Transcript Training

Chronic Lyme
An Evidence-Based Review
by
Steven Phillips, MD
ILADS 2008
In Their Own Words
ξ
ξ
“…patients who remain seronegative, despite continuing
symptoms for 6–8 weeks, are unlikely to have Lyme
disease…”
*Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner
MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler
JS, Nadelman RB. The clinical assessment, treatment, and prevention of lyme
disease, human granulocytic anaplasmosis, and babesiosis: clinical practice
guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006 Nov
1;43(9):1089-134. Epub 2006 Oct 2.
ξ
ξ
“…unproven and very improbable assumption that chronic
B. burgdorferi infection can occur in the absence of
antibodies against B. burgdorferi in serum.”
*Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser GP; Ad Hoc
International Lyme Disease Group (Bockenstedt LK, Dattwyler RJ, Nadelman RB,
Halperin JJ, Klempner MS, Krause PJ, Dumler JS, Bakken JS, et al). A critical appraisal
of "chronic Lyme disease".N Engl J Med. 2007 Oct 4;357(14):1422-30.
ξ
*In articles referenced throughout this presentation, the
authors above will be underlined and in red.
Diagnosis: Laboratory Testing
False Seronegativity Extensively Documented
ξ
41 Patients with late Lyme disease confirmed by
Positive Culture or Positive PCR
ξ 54% had been sick for more than 1 year
ξ 63.5% had a negative or borderline ELISA.
ξ
“We conclude that antibodies to B. burgdorferi often are
present in only low levels or are even absent in culture- or
PCR-positive patients who have been suffering for years
from symptoms compatible with LB.”
ξ
Oksi J, Uksila J, Marjamäki M, Nikoskelainen J, Viljanen MK. Antibodies
against whole sonicated Borrelia burgdorferi spirochetes, 41-kilodalton flagellin,
and P39 protein in patients with PCR- or culture-proven late Lyme borreliosis. J
Clin Microbiol. 1995 Sep;33(9):2260-4
Diagnosis: Laboratory Testing
False Seronegativity Extensively Documented
ξ
Only 50% of patients with late Lyme frankly seropositive.
ξ “Late-phase ocular Lyme borreliosis is probably
underdiagnosed because of weak seropositivity or
seronegativity in ELISA assays.”
ξ
Karma A, Seppälä I, Mikkilä H, Kaakkola S, Viljanen M, Tarkkanen A.
Diagnosis and clinical characteristics of ocular Lyme borreliosis. Am J Ophthalmol.
1995 Feb;119(2):127-35.
ξ
240 hospitalized patients with diagnoses c/w late Lyme
ξ 32/240 (13.3 %) PCR positive
ξ 18/32 (56.3%) were seronegative.
ξ
Chmielewski T, Fiett J, Gniadkowski M, Tylewska-Wierzbanowska S.
Improvement in the laboratory recognition of lyme borreliosis with the combination
of culture and PCR methods. Mol Diagn. 2003;7(3-4):155-62.
Diagnosis: Laboratory Testing
False Seronegativity Extensively Documented
ξ
“…a patient with active Lyme disease may have a
negative test result…”
ξ
Brown SL, Hansen SL, Langone JJ. (FDA Medical Bulletin) Role
of serology in the diagnosis of Lyme disease. JAMA. 1999 Jul
7;282(1):62-6.
ξ
“Specific borrelia IgM and IgG value in serum and CSF
were normal”
“The bacteria were cultured both from blood and from CSF,
in CSF they were also identified by PCR.”
3 fatalities due to Lyme
ξ
ξ
ξ
Bertrand E, Szpak GM, Piłkowska E, Habib N, LipczyńskaLojkowska W, Rudnicka A, Tylewska-Wierzbanowska S,
Kulczycki J.. Central nervous system infection caused by Borrelia
burgdorferi. Clinico-pathological correlation of three post-mortem
cases. Folia Neuropathol. 1999;37(1):43-51.
Diagnosis: Laboratory Testing—5 More Studies
False Seronegativity Extensively Documented
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Breier F, Khanakah G, Stanek G, Kunz G, Aberer E, Schmidt B,
Tappeiner G. Isolation and polymerase chain reaction typing of
Borrelia afzelii from a skin lesion in a seronegative patient with
generalized ulcerating bullous lichen sclerosus et atrophicus. Br J
Dermatol. 2001 Feb;144(2):387-92.
Brunner M, Sigal LH. Immune complexes from serum of patients
with lyme disease contain Borrelia burgdorferi antigen and antigenspecific antibodies: potential use for improved testing. J Infect Dis.
2000 Aug;182(2):534-9. Epub 2000 Jul 28.
Brunner M. New method for detection of Borrelia burgdorferi
antigen complexed to antibody in seronegative Lyme disease. J
Immunol Methods. 2001 Mar 1;249(1-2):185-90.
Wang P, Hilton E. Contribution of HLA alleles in the regulation of
antibody production in Lyme disease. Front Biosci. 2001 Sep
1;6:B10-6.
Dinerman H, Steere AC. Lyme disease associated with
fibromyalgia. Ann Intern Med. 1992 Aug 15;117(4):281-5.
Diagnosis: Laboratory Testing—5 More Studies
False Seronegativity Extensively Documented
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Fraser DD, Kong LI, Miller FW. Molecular detection of persistent
Borrelia burgdorferi in a man with dermatomyositis. Clin Exp
Rheumatol 1992 Jul-Aug;10(4):387-90.
Dejmkova H, Hulinska D, Tegzova D, Pavelka K, Gatterova J,
Vavrik P. Seronegative Lyme arthritis caused by Borrelia garinii. Clin
Rheumatol. 2002 Aug;21(4):330-4.
Oksi J, Mertsola J, Reunanen M, Marjamaki M, Viljanen MK.
Subacute multiple-site osteomyelitis caused by Borrelia burgdorferi.
Clin Infect Dis 1994 Nov; 19(5): 891-6.
Honegr K, Hulinska D, Dostal V, Gebousky P, Hankova E,
Horacek J, Vyslouzil L, Havlasova J. Persistence of Borrelia
burgdorferi sensu lato in patients with Lyme borreliosis. Epidemiol
Mikrobiol Imunol. 2001 Feb;50(1):10-6.
Wilke M, Eiffert H, Christen HJ, Hanefeld F. Primarily chronic and
cerebrovascular course of Lyme neuroborreliosis: case reports and
literature review. Arch Dis Child 2000 Jul;83(1):67-71.
Diagnosis: Laboratory Testing
Seronegative Patients Worse Off
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ξ
Double-blind, randomized, controlled trial
Partial response by end of treatment associated with higher
rate of relapse
57% of total relapsing patients seronegative at the time.
