattwyler R. J., Halperin J. J. Failure of tetracycline therapy
in early Lyme disease. Arthritis Rheum 1987; 30(4): 448-
450.
134. Nanagara R., Duray P. H., Schumacher H. R., Jr
Ultrastructural demonstration of spirochetal antigens in
synovial fluid and synovial membrane in chronic
Lyme disease: possible factors contributing to persistence
of organisms. Hum Pathol 1996; 27(10):
1025-1034.
135. Steere A. C., Dwyer E., Winchester R. Association of
chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles.
N Engl J Med 1990; 323(4): 219-223.
136. Pachner A. R. Spirochetal diseases of the CNS. Neurol Clin
1986; 4(1): 207-222.
137. Preac Mursic V. et al. Kill kinetics of Borrelia burgdorferi
and bacterial findings in relation to the treatment of
Lyme borreliosis (published erratum appears in Infection
1996 Mar-Apr; 24(2): 169). Infection 1996; 24(1):
9-16.
138. Rittig M. G. et al. Borrelia burgdorferi-induced
ultrastructural alterations in human phagocytes:
a clue to pathogenicity? J Pathol 1994; 173(3):
269-282.
139. Mursic V. P. et al. Formation and cultivation of Borrelia
burgdorferi spheroplast-L-form variants (published erratum
appears in Infection 1996 Jul-Aug; 24(4): 335). Infection
1996; 24(3): 218-226.
140. Georgilis K., Steere A. C., Klempner M. S. Infectivity of
Borrelia burgdorferi correlates with resistance to
elimination by phagocytic cells. J Infect Dis 1991; 163(1):
150-155.
141. Georgilis K., Peacocke M., Klempner M. S. Fibroblasts
protect the Lyme disease spirochete, Borrelia burgdorferi,
from ceftriaxone in vitro. J Infect Dis 1992; 166(2): 440-
444.
142. Pachner A. R. Neurologic manifestations of Lyme disease,
the new `great imitator''. Rev Infect Dis 1989; 11(Suppl. 6):
S1482-S1486.
143. Gruntar I. et al. Conversion of Borrelia garinii cystic forms
to motile spirochetes in vivo. Apmis 2001; 109(5): 383-
388.
144. Sell S. et al. Host response to Treponema pallidum in
intradermally-infected rabbits: evidence for persistence of
infection at local and distant sites. J Invest Dermatol 1980;
75(6): 470-475.
145. Burmester G. R. et al. Immunology of reactive arthritides.
Annu Rev Immunol 1995; 13: 229-250.
146. Klempner M. S., Huber B. T. Is it thee or me? -
autoimmunity in Lyme disease (news; comment). Nat Med
1999; 5(12): 1346-1347.
147. Sigal L. H. Antibiotics for the treatment of rheumatologic
syndromes. Rheum Dis Clin North Am 1999; 25(4): 861-
981, viii.
148. Sigal L. H., Williams S. A monoclonal antibody to Borrelia
burgdorferi flagellin modifies neuroblastoma cell
neuritogenesis in vitro: a possible role for autoimmunity in
the neuropathy of Lyme disease. Infect Immun 1997; 65(5):
1722-1728.
149. Asch E. S. et al. Lyme disease: an infectious and
postinfectious syndrome. J Rheumatol 1994; 21(3): 454-
461.
150. Palacios R. et al. Positive IgG Western blot for Borrelia
burgdorferi in Colombia. Mem Inst Oswaldo Cruz 1999;
94(4): 499-503.
151. Baranton G., Marti Ras N., Postic D. Borrelia burgdorferi,
taxonomy, pathogenicity and spread. Ann Med Interne
(Paris) 1998; 149(7): 455-458.
152. Brown R. N., Lane R. S. Lyme disease in California: a novel
enzootic transmission cycle of Borrelia burgdorferi. Science
1992; 256(5062): 1439-1442.
`Lyme disease' 757
� 2003 Elsevier Science Ltd. All rights reserved. Medical Hypotheses (2003) 60(5), 742-759
153. Cimmino M. A. et al. The epidemiology of Lyme borreliosis
in Italy. Microbiologica 1992; 15(4): 419-424.
154. Davidson M. M. et al. Isolation of Borrelia burgdorferi from
ticks in the Highlands of Scotland. J Med Microbiol 1999;
48(1): 59-65.
155. Fivaz B. H., Petney T. N. Lyme disease - a new disease in
southern Africa? J S Afr Vet Assoc 1989; 60(3): 155-158.
