Re: Posttreatment Chronic Lyme Disease?

Thank you- yes, he is a criminal then in regard to this research- WHY
in the heck would they publish anything of his in relation to TBDs???
WhY>?! What a bad guy!!! Hmm, I could only get bits and pieces cut &
pasted, have to experiment- weird-
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948 •JID 2005:192 (15 September) •EDTORIAL COMMENTARY
E D T O R I A L CO M M E N TA R Y
Posttreatment Chronic Lyme Disease—What It Is Not
Justin Radolf
Center for Microbial Pathogenesis, University of Connecticut Health
Center, Farmington, Connecticut
(See the article by Klempner et al., on pages 1010–3.)
Received 24 April 2005; accepted 4 May 2005; electronically
published 4 August 2005.
Potential conflicts of interest: none reported.
Reprints or correspondence: Dr. Justin Radolf, University of
Connecticut Health Center, Center for Microbial Pathogenesis,
263 Farmington Ave., Farmington, CT 06030-3710 (jradolf@up
..uchc.edu).
The Journal of Infectious Diseases 2005; 192:948–9
2005 by the Infectious Diseases Society of America. All
rights reserved.
0022-1899/2005/19206-0002$15.00
We have come a long way in our under-standing
of Lyme disease (LD). Although
it was originally mistaken for juvenile
rheumatoid arthritis when it first appeared
in the mid-1970s as an epidemic of oli-goarthritis
among children and adults in
eastern Connecticut, subsequent epidemi-ologic
investigations established a proba-ble
microbial etiology for the disease [1].
This prediction was fulfilled by the dis-covery
in 1981 of a new spirochetal bac-terium,
Borrelia burgdorferi, residing with-in
the midgut of a new species of hard
tick, Ixodes scapularis [2], and, shortly
thereafter, by the isolation of the spiro-chete
from a small number of patients
[3, 4]. Increasingly sophisticated meth-ods
for detecting and genotyping LD spi-rochetes
in ticks, small mammal reser-voirs,
and humans—an incidental host—
have enabled investigators to define the
disease’s enzootic cycle, major clinical
manifestations, and prevalence in the
United States and globally [5]. Although
B. burgdorferi is far from an easy bacte-rium
to study, considerable progress has
been made in unraveling the mechanisms
that enable this zoonotic parasite to cycle
back and forth between 2 strikingly dif-ferent
milieus. Studies of LD pathogen-esis
have been greatly facilitated by the
availability of the bacterium’s genomic
sequence [6, 7] and by the development
of techniques for genetically manipulat-ing
virulent spirochetes [8]. The devel-opment
of a murine model that faith-fully
reproduces most clinical features of
the disease represents another milestone
in LD research [9]. Work in the murine
model, in conjunction with in vitro and
translational studies in humans, has firm-ly
established that disease manifestations
result from the inflammatory response
evoked by the spirochete and its constit-uents
[10, 11]. The borrelial genome en-codes
an astonishing number (摯瑬敳獩 150) of
lipid-modified polypeptides [6, 7], in-cluding
numerous outer surface proteins
(Osps) that are expressed at different
times during the enzootic cycle [12]. Li-poprotein-
mediated activation of innate
immune cells is believed to be a principal
trigger of acute inflammation at sites of
infection [10].
Most patients with LD present with a
slowly expanding annular skin lesion, er-ythema
migrans (EM), which develops at
the site of tick feeding [5]. Although os-tensibly
localized at the time of presen-tation,
patients with solitary EM often
have impressive flulike symptoms (mal-aise,
headache, arthralgias, myalgias) that
are believed to be indicative of spirochetal
dissemination [5]. Indeed, culture and/or
polymerase chain reaction (PCR)–based
studies indicate that as many as one-half
of patients with EM are spirochetemic at
presentation, although spirochete concen-trations
in the blood are usually quite low
[13]. Thus, B. burgdorferi appears to be a
potent inducer of inflammation in vivo,
and this supposition is mirrored by in
vitro systems in which extremely low
spirochete: cell ratios elicit the production
of proinflammatory cytokines [14]. In ad-dition
to being disproportionate to the vis-ible
lesion, constitutional symptoms may
take weeks to months to resolve after ther-apy.
Physicians need to anticipate this en-igmatic
delayed response and not rush to
re-treat.
The major clinical controversies in LD
center on the small percentage of patients
who do not return to a state of well-be-ing
after therapy. Two posttreatment syn-dromes
have been distinguished [15]. The
rarer one is a persistent large-joint syno-vitis
that, on the basis of negative PCR
results and culture analyses of synovi-al
fluids, is clearly not due to persistent
infection. The association between this
syndrome and the HLA-DR4 histocom-patibility
allele [16] was the first major
evidence that “treatment-resistant Lyme
arthritis” is an autoimmune process. Sub-sequent
studies demonstrating possible
molecular mimicry between an immu-nodominant
epitope of OspA and a pep-tide
derived from lymphocyte function–
*****
EDTORIAL COMMENTARY •JID 2005:192 (15 September) •949
associated antigen–1 (LFA-1), an adhe-sion
molecule expressed on the surface
of T cells [17], further support an au-toimmune
etiology.