75% of amoxicillin treated relapsing patients seronegative at
the time
“…development of an antibody response increased the
possibility of achieving a complete response.”
ξ
Luft BJ, Dattwyler RJ, Johnson RC, Luger SW, Bosler EM, Rahn DW, Masters
EJ, Grunwaldt E, Gadgil SD. Azithromycin compared with amoxicillin in the
treatment of erythema migrans. A double-blind, randomized, controlled trial. Ann
Intern Med. 1996 May 1;124(9):785-91.
ξ
Serologic status & PCR status inversely correlated
ξ
Mouritsen CL, Wittwer CT, Litwin CM, Yang L, Weis JJ, Martins TB,
Jaskowski TD, Hill HR. Polymerase chain reaction detection of Lyme disease:
correlation with clinical manifestations and serologic responses.Am. J. Clin. Pathol.
1996 May;105(5):647-54.
Diagnosis: Laboratory Testing
Seronegative Patients Worse Off
ξ
ξ
ξ
Seronegative patients in the study had higher rates
of positive CSF PCR
57% of seronegative patients had not received prior
antibiotics before serologies were performed
106 patient & contamination controls were negative
ξ
Keller TL, Halperin JJ, Whitman M. PCR detection of Borrelia
burgdorferi DNA in cerebrospinal fluid of Lyme neuroborreliosis
patients. Neurology. 1992 Jan;42(1):32-42.
ξ
“Lyme borreliosis patients who have live spirochetes
in body fluids have low or negative levels of
borrelial antibodies in their sera”
ξ
Tylewska-Wierzbanowska S, Chmielewski T. Limitation of
serological testing for Lyme borreliosis: evaluation of ELISA and
western blot in comparison with PCR and culture methods. Wien Klin
Wochenschr. 2002 Jul 31;114(13-14):601-5.
Diagnosis: Laboratory Testing—5 More Studies
False Seronegativity Extensively Documented
ξ
ξ
ξ
ξ
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Schubert HD, Greenebaum E, Neu HC. Cytologically proven seronegative
Lyme choroiditis and vitritis. Retina. 1994;14(1):39-42.
Haupl T, Hahn G, Rittig M, Krause A, Schoerner C, Schonherr U,
Kalden JR, Burmester GR. Persistence of Borrelia burgdorferi in
ligamentous tissue from a patient with chronic Lyme borreliosis. Arthritis
Rheum 1993 Nov; 36(11): 1621-6.
Hulinska D, Krausova M, Janovska D, Rohacova H, Hancil J, Mailer H.
Electron microscopy and the polymerase chain reaction of spirochetes from
the blood of patients with Lyme disease. Cent Eur J Public Health 1993 Dec;
1(2): 81-5.
Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L.
Recurrent erythema migrans despite extended antibiotic treatment with
minocycline in a patient with persisting Borrelia burgdorferi infection. J.
Am. Acad. Dermatol. 1993 Feb;28(2 Pt 2):312-4.
Preac Mursic V, Marget W, Busch U, Pleterski Rigler D, Hagl S. Kill kinetics of
Borrelia burgdorferi and bacterial findings in relation to the treatment of Lyme
borreliosis. Infection. 1996 Jan-Feb;24(1):9-16.
Diagnosis: Laboratory Testing—5 More Studies
False Seronegativity Extensively Documented
ξ
ξ
ξ
ξ
ξ
Mursic VP, Wanner G, Reinhardt S, Wilske B, Busch U, Marget
W. Formation and cultivation of Borrelia burgdorferi spheroplast-Lform variants. Infection 1996 Jul-Aug;24(4):335.
Millner M. Neurologic manifestations of Lyme borreliosis in children
Wien Med Wochenschr. 1995;145(7-8):178-82.
Kmety E. Dynamics of antibodies in Borrelia burgdorferi sensu lato
infections. Bratisl Lek Listy. 2000;101(1):5-7.
Pikelj F, Strle F, Mozina M. Seronegative Lyme disease and
transitory atrioventricular block. Ann Intern Med 1989 Jul
1;111(1):90.
Pachner AR. Borrelia burgdorferi in the nervous system: the new
"great imitator".Ann N Y Acad Sci. 1988;539:56-64.
Diagnosis: Laboratory Testing
False Seronegativity Extensively Documented
ξ
ξ
“…chronic Lyme disease cannot be excluded by the
absence of antibodies against B. burgdorferi.”
Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J,
Golightly MG. Seronegative Lyme disease. Dissociation of specific
T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J
Med. 1988 Dec 1;319(22):1441-6.
ξ
Greater than 70% of patients with chronic Lyme
disease were seronegative by CDC criteria
ξ
Donta ST. Tetracycline therapy for chronic Lyme disease. Clin Infect
Dis 1997 Jul;25 Suppl 1:S52-6.
Diagnosis: Laboratory Testing—5 More Studies
False Seronegativity Extensively Documented
ξ
ξ
ξ
ξ
ξ
Pleyer U, Priem S, Bergmann L, Burmester G, Hartmann C,
Krause A. Detection of Borrelia burgdorferi DNA in urine of patients
with ocular Lyme borreliosis. Br J Ophthalmol. 2001 May;85(5):5525.
Eldøen G, Vik IS, Vik E, Midgard R. [Lyme neuroborreliosis in
More and Romsdal] Tidsskr Nor Laegeforen. 2001 Jun
30;121(17):2008-11.
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 Oct;49(10):911-5.
Mikkilä H, Karma A, Viljanen M, Seppälä I. The laboratory
diagnosis of ocular Lyme borreliosis. Graefes Arch Clin Exp
Ophthalmol. 1999 Mar;237(3):225-30.
Aberer E, Kersten A, Klade H, Poitschek C, Jurecka W.
Heterogeneity of Borrelia burgdorferi in the skin. Am J
Dermatopathol. 1996 Dec;18(6):571-9.
Diagnosis: Laboratory Testing—5 More Studies
False Seronegativity Extensively Documented
ξ
Steere AC. Seronegative Lyme disease. JAMA. 1993 Sep
15;270(11):1369.
ξ Preac-Mursic V, Pfister HW, Spiegel H, Burk R, Wilske B,
Reinhardt S, Bohmer R. First isolation of Borrelia burgdorferi from
an iris biopsy. J. Clin. Neuroophthalmol. 1993 Sep;13(3):155-61.
ξ Oksi J, Viljanen MK, Kalimo H, Peltonen R, Marttía R, Salomaa
P, Nikoskelainen J, Budka H, Halonen P. Fatal encephalitis caused
by concomitant infection with tick-borne encephalitis virus and
Borrelia burgdorferi. Clin Infect Dis. 1993 Mar;16(3):392-6.
ξ Skripnikova IA, Anan'eva LP, Barskova VG, Ushakova MA. [The
humoral immunological response of patients with Lyme disease.]Ter
Arkh 1995;67(11):53-6.