156. Fridriksdottir V., Nesse L. L., Gudding R.
Seroepidemiological studies of Borrelia burgdorferi
infection in sheep in Norway. J Clin Microbiol 1992; 30(5):
1271-1277.
157. Gern L. et al. European reservoir hosts of Borrelia
burgdorferi sensu lato. Zentralbl Bakteriol 1998; 287(3):
196-204.
158. Gruver K. S., Guthrie J. W. Parasites and selected diseases
of collared peccaries (Tayassu tajacu) in the trans-pecos
region of Texas. J Wildl Dis 1996; 32(3): 560-562.
159. Kim T. H. et al. Serologically diagnosed Lyme disease
manifesting erythema migrans in Korea. J Korean Med Sci
1999; 14(1): 85-88.
160. Lawrence R. H., Bradbury R., Cullen J. S. Lyme disease on
the NSW central coast. Med J Aust 1986; 145(7): 364.
161. Marguet C. et al. Lyme disease in Upper Normandy: report
of a hospital survey. Arch Pediatr 2000; 7(Suppl 3): 517s-
522s.
162. Matuschka F. R. et al. Transmission of the agent of Lyme
disease on a subtropical island. Trop Med Parasitol 1994;
45(1): 39-44.
163. Matuschka F. R. et al. Characteristics of Lyme disease
spirochetes in archived European ticks. J Infect Dis 1996;
174(2): 424-426.
164. McCrossin I. Lyme disease on the NSW south coast. Med J
Aust 1986; 144(13): 724-725.
165. Mhalu F. S., Matre R. Serological evidence of Lyme
borreliosis in Africa: results from studies in Dar es Salaam,
Tanzania. East Afr Med J 1996; 73(9): 583-585.
166. Neira O. et al. Lyme disease in Chile. Prevalence study
in selected groups. Rev Med Chil 1996; 124(5):
537-544.
167. Postic D. et al. Common ancestry of Borrelia burgdorferi
sensu lato strains from North America and Europe. J Clin
Microbiol 1999; 37(9): 3010-3012.
168. Prukk T. et al. Seroprevalence of tick-borne Lyme
borreliosis in a defined population in Estonia. Scand J Infect
Dis 1999; 31(4): 421-422.
169. Qiu W. G. et al. A population genetic study of Borrelia
burgdorferi sensu stricto from eastern Long Island, New
York, suggested frequency-dependent selection, gene flow
and host adaptation. Hereditas 1997; 127(3): 203-216.
170. Schmid G. The global distribution of Lyme Disease. Rev
Infect Dis 1985; 7(1): 41-50.
171. Stanek, G., Flamm H., Groh V., et al. Epidemiology of
borrelia infections in Austria. Zentralbl Bakteriol Mikrobiol
Hyg [A] 1987; 263(3): 442-449.
172. Stanek G. et al. European Union concerted action on risk
assessment in Lyme borreliosis: clinical case definitions for
Lyme borreliosis. Wien Klin Wochenschr 1996; 108(23):
741-747.
173. Smith R., O'Connell S., Palmer S. Lyme disease surveillance
in England and Wales, 1986-1998. Emerg Infect Dis 2000;
6(4): 404-407.
174. Shih C. M. et al. Lyme disease in Taiwan: first human
patient with characteristic erythema chronicum migrans
skin lesion. J Clin Microbiol 1998; 36(3): 807-808.
175. Stefancikova A. et al. IgG antibodies to Borrelia in dogs in
the area of Kosice. Vet Med (Praha) 1996; 41(3): 83-86.
176. Strle F. Lyme borreliosis in Slovenia. Zentralbl Bakteriol
1999; 289(5-7): 643-652.
177. Sugiyama Y., Minamoto N., Kinjo T. Serological surveillance
of Lyme borreliosis in wild Japanese serows (Capricornis
crispus). J Vet Med Sci 1998; 60(6): 745-747.
178. Zhang Z. F., Wan K. L., Zhang J. S. Studies on epidemiology
and etiology of Lyme disease in China. Chung Hua Liu
Hsing Ping Hsueh Tsa Chih 1997; 18(1): 8-11.
179. Zhioua E. et al. Longitudinal study of Lyme borreliosis in a
high risk population in Switzerland. Parasite 1998; 5(4):
383-386.
180. Marshall III W. F. et al. Detection of Borrelia burgdorferi
DNA in museum specimens of Peromyscus leucopus. J Infect
Dis 1994; 170(4): 1027-1032.