The far more common posttreatment
syndrome is a constellation of chronic
musculoskeletal and neurocognitive symp-toms
variously referred to as “chronic
Lyme disease,” “post–Lyme disease syn-drome,”
or “posttreatment chronic Lyme
disease” (PTCLD) [15]. Differences of
opinion regarding the cause and man-agement
of PTCLD have polarized the
medical community [18]. One camp holds
that posttreatment symptoms are indic-ative
of deep-seated, persistent infection
requiring prolonged and intensive anti-biotic
therapy. The majority of physicians
and scientists, the so-called mainstream
camp, maintain that PTCLD is neither
infective nor inflammatory in nature.
Over the years, the mainstream viewpoint
has slowly gained acceptance, largely be-cause
researchers have failed to garner
convincing and reproducible evidence for
either persistent infection or ongoing in-flammation.
Pivotal in this regard were
the 2 randomized, multicenter trials re-ported
by Klempner et al. in 2001 [19]
that found no evidence for persistent B.
burgdorferi infection in patients with PTCLD
and failed to demonstrate any benefit from
prolonged antimicrobial therapy (30 days of
intravenous ceftriaxone plus 60 days of oral
doxycycline). This study did, however, doc-ument
that individuals with PTCLD expe-rience
considerable impairment in their
health-related quality of life.
The follow-up study by Klempner et al.
reported in this issue of The Journal of
Infectious Diseases [20] has provided an-other
piece to this complex puzzle by help-ing
to rule out an autoimmune mecha-nism
in PTCLD. Using banked samples
from their treatment cohorts and matched
samples from asymptomatic subjects who
were treated for LD, these researchers were
unable to establish a clear link between
treatment outcome and HLA haplotype.
Nevertheless, 2 cautionary notes must be
sounded. First, an increased frequency of
DRB1*0401 (an allele associated with an-tibiotic
treatment–resistant Lymearthritis)
was observed but did not reach statistical
significance, suggesting that the study may
have been underpowered. Second, not all
autoimmune processes are associated with
specific HLA haplotypes, a point acknowl-edged
by the authors.
After more than a decade of contro-versy,
we now can state with a reasonable
degree of certainty what PTCLD is not.
However, we still do not understand this
baffling entity and whether spirochetal in-fection
has a causal role in its pathogen-esis.
In the meantime, clinicians caring for
patients with PTCLD must forego costly,
irrational, and potentially harmful anti-microbial
regimens. Prompt recognition
and treatment of early LD remains the
only proven strategy for preventing long-term
complications.
References
1. Steere AC, Malawista SE, Syndman DR, et al.
An epidemic of oligoarticular arthritis in chil-dren
and adults in three Connecticut com-munities.
Arthritis Rheum 1977; 20:7–17.
2. Burgdorfer W, Barbour AG, Hayes SF, Benach
JL, Grunwaldt E, Davis JP. Lyme disease—
a tick-borne spirochetosis? Science 1982; 216:
1317–9.
3. Benach JL, Bosler EM, Hanrahan JP, et al. Spi-rochetes
isolated from the blood of two pa-tients
with Lyme disease. N Engl J Med 1983;
308:740–2.
4. Steere AC, Grodzicki RL, Kornblatt AN, et al.
The spirochetal etiology of Lyme disease. N
Engl J Med 1983; 308:733–40.
5. Hengge UR, Tannapfel A, Tyring SK, Erbel R,
Arendt G, Ruzicka T. Lyme borreliosis. Lancet
Infect Dis 2003; 3:489–500.
6. Casjens S, Palmer N, van Vugt R, et al. A
bacterial genome in flux: the twelve linear and
nine circular extrachromosomal DNAs in an
infectious isolate of the Lyme disease spiro-chete
Borrelia burgdorferi. Mol Microbiol 2000;
35:490–516.
7. Fraser CM, Casjens S, Huang WM, et al. Ge-nomic
sequence of a Lyme disease spirochaete,
Borrelia burgdorferi. Nature 1997; 390:580–6.
8. Rosa PA, Tilly K, Stewart PE. The burgeoning
molecular genetics of the Lyme disease spi-rochaete.
Nat Rev Microbiol 2005; 3:129–43.
9. Barthold SW, Beck DS, Hansen GM, Terwil-liger
AA, Moody KD. Lyme borreliosis in se-lected
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11. Salazar JC, Pope CD, Sellati TJ, et al. Coevo-lution
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12. Pal U, Fikrig E. Adaptation of Borrelia burg-dorferi
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13. Wormser GP, Bittker S, Cooper D, Nowakowski
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15. Weinstein A, Britchkov M. Lyme arthritis and
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16. Steere AC, Dwyer E, Winchester R. Associa-tion
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17. Gross DM, Forsthuber T, Tary-Lehmann M,
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18. Edlow JA. Bull’s eye: unraveling the mystery
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19. Klempner MS, Hu LT, Evans J, et al. Two con-trolled
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A case-control study to examine HLA hap-lotype
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192:1010–3 (in this issue).

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