ξ Klempner MS, Schmid CH, Hu L, Steere AC, Johnson G,
McCloud B, Noring R, Weinstein A. Intralaboratory reliability of
serologic and urine testing for Lyme disease. Am J Med. 2001 Feb
15;110(3):217-9.
Diagnosis: Laboratory Testing—5 More Studies
False Seronegativity Extensively Documented
ξ
ξ
ξ
ξ
ξ
Banyas GT. Difficulties with Lyme serology. J Am Optom Assoc.
1992 Feb;63(2):135-9.
Faller J, Thompson F, Hamilton W. Foot and ankle disorders
resulting from Lyme disease. Foot Ankle. 1991 Feb;11(4):236-8.
Nields JA, Kueton JF. Tullio phenomenon and seronegative Lyme
borreliosis. Lancet. 1991 Jul 13;338(8759):128-9.
Schutzer SE, Coyle PK, Belman AL, Golightly MG, Drulle J.
Sequestration of antibody to Borrelia burgdorferi in immune
complexes in seronegative Lyme disease. Lancet. 1990 Feb
10;335(8685):312-5.
Paul A. [Arthritis, headache, facial paralysis. Despite negative
laboratory tests Borrelia can still be the cause]. MMW Fortschr. Med
2001 Feb 8;143(6):17.
In Their Own Words
ξ
“…patients who remain seronegative, despite continuing
symptoms for 6–8 weeks, are unlikely to have Lyme
disease…”
ξ
Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS,
Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler JS, Nadelman
RB. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic
anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society
of America. Clin Infect Dis. 2006 Nov 1;43(9):1089-134. Epub 2006 Oct 2.
ξ
“…unproven and very improbable assumption that chronic
B. burgdorferi infection can occur in the absence of
antibodies against B. burgdorferi in serum.”
ξ
Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser GP; Ad Hoc
International Lyme Disease Group (Bockenstedt LK, Dattwyler RJ, Nadelman RB,
Halperin JJ, Klempner MS, Krause PJ, Dumler JS, Bakken JS, et al). A critical appraisal
of "chronic Lyme disease".N Engl J Med. 2007 Oct 4;357(14):1422-30.
ξ
8 out of the previous 46 articles documenting late
seronegative Lyme were written by some of the authors of
the IDSA and NEJM papers as referenced above
Diagnosis: Laboratory Testing
False Negative CSF (& Seronegative Also)
ξ
ξ
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Of 35 patients with specific Lyme Antigen (Osp A) in
CSF:
ξ 15 (43%) were antibody-negative in CSF.
ξ Seven of these 15 (47%) had otherwise normal routine
CSF analyses.
ξ Nine of these 15 (60%) patients were seronegative
“…neurologic infection by B. burgdorferi should not be
excluded solely on the basis of normal routine CSF or
negative CSF antibody analyses.”
Coyle PK, Schutzer SE, Deng Z, Krupp LB, Belman AL, Benach JL, Luft BJ.
Detection of Borrelia burgdorferi-specific antigen in antibody-negative
cerebrospinal fluid in neurologic Lyme disease. Neurology. 1995 Nov;45(11):20105.
Diagnosis: Laboratory Testing
CSF False Negative Antibodies
“...local antibody production in CSF is an inconsistent
finding in American patients with late neurologic
manifestations of the disorder.”
ξ
Steere AC, Berardi VP, Weeks KE, Logigian EL, Ackermann R. Evaluation of
the intrathecal antibody response to Borrelia burgdorferi as a diagnostic test for
Lyme neuroborreliosis. J Infect Dis 1990 Jun;161(6):1203-9.
ξ
39%-54% of patients with late neurologic Lyme
were antibody negative in CSF
ξ
Logigian EL, Kaplan RF, Steere AC. Successful treatment of Lyme
encephalopathy with intravenous ceftriaxone. J Infect Dis 1999;180:377–83.
Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme
disease. N Engl J Med 1990;323:1438–44.
ξ
Diagnosis: Laboratory Testing
CSF False Negative Antibodies Extensively Documented
Pfister HW, Preac-Mursic V, Wilske B, Einhaupl KM, Weinberger K. Latent
Lyme neuroborreliosis: presence of Borrelia burgdorferi in the cerebrospinal fluid
without concurrent inflammatory signs. Neurology. 1989 Aug;39(8):1118-20.
ξ Preac-Mursic V, Weber K, Pfister HW, Wilske B, Gross B, Baumann A, Prokop
J. Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme
borreliosis. Infection. 1989 Nov-Dec;17(6):355-9.
ξ Peter O, Bretz AG, Zenhausern R, Roten H, Roulet E. Isolation of Borrelia
burgdorferi in the cerebrospinal fluid of 3 children with neurological involvement.
Schweiz Med Wochenschr 1993 Jan 13; 123(1-2): 14-9.
ξ Oksi J, Kalimo H, Marttila RJ, Marjamaki M, Sonninen P, Nikoskelainen J,
Viljanen MK. Inflammatory brain changes in Lyme borreliosis. A report on three
patients and review of literature. Brain 1996 Dec; 119 ( Pt 6): 2143-54.
ξ Kaiser R, Rasiah C, Gassmann G, Vogt A, Lücking CH. Intrathecal antibody
synthesis in Lyme neuroborreliosis: use of recombinant p41 and a 14-kDa flagellin
fragment in ELISA. J Med Microbiol. 1993 Oct;39(4):290-7.
ξ Honegr K, Hulinska D, Dostal V, Gebousky P, Hankova E, Horacek J, Vyslouzil
L, Havlasova J. Persistence of Borrelia burgdorferi sensu lato in patients with Lyme
borreliosis. Epidemiol Mikrobiol Imunol 2001 Feb;50(1):10-6.
ξ
Diagnosis: Laboratory Testing
CSF PCR—Useful or Not?
ξ
In children with known Lyme meningitis, Lyme
CSF-PCR had a sensitivity of 5% and a specificity
of 99%
ξ
Avery RA, Frank G, Eppes SC. Diagnostic utility of Borrelia
burgdorferi cerebrospinal fluid polymerase chain reaction in children
with Lyme meningitis. Pediatr Infect Dis J. 2005 Aug;24(8):705-8.
ξ
Nested CSF PCR sensitivity in known Lyme
neuroborreliosis was 35%.
ξ
Picha D, Moravcova L, Zdarsky E, Maresova V, Hulinsky V. PCR
in lyme neuroborreliosis: a prospective study. Acta Neurol Scand.
2005 Nov;112(5):287-92.
In Their Own Words
ξ
“Re-treatment is not recommended unless relapse is shown
by reliable objective measures.”