181. Aberer E. et al. Heterogeneity of Borrelia burgdorferi in the
skin. Am J Dermatopathol 1996; 18(6): 571-579.
182. Duray P. H., Asbrink E., Weber K. The cutaneous
manifestations of human Lyme disease: a widening
spectrum. Adv Dermatol 1989; 4: 255-275.
183. Houtman P. M., Tazelaar D. J. Joint and bone involvement
in Dutch patients with Lyme borreliosis presenting with
acrodermatitis chronica atrophicans. Neth J Med 1999;
54(1): 5-9.
184. Kaufman L. D. et al. Late cutaneous Lyme disease:
acrodermatitis chronica atrophicans. Am J Med 1989;
86(6 Pt 2): 828-830.
185. Ohlenbusch A. et al. Etiology of the acrodermatitis
chronica atrophicans lesion in Lyme disease. J Infect Dis
1996; 174(2): 421-423.
186. Hinnebusch J., Barbour A. G. Linear plasmids of Borrelia
burgdorferi have a telomeric structure and sequence
similar to those of a eukaryotic virus. J Bacteriol 1991;
173(22): 7233-7239.
187. Lewis B. A. Prehistoric juvenile rheumatoid arthritis in a
precontact Louisiana native population reconsidered. Am J
Phys Anthropol 1998; 106(2): 229-248.
188. Lewis B. Treponematosis and Lyme borreliosis
connections: explanation for Tchefuncte disease
syndromes. Am J Phys Anthropol 1994; 93(4):
455-475.
189. Baranton G., Marti Ras N., Postic D. Molecular
epidemiology of the aetiological agents of Lyme
borreliosis. Wien Klin Wochenschr 1998; 110(24): 850-855.
190. Barskova V. G., Fedorov E. S., Ananieva L. P. The course of
Lyme disease in different age groups. Wien Klin
Wochenschr 1999; 111(22-23): 978-980.
191. Hansen K., Lebech A. M. The clinical and epidemiological
profile of Lyme neuroborreliosis in Denmark 1985-1990. A
prospective study of 187 patients with Borrelia burgdorferi
specific intrathecal antibody production. Brain 1992;
115(Pt 2): 399-423.
192. Aaron L. A., Buchwald D. A review of the evidence for
overlap among unexplained clinical conditions. Ann Intern
Med 2001; 134(9 Pt 2): 868-881.
193. Clauw D. J., Chrousos G. P. Chronic pain and fatigue
syndromes: overlapping clinical and neuroendocrine
features and potential pathogenic mechanisms.
Neuroimmunomodulation 1997; 4(3): 134-153.
194. Buchwald D., Garrity D. Comparison of patients with
chronic fatigue syndrome, fibromyalgia, and multiple
chemical sensitivities. Arch Intern Med 1994; 154(18):
2049-2053.
758 Harvey and Salvato
Medical Hypotheses (2003) 60(5), 742-759 � 2003 Elsevier Science Ltd. All rights reserved.
195. Nicolson G. L., Bruton D. M., Jr, Nicolson N. L. Chronic
fatigue illness and Operation Desert Storm. J Occup Environ
Med 1996; 38(1): 14-16.
196. Rowbottom D. G. et al. The haematological, biochemical
and immunological profile of athletes suffering from the
overtraining syndrome. Eur J Appl Physiol Occup Physiol
1995; 70(6): 502-509.
197. Wessely S., Nimnuan C., Sharpe M. Functional somatic
syndromes: one or many. Lancet 1999; 354(9182):
936-939.
198. Pachner A. R., Steere A. C. The triad of neurologic
manifestations of Lyme disease: meningitis, cranial
neuritis, and radiculoneuritis. Neurology 1985; 35(1):
47-53.
199. Brebner K. et al. Synergistic effects of interleukin-1b,
interleukin-6, and tumor necrosis factor-a: central
monoamine, corticosterone, and behavioral variations.
Neuropsychopharmacology 2000; 22(6): 566-580.
200. Coxon R. E. et al. The effect of antibody against TNF a on
cytokine response in Jarisch-Herxheimer reactions of
louse-borne relapsing fever. Qjm 1997; 90(3): 213-221.
201. Erdile L. F., Guy B. OspA lipoprotein of Borrelia burgdorferi
is a mucosal immunogen and adjuvant. Vaccine 1997;
15(9): 988-996.
202. Giambartolomei G. H., Dennis V. A., Philipp M. T. Borrelia
burgdorferi stimulates the production of interleukin-10 in
peripheral blood mononuclear cells from uninfected
humans and rhesus monkeys. Infect Immun 1998; 66(6):
2691-2697.
203. Giambartolomei G. H. et al. Induction of pro- and antiinflammatory
cytokines by Borrelia burgdorferi
lipoproteins in monocytes is mediated by CD14. Infect
Immun 1999; 67(1): 140-147.
204. Habicht G. S., Katona L. I., Benach J. L. Cytokines and the
pathogenesis of neuroborreliosis: Borrelia burgdorferi
induces glioma cells to secrete interleukin-6. J Infect Dis
1991; 164(3): 568-574.
205. Hayashi F. et al. The innate immune response to bacterial
flagellin is mediated by Toll-like receptor 5. Nature 2001;
410(6832): 1099-1103.
206. Hurtenbach U. et al. Studies on early events of Borrelia
burgdorferi-induced cytokine production in
immunodeficient SCID mice by using a tissue chamber
model for acute inflammation. Int J Exp Pathol 1995; 76(2):
111-123.
207. Isogai E. et al. Cytokines in the serum and brain in mice
infected with distinct species of Lyme disease Borrelia.
Microb Pathog 1996; 21(6): 413-419.
208. Isogai H. et al. Levels of endogenous interleukin-1,
interleukin-6, and tumor necrosis factor in congenic mice
infected with Borrelia garinii. Microbiol Immunol 1997;
41(5): 427-430.
209. Miller L. C. et al. Live Borrelia burgdorferi preferentially
activate interleukin-1 b gene expression and protein
synthesis over the interleukin-1 receptor antagonist. J Clin
Invest 1992; 90(3): 906-912.
210. Moutschen M. et al. Pathogenic tracks in fatigue
syndromes. Acta Clin Belg 1994; 49(6):
274-289.
211. Porcella S. F., Schwan T. G. Borrelia burgdorferi and
Treponema pallidum: a comparison of functional
genomics, environmental adaptations, and
pathogenic mechanisms. J Clin Invest 2001; 107(6):
651-656.
212. Reichenberg A. et al. Cytokine-associated emotional and
cognitive disturbances in humans. Arch Gen Psychiatry
2001; 58(5): 445-452.
213. Straubinger R. K. et al. Borrelia burgdorferi induces the
production and release of proinflammatory cytokines in
canine synovial explant cultures. Infect Immun 1998; 66(1):
247-258.
214. Talkington J., Nickell S. P. Borrelia burgdorferi spirochetes
induce mast cell activation and cytokine release. Infect
Immun 1999; 67(3): 1107-1115.
215. Weis J. J. et al. Pathological manifestations in murine Lyme
disease: association with tissue invasion and spirochete
persistence. Clin Infect Dis 1997; 25(Suppl. 1):
S18-S24.
216. Wolfe F. Fibromyalgia. Rheum Dis Clin North Am 1990;
16(3): 681-698.
217. Wolfe F. et al. The prevalence and characteristics of
fibromyalgia in the general population. Arthritis Rheum
1995; 38(1): 19-28.
218. Jason L. A. et al. A community-based study of chronic
fatigue syndrome. Arch Intern Med 1999; 159(18): 2129-
2137.
219. Steele L. Prevalence and patterns of Gulf War illness in
Kansas veterans: association of symptoms with
characteristics of person, place, and time of
military service. Am J Epidemiol 2000; 152(10):
992-1002.
220. Proctor S. P. Chemical sensitivity and gulf war veterans'
illnesses. Occup Med 2000; 15(3): 587-599.
221. Masters E. J., Donnell H. D. Epidemiologic and diagnostic
studies of patients with suspected early Lyme disease
Missouri, 1990-1993 (letter; comment. J Infect Dis 1996;
173(6): 1527-1528.
222. K. Frazier (ed). The Hundredth Monkey, 1st edn. Buffalo,
NY: Promethius Books, 1991: 400.
223. Ruchlis H. In: Clear Thinking: A Practical Introduction, 1st
edn. Buffalo, NY: Promethius Books, 1990: 271.
224. Kiple K., (ed.). The Cambridge World History of Human
Disease, 1st edn. Vol. 1. New York, London, Melbourne:
Cambridge University Press, 1993: 1176.
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�

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Connie

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It would be good to hear from you again!!

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Best wishes,
Karen

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Thanks guys!!

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