ξ
Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner
MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler
JS, Nadelman RB. The clinical assessment, treatment, and prevention of lyme
disease, human granulocytic anaplasmosis, and babesiosis: clinical practice
guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006 Nov
1;43(9):1089-134. Epub 2006 Oct 2.
ξ
“Although proponents of the chronic Lyme disease
diagnosis believe that patients are persistently infected with
B. burgdorferi, they do not require objective clinical or
laboratory evidence...”
ξ
Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser GP;
Ad Hoc International Lyme Disease Group (Bockenstedt LK, Dattwyler RJ,
Nadelman RB, Halperin JJ, Klempner MS, Krause PJ, Dumler JS, Bakken JS,
et al). A critical appraisal of "chronic Lyme disease".N Engl J Med. 2007 Oct
4;357(14):1422-30.
CDC Case Definition is Not for Diagnosis
ξ
CDC Surveillance Case Definition
ξ
a) a case with EM or;
b) a case with at least one objective manifestation such
as meningitis, cranial neuropathy, arthritis, or AV block,
that is laboratory confirmed.
“This surveillance case definition was developed for
national reporting of Lyme disease; it is not intended to
be used in clinical diagnosis.”
ξ
ξ
ξ
http://www.cdc.gov/ncphi/disss/nndss/casedef/lyme_disease_2008.htm
ξ
Cases reported to CDC are estimated to be 10 times less
than the actual number of Lyme cases
ξ
Roberts DM, Carlyon JA, Theisen M, Marconi RT. The bdr gene
families of the Lyme disease and relapsing fever spirochetes:
potential influence on biology, pathogenesis, and evolution. Emerg
Infect Dis. 2000 Mar-Apr;6(2):110-22.
http://www.cdc.gov/ncidod/eid/vol6no2/ascii/roberts.txt
ξ
Early Lyme:
Objective Findings Poor-Subjective Findings Rich
Objective Findings
EM as Entry Criteria
No A-V Block
No Meningitis
No Cranial Neuritis
No encephalomyelitis
Joint swelling in 10.8%
Subjective Symptoms
Fatigue
56.8%
Myalgias
43.2%
Headache
39.2%
Chills
35.1%
Joint pain
35.1%
(without swelling)
Trevejo RT, Krause PJ, Sikand VK, Schriefer ME, Ryan R, Lepore T, Porter W,
Dennis DT. Evaluation of two-test serodiagnostic method for early Lyme disease in
clinical practice. J Infect Dis. 2000 Feb;181(2):802-3.
Only 22% of late Lyme patients had a prior history of EM.
Qureshi MZ, New D, Zulqarni NJ, Nachman S. Overdiagnosis and overtreatment of
Lyme disease in children. Pediatr Infect Dis J. 2002 Jan;21(1):12-4.
Late Lyme:
Objective Findings Poor-Subjective Findings Rich
ξ
18 patients with documented persistent
infection by immuno-electron microscopy and
PCR
ξ 50% had only non-specific subjective symptoms,
nothing objective.
ξ 39% were seronegative initially
ξ 67% were seronegative on repeat testing.
ξ 50% had completely negative CSF for Lyme
antibodies, chemistries, and cell count
ξ Honegr K, Hulinska D, Dostal V, Gebousky P, Hankova E, Horacek J, Vyslouzil
L, Havlasova J. Persistence of Borrelia burgdorferi sensu lato in patients with Lyme
borreliosis. Epidemiol Mikrobiol Imunol 2001 Feb;50(1):10-6.
Chronic Lyme Disease Non-Specific Symptoms
ξ
120 Lyme patients evaluated
ξ
“vague, non-specific dental, facial or head pain, who present
with a multisystemic, multi-treatment history, are suspect.”
ξ
Heir GM, Fein LA. Lyme disease awareness for the New Jersey dentist. A survey of
orofacial and headache complaints associated with Lyme disease. J N J Dent Assoc 1998
Winter;69(1):19, 21, 62-3 passim.
ξ
“… even non-specific symptoms should alert the physician to
the possibility of infection caused by the spirochete.”
“...neuroborreliosis may be the cause for persisting,
irreversible intellectual impairment…Brain lesions are the
result of misdiagnosis and delayed antibiotic treatment.”
ξ
ξ
Poplawska R, Konarzewska B, Gudel-Trochimowicz I, Szulc A. Psychologic disorders in
acute and persistent neuroborreliosis. Pol Merkuriusz Lek 2001 Jan;10(55):36-7.
ξ
27 Chronic Lyme patients evaluated
56% of the total had Brain lesions on MRI.
ξ
ξ
Morgen K, Martin R, Stone RD, Grafman J, Kadom N, McFarland HF, Marques A.
FLAIR and magnetization transfer imaging of patients with post-treatment Lyme disease
syndrome. Neurology. 2001 Dec 11;57(11):1980-5.
Seronegative, Non-specific, Life-threatening
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ξ
ξ
“…chronic form of neuroborreliosis and displayed only
non-specific symptoms.”
One child: Vasculitis by CNS biopsy. PCR positive in CSF.
No specific antibodies were detectable.
Three other children: Culture Positive from CSF in the
absence of specific antibodies in CSF or blood.
ξ Patient #1: Severe weight loss and chronic headaches
ξ Patient #2: Seizures and failure to thrive.
ξ Patients #3 & #4: Acute hemiparesis from ischemic
CVA’s-cerebrovascular course of neuroborreliosis.
Following adequate antibiotic treatment, all patients showed
substantial improvement of their respective symptoms.
Wilke M, Eiffert H, Christen HJ, Hanefeld F. Primarily chronic and
cerebrovascular course of Lyme neuroborreliosis: case reports and literature review.
Arch Dis Child 2000 Jul;83(1):67-71.
Treatment Outcomes:
High Failure Rates in Late Disease
ξ Short term antibiotics fail in 25%-71% of patients with
late stage disease.
ξ Treib J, Fernandez A, Haass A, Grauer MT, Holzer G, Woessner R. Clinical
and serologic follow-up in patients with neuroborreliosis. Neurology. 1998
Nov;51(5):1489-91.
ξ Steere AC, Berardi VP, Weeks KE, Logigian EL, Ackermann R. Evaluation of
the intrathecal antibody response to Borrelia burgdorferi as a diagnostic test for
Lyme neuroborreliosis. J Infect Dis 1990 Jun;161(6):1203-9.
ξ Dvorakova J, Celer V. [Pharmacological aspects of Lyme borreliosis]Ceska Slov
Farm. 2004 Jul;53(4):159-64.
ξ Kaiser R. Clinical courses of acute and chronic neuroborreliosis following
treatment with ceftriaxone.Nervenarzt.2004 Jun;75(6):553-7.
ξ Berglund J, Stjernberg L, Ornstein K, Tykesson-Joelsson K, Walter H. 5-y
Follow-up study of patients with neuroborreliosis. Scand J Infect Dis.
2002;34(6):421-5.
ξ Valesová H, Mailer J, Havlík J, Hulínská D, Hercogová J. Long-term results in
patients with Lyme arthritis following treatment with ceftriaxone. Infection. 1996
Jan-Feb;24(1):98-102.
ξ Rohácová H, Hancil J, Hulinská D, Mailer H, Havlík J. Ceftriaxone in the
treatment of Lyme neuroborreliosis. Infection. 1996 Jan-Feb;24(1):88-90.
Severe Chronic Symptoms
ξ “mild and self-limiting subjective symptoms”
ξ “common, and some occur in more than 10% of the general
population”
ξ
Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser GP; Ad Hoc
International Lyme Disease Group (Bockenstedt LK, Dattwyler RJ, Nadelman RB,
Halperin JJ, Klempner MS, Krause PJ, Dumler JS, Bakken JS, et al). A critical appraisal
of "chronic Lyme disease".N Engl J Med. 2007 Oct 4;357(14):1422-30.
ξ
“Base-line assessments documented severe impairment in the
patients' health-related quality of life”
ξ
Klempner MS, Hu LT, Evans J, Schmid CH, Johnson GM, Trevino RP, Norton D,
Levy L, Wall D, McCall J, Kosinski M, Weinstein A. Two controlled trials of antibiotic
treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med.
2001 Jul 12;345(2):85-92.
ξ
“marked levels of fatigue, pain, and impaired physical
functioning.” (which was NOT entry criteria for the study)
ξ pain similar to post-surgery patients; fatigue similar
multiple sclerosis patients; functional limitations
comparable to CHF patients
ξ
Fallon BA, Keilp JG, Corbera KM, Petkova E, Britton CB, Dwyer E, Slavov I, Cheng J,
Dobkin J, Nelson DR, Sackeim HA. A randomized, placebo-controlled trial of repeated IV
antibiotic therapy for Lyme encephalopathy. Neurology. 2007 Oct 10; [Epub ahead of print]
In Their Own Words
ξ
“To date, there is no convincing biologic evidence
for the existence of symptomatic chronic B.
burgdorferi infection among patients after receipt of
recommended treatment regimens for Lyme
disease.”
ξ
Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner
MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler
JS, Nadelman RB. The clinical assessment, treatment, and prevention of lyme
disease, human granulocytic anaplasmosis, and babesiosis: clinical practice
guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006 Nov
1;43(9):1089-134. Epub 2006 Oct 2.
ξ
“Chronic Lyme disease due to antibiotic resistant
infection has not been demonstrated.”
ξ
Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser GP;
Ad Hoc International Lyme Disease Group (Bockenstedt LK, Dattwyler RJ,
Nadelman RB, Halperin JJ, Klempner MS, Krause PJ, Dumler JS, Bakken JS,
et al). A critical appraisal of "chronic Lyme disease".N Engl J Med. 2007 Oct
4;357(14):1422-30.
Animal Data Persistent Infection Despite ABX
ξ
Infected dogs received amoxicillin; azithromycin;
ceftriaxone; or doxycycline for 30 days
ξ PCR positvity despite antibiotic treatment
ξ Corticosteroid treatment reactivated subclinical Lyme2
ξ
Straubinger RK, Straubinger AF, Summers BA, Jacobson RH, Erb HN.
Clinical manifestations, pathogenesis, and effect of antibiotic treatment on Lyme
borreliosis in dogs. Wien Klin Wochenschr 1998 Dec 23;110(24):874-81.
2Straubinger RK, Straubinger AF, Summers BA, Jacobson RH. Status of
Borrelia burgdorferi infection after antibiotic treatment and the effects of
corticosteroids: An experimental study. J Infect Dis. 2000 Mar;181(3):1069-81.
ξ
ξ
ξ
ξ
Mice treated with doxycycline and ceftriaxone for 30 days
Bb Culture Positive—from 40% 3 months after treatment
PCR positive—6 & 9 months after antibiotic therapy.
ξ Bockenstedt LK, Mao J, Hodzic E, Barthold SW, Fish D.
Detection of attenuated, noninfectious spirochetes in Borrelia
burgdorferi-infected mice after antibiotic treatment. J Infect Dis. 2002
Nov 15;186(10):1430-7.
Animal Data Persistent Infection Despite ABX
ξ
Mice were divided into 2 groups by stage of infection:
ξ Early disease--3 weeks duration & Late disease--4 months duration
ξ
ξ
All mice were treated with 30 days ceftriaxone, then examined
for persistent infection at 1 and 3 months later.
Methods of examination were
ξ Culture, PCR, and Pathology as well as:
ξ Xenodiagnosis—Uninfected larval ticks fed on mice that have been
infected, then treated. Ticks matured to nymphs and assessed for
presence of B. burgdorferi by PCR.
ξ Allograft Transplantation—Tissues from mice that have been
infected, then treated, were transplanted into mice without infection.
These naïve mice were evaluated for infection by culture & PCR
ξ Hodzic E, Feng S, Holden K, Freet KJ, Barthold SW. Persistence of Borrelia
burgdorferi following Antibiotic Treatment in Mice. Antimicrob Agents Chemother.
2008 May;52(5):1728-36. Epub 2008 Mar 3.
Animal Data Persistent Infection Despite ABX
Pathology PCR
Xenodiag.
Allograft
Early infection
1 month p-tx.
1/5(20%) 2/5(40%)
1/5(20%)
Neg
Early infection
3 month p-tx.
Neg
1/3(33%)
Neg
Late infection
1 month p-tx.
3/8(38%) 8/8(100%) 3/8(38%)
Neg
Late infection
3 month p-tx.
1/5(20%) 2/5(40%)
Neg
*1/3 Not Done
*1/8 Not Done
2/5(40%)
1/5 (20%)
ξ 8/9 (89%) of SCID mice exposed to xenodiagnosis positive ticks
became infected with B. burgdorferi, by either culture or PCR
ξ Hodzic E, Feng S, Holden K, Freet KJ, Barthold SW. Persistence of Borrelia
burgdorferi following Antibiotic Treatment in Mice. Antimicrob Agents Chemother.
2008 May;52(5):1728-36. Epub 2008 Mar 3.
Chronic Lyme Disease
Verified Persistent Infection Despite Antibiotics
ξ 30% Remained PCR Positive Despite Multiple
Courses of “Adequate” Antibiotic Therapy
ξ
Nocton J J; Dressler F; Rutledge B J; Rys P N; Persing D H;
Steere A C. Detection of Borrelia burgdorferi DNA by polymerase
chain reaction in synovial fluid from patients with Lyme arthritis N.
Engl. J. Med. 1994 Jan, 330:4, 229-34.
ξ “....DNA of heat-killed borrelia was not detectable for very
long in skin tissue of an uninfected dog, implying that during
natural infection the DNA of killed organisms is removed
quickly and completely within a few days."
ξ
Straubinger RK. PCR-Based quantification of Borrelia burgdorferi organisms in
canine tissues over a 500-Day postinfection period. J Clin Microbiol. 2000
Jun;38(6):2191-9.
ξ
74% Remained PCR Positive Despite Extended Antibiotic
Therapy
ξ
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 Sep, 24:5, 347-53.
Chronic Lyme Disease
Verified Persistent Infection Despite Antibiotics
ξ
ξ
ξ
165 Lyme patients treated for at least 3 months
ξ 32 (19.4%) relapsed despite therapy
38% of relapsers were culture or PCR positive
ξ “We conclude that the treatment of Lyme
borreliosis with appropriate antibiotics for even
more than 3 months may not always eradicate the
spirochete.”
Oksi J, Marjamaki M, Nikoskelainen J, et al. Borrelia burgdorferi
detected by culture and PCR in clinical relapse of disseminated Lyme
borreliosis. Ann Med. 1999 Jun;31(3):225-232.
Chronic Lyme Disease
Verified Persistent Infection Despite Antibiotics
ξ
ξ
ξ
Retrospective cohort study: 38 patients, 43 controls
ξ 10/38 (26.3%) relapsed within 1 year of treatment
ξ 13/38 (34.2%) had increased symptoms
(musculoskeletal, neuropathic, or neurocognitive
impairment) a mean of 6.2 years after symptom onset
Patient #12 developed severe neurologic disease
ξ CSF Lyme antibody negative
ξ The patient died. Spirochetes present in brain biopsy.
Shadick NA, Phillips CB, Logigian EL, Steere AC, Kaplan RF, Berardi VP,
Duray PH, Larson MG, Wright EA, Ginsburg KS, Katz JN, Liang MH. The
long-term clinical outcomes of Lyme disease. A population-based retrospective
cohort study. Ann Intern Med. 1994 Oct 15;121(8):560-7.
Chronic Lyme Disease
Verified Persistent Infection Despite Antibiotics
ξ
ξ
ξ
ξ
ξ
64-year-old woman presented with bullous and
ulcerating lichen sclerosus et atrophicus (LSA)
Lyme serologies were repeatedly negative
B. burgdorferi was isolated by live culture from
from enlarging LSA lesions even after 4 courses of
ceftriaxone.
After 5th course of ceftriaxone, improvements in
skin and negative cultures for B. burgdorferi
Breier F, Khanakah G, Stanek G, Kunz G, Aberer E, Schmidt B, Tappeiner G.
Isolation and polymerase chain reaction typing of Borrelia afzelii from a skin lesion
in a seronegative patient with generalized ulcerating bullous lichen sclerosus et
atrophicus. Br J Dermatol. 2001 Feb;144(2):387-92.
Chronic Lyme Disease
Verified Persistent Infection Despite Antibiotics
ξ
Erythema migrans--Histopathology and PCR
positive despite long term antibiotics
ξ
Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L.
Recurrent erythema migrans despite extended antibiotic treatment with minocycline
in a patient with persisting Borrelia burgdorferi infection. J. Am. Acad. Dermatol.
1993 Feb;28(2 Pt 2):312-4.
ξ
Erythema migrans--Culture positive oral antibiotic
failure
ξ
Strle F, Maraspin V, Lotric-Furlan S, Ruzić-Sabljić E, Cimperman J.
Azithromycin and doxycycline for treatment of Borrelia culture-positive erythema
migrans. Infection. 1996 Jan-Feb;24(1):64-8.
ξ
Skin--Culture positive despite repeated antibiotic
treatments
ξ
Hudson BJ, Stewart M, Lennox VA, Fukunaga M, Yabuki M, Macorison H,
Kitchener-Smith J. Culture-positive Lyme borreliosis. Med J Aust. 1998 May
18;168(10):500-2.
Chronic Lyme Disease
Verified Persistent Infection Despite Antibiotics
ξ
ξ
7 courses of IV antibiotics & 3 years continuous oral
“Although the patient never had detectable free antibodies
to B. burgdorferi in serum or spinal fluid, the CSF was
positive on multiple occasions for complexed anti-B.
burgdorferi antibodies, B. burgdorferi nucleic acids and free
antigen.”
ξ
Lawrence C, Lipton RB, Lowy FD, Coyle PK Seronegative chronic relapsing
neuroborreliosis. Eur. Neurol. 1995;35(2):113-7.
ξ
“chronic septic Lyme arthritis of the knee for seven years
despite multiple antibiotic trials and multiple arthroscopic
and open synovectomies.”
“Spirochetes were documented in synovium and synovial
fluid (SF). Polymerase chain reaction (PCR) analysis of the
SF was consistent with Borrelia infection.”
ξ
ξ
Battafarano DF, Combs JA, Enzenauer RJ, Fitzpatrick JE. Chronic septic
arthritis caused by Borrelia burgdorferi. Clin Orthop 1993 Dec(297): 238-41.
Chronic Lyme Disease-5 More Studies
Verified Persistence of Infection Despite Antibiotics
ξ
ξ
ξ
ξ
ξ
Reimers CD, de Koning J, Neubert U, Preac Mursic V, Koster JG,
Muller Felber W, Pongratz DE, Duray PH. Borrelia burgdorferi myositis:
report of eight patients. J Neurol 1993 May; 240(5): 278-83.
Honegr K, Hulinska D, Dostal V, Gebousky P, Hankova E, Horacek J,
Vyslouzil L, Havlasova J. [Persistence of Borrelia burgdorferi sensu lato in
patients with Lyme borreliosis]. Epidemiol Mikrobiol Imunol 2001
Feb;50(1):10-6.
Mursic VP, Wanner G, Reinhardt S, Wilske B, Busch U, Marget W.
Formation and cultivation of Borrelia burgdorferi spheroplast-L-form
variants. Infection 1996 Jul-Aug;24(4):335.
López-Andreu JA, Ferrís J, Canosa CA, Sala-Lizárraga JV. Treatment of
late Lyme disease: a challenge to accept. J Clin Microbiol. 1994
May;32(5):1415-6.
Oksi J, Kalimo H, Marttila RJ, Marjamaki M, Sonninen P,
Nikoskelainen J, Viljanen MK. Inflammatory brain changes in Lyme
borreliosis. A report on three patients and review of literature. Brain 1996
Dec; 119 ( Pt 6): 2143-54.
“Post-Lyme Fibromyalgia”
Verified Persistence of Infection Despite Antibiotics
ξ 30% of Lyme patients who fail a short course
of antibiotics meet diagnostic criteria for
fibromyalgia.
ξ Bujak DI, Weinstein A, Dornbush RL. Clinical and neurocognitive features of the
post Lyme syndrome. J Rheumatol. 1996 Aug;23(8):1392-7.
ξ
ξ
Muscle Biopsies from Patients with “PostLyme Fibromyalgia”—Lyme PCR Positive
Frey M, Jaulhac B, Piemont Y, Marcellin L, Boohs PM, Vautravers P, Jesel M,
Kuntz JL, Monteil H, Sibilia J. Detection of Borrelia burgdorferi DNA in muscle
of patients with chronic myalgia related to Lyme disease. Am J Med 1998
Jun;104(6):591-4.
Chronic Lyme Arthritis-Autoimmune?
Verified Persistence of Infection Despite Antibiotics
ξ
After treatment, synovial fluid PCR negative,
but synovial membrane PCR positive
ξ
Priem S, Burmester GR, Kamradt T, Wolbart K, Rittig MG, Krause A.
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 Feb;57(2):118-21.
ξ
After antibiotic treatment, synovial membrane
still demonstrates spirochetes
ξ
Nanagara R, Duray PH, Schumacher HR 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
Oct;27(10):1025-34.
Chronic Lyme Disease-7 More Studies
Verified Persistence of Infection Despite Antibiotics
ξ
ξ
ξ
ξ
ξ
ξ
ξ
Meier P, Blatz R, Gau M, Spencker FB, Wiedemann P. [Pars plana vitrectomy in
Borrelia burgdorferi endophthalmitis][German] Klin Monatsbl Augenheilkd 1998
Dec;213(6):351-4.
Cimmino MA, Azzolini A, Tobia F, Pesce CM. Spirochetes in the spleen of a
patient with chronic Lyme disease. Am J Clin Pathol 1989 Jan;91(1):95-7.
Hulinska D, Votypka J, Valesova M. Persistence of Borrelia garinii and Borrelia
afzelii in patients with Lyme arthritis. Int J Med Microbiol Virol Parasitol Infect Dis
1999 Jul;289(3):301-18.
Schoen RT, Aversa JM, Rahn DW, Steere AC. Treatment of refractory chronic
Lyme arthritis with arthroscopic synovectomy. Arthritis Rheum 1991 Aug; 34(8):
1056-60.
Kirsch M, Ruben FL, Steere AC, Duray PH, Norden CW, Winkelstein A. Fatal
adult respiratory distress syndrome in a patient with Lyme disease. JAMA 1988 May
13; 259(18): 2737-9.
Preac-Mursic V, Weber K, Pfister HW, Wilske B, Gross B, Baumann A, Prokop
J. Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme
borreliosis. Infection. 1989 Nov-Dec;17(6):355-9.
Aberer E, Kersten A, Klade H, Poitschek C, Jurecka W. Heterogeneity of
Borrelia burgdorferi in the skin. Am J Dermatopathol. 1996 Dec;18(6):571-9.
Chronic Lyme Disease-7 More Studies
Verified Persistence of Infection Despite Antibiotics
Preac-Mursic V, Pfister HW, Spiegel H, Burk R, Wilske B, Reinhardt S,
Bohmer R. First isolation of Borrelia burgdorferi from an iris biopsy. J. Clin.
Neuroophthalmol. 1993 Sep;13(3):155-61.
ξ Haupl T, Hahn G, Rittig M, Krause A, Schoerner C, Schonherr U, Kalden JR,
Burmester GR. Persistence of Borrelia burgdorferi in ligamentous tissue from a
patient with chronic Lyme borreliosis. Arthritis Rheum 1993 Nov; 36(11): 1621-6.
ξ Hulinska D, Krausova M, Janovska D, Rohacova H, Hancil J, Mailer H.
Electron microscopy and the polymerase chain reaction of spirochetes from the
blood of patients with Lyme disease. Cent Eur J Public Health 1993 Dec; 1(2): 81-5.
ξ Pfister HW, Preac-Mursic V, Wilske B, Schielke E, Sorgel F, Einhaupl KMJ.
Randomized comparison of ceftriaxone and cefotaxime in Lyme neuroborreliosis.
Infect. Dis. 1991 Feb;163(2):311-8.
ξ Preac Mursic V, Marget W, Busch U, Pleterski Rigler D, Hagl S. Kill kinetics of
Borrelia burgdorferi and bacterial findings in relation to the treatment of Lyme
borreliosis. Infection. 1996 Jan-Feb;24(1):9-16.
ξ Schmidli J, Hunziker T, Moesli P, Schaad UB. Cultivation of Borrelia burgdorferi
from joint fluid three months after treatment of facial palsy due to Lyme borreliosis
[letter]. J Infect Dis 1988 Oct; 158(4): 905-6.
ξ Strle F, Preac-Mursic V, Cimperman J, Ruzic E, Maraspin V, Jereb M.
Azithromycin versus doxycycline for treatment of erythema migrans: clinical and
microbiological findings. Infection. 1993 Mar-Apr;21(2):83-8.
ξ
In Their Own Words
ξ
“To date, there is no convincing biologic evidence for the
existence of symptomatic chronic B. burgdorferi infection
among patients after receipt of recommended treatment
regimens for Lyme disease.”
ξ
Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS,
Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler JS, Nadelman
RB. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic
anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society
of America. Clin Infect Dis. 2006 Nov 1;43(9):1089-134. Epub 2006 Oct 2.
ξ
“Chronic Lyme disease due to antibiotic resistant infection has
not been demonstrated.”
ξ
Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser GP; Ad Hoc
International Lyme Disease Group (Bockenstedt LK, Dattwyler RJ, Nadelman RB,
Halperin JJ, Klempner MS, Krause PJ, Dumler JS, Bakken JS, et al). A critical appraisal
of "chronic Lyme disease".N Engl J Med. 2007 Oct 4;357(14):1422-30.
ξ
7 of the previous 32 articles documenting, despite even
aggressive antibiotic therapy, persistence of B. burgdorferi in
chronic Lyme patients by live culture, histopathology, PCR
and specific immune complexes were written by authors of
the IDSA and NEJM papers referenced above
Treatment Failure—Intracellular B. burgdorferi
ξ
“Lyme disease lacks characteristics of other
infections that justify longer treatment courses, such
as infections…caused by an intracellular pathogen”
ξ
Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner
MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler
JS, Nadelman RB. The clinical assessment, treatment, and prevention of lyme
disease, human granulocytic anaplasmosis, and babesiosis: clinical practice
guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006 Nov
1;43(9):1089-134. Epub 2006 Oct 2.
ξ
“there is no evidence that the organism may be
sheltered from antibiotics during an intracellular
phase”
ξ
Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser GP;
Ad Hoc International Lyme Disease Group (Bockenstedt LK, Dattwyler RJ,
Nadelman RB, Halperin JJ, Klempner MS, Krause PJ, Dumler JS, Bakken JS,
et al). A critical appraisal of "chronic Lyme disease".N Engl J Med. 2007 Oct
4;357(14):1422-30.
Treatment Failure—Intracellular B. burgdorferi
ξ
ξ
ξ
ξ
ξ
Ma Y, Sturrock A, Weis JJ. Intracellular localization of Borrelia burgdorferi within
human endothelial cells. Infect Immun 1991 Feb;59(2):671-8.
Dorward DW, Fischer ER, Brooks DM. Invasion and cytopathic killing of human
lymphocytes by spirochetes causing Lyme disease. Clin Infect Dis 1997 Jul;25
Suppl 1:S2-8.
Montgomery RR, Nathanson MH, Malawista SE. The fate of Borrelia
burgdorferi, the agent for Lyme disease, in mouse macrophages. Destruction,
survival, recovery. J Immunol 1993 Feb 1;150(3):909-15.
Aberer E; Kersten A; Klade H; Poitschek C; Jurecka W. Heterogeneity of
Borrelia burgdorferi in the skin. American Journal of Dermatopathology,
1996;18(6):571-9.
Girschick HJ, Huppertz HI, Russmann H, Krenn V, Karch H. Intracellular
persistence of Borrelia burgdorferi in human synovial cells. Rheumatol Int
1996;16(3):125-32.
ξ
“In these experiments, we demonstrated that fibroblasts and
keratinocytes were able to protect B. burgdorferi from the
action of this B-lactam antibiotic [ceftriaxone] even at
antibiotic concentrations > or = 10 times the MBC of the
antibiotic.”
ξ
Klempner MS, Noring R, Rogers RA. Invasion of human skin fibroblasts by the
Lyme disease spirochete, Borrelia burgdorferi. J Infect Dis 1993 May;167(5):107481.
In Their Own Words
ξ
“… failure of treatment for bacterial
infections…resistance to antibiotics … impaired
host-defense mechanisms. None of these factors are
generally applicable to infection with B.
burgdorferi.”
ξ
Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser GP;
Ad Hoc International Lyme Disease Group. A critical appraisal of "chronic Lyme
disease".N Engl J Med. 2007 Oct 4;357(14):1422-30.
ξ
Documented immunosuppression due to
B. burgdorferi
ξ
Hartiala P, Hytönen J, Suhonen J, Leppäranta O, Tuominen-Gustafsson H,
Viljanen MK. Borrelia burgdorferi inhibits human neutrophil functions. Microbes
Infect. 2008 Jan;10(1):60-8. Epub 2007 Oct 18.
Diterich I, Rauter C, Kirschning CJ, Hartung T. Borrelia burgdorferi-induced
tolerance as a model of persistence via immunosuppression. Infect Immun. 2003
Jul;71(7):3979-87.
ξ
B. Burgdorferi-Antibiotic Resistance
ξ
Erythromycin
ξ “resistance is increased by pre-exposure to the antibiotic”
ξ
Terekhova D, Sartakova ML, Wormser GP, Schwartz I, Cabello FC.
Erythromycin resistance in Borrelia burgdorferi. Antimicrob Agents Chemother.
2002 Nov;46(11):3637-40
ξ
Amoxicillin, Doxycycline, & Cefuroxime
ξ 10% of isolates cefuroxime resistant without pre-exposure
ξ Pre-exposure to amoxicillin, cefuroxime & doxycycline
increased resistance
ξ
Ruzić-Sabljić E, Podreka T, Maraspin V, Strle F. Susceptibility of Borrelia afzelii
strains to antimicrobial agents. Int J Antimicrob Agents. 2005 Jun;25(6):474-8.
ξ
Pre-exposure to erythromycin, cefoxitin and
tetracycline caused resistance to those drugs and drugs
of the same family
ξ
Santino I, Scazzocchio F, Ciceroni L, Ciarrocchi S, Sessa R, Del Piano M. In
vitro susceptibility of isolates of Borrelia burgdorferi s.l. to antimicrobial agents. Int J
Immunopathol Pharmacol. 2006 Jul-Sep;19(3):545-9.
B. Burgdorferi-Antibiotic Resistance
ξ
Macrolide-Lincosamide-Streptogramin A (MLS(A))
ξ
Jackson CR, Boylan JA, Frye JG, Gherardini FC. Evidence of a conjugal
erythromycin resistance element in the Lyme disease spirochete Borrelia
burgdorferi. Int J Antimicrob Agents. 2007 Sep 28; [Epub ahead of print]
ξ
Fluoroquinolones
ξ
Galbraith KM, Ng AC, Eggers BJ, Kuchel CR, Eggers CH, Samuels DS.
ParC mutations in fluoroquinolone-resistant Borrelia burgdorferi.
Antimicrob Agents Chemother. 2005 Oct;49(10):4354-7.
ξ
Aminoglycosides & Spectinomycin
ξ
Criswell D, Tobiason VL, Lodmell JS, Samuels DS. Mutations conferring
aminoglycoside and spectinomycin resistance in Borrelia burgdorferi.
Antimicrob Agents Chemother. 2006 Feb;50(2):445-52.
ξ
Penicillin G—clinical case
ξ
Diringer MN, Halperin JJ, Dattwyler RJ. Lyme meningoencephalitis:
report of a severe, penicillin-resistant case. Arthritis Rheum. 1987
Jun;30(6):705-8.
Additional Persistence Mechanisms
ξ
“The extracellular matrix appears to provide a protective
niche for the spirochete.”
ξ
Cabello FC, Godfrey HP, Newman SA. Hidden in plain sight:
Borrelia burgdorferi and the extracellular matrix. Trends Microbiol.
2007 Aug;15(8):350-4.
ξ
“borrelial persistence in some EM patients at the site of the
infectious lesion despite antibiotic treatment over a
reasonable time period.”
“Borrelial persistence, however, was not caused by
increasing MICs or minimal borreliacidal concentrations...”
ξ
ξ
Hunfeld KP, Ruzic-Sabljic E, Norris DE, Kraiczy P, Strle F. In
Vitro Susceptibility Testing of Borrelia burgdorferi Sensu Lato
Isolates Cultured from Patients with Erythema Migrans before and
after Antimicrobial Chemotherapy. Antimicrob Agents Chemother.
2005 Apr;49(4):1294-301.
Re-Treatment Studies
Only 3 NIH Funded Controlled Studies
ξ
Klempner MS, Hu LT, Evans J, Schmid CH, Johnson GM,
Trevino RP, Norton D, Levy L, Wall D, McCall J, Kosinski M,
Weinstein A. Two controlled trials of antibiotic treatment in patients
with persistent symptoms and a history of Lyme disease. N Engl J
Med. 2001 Jul 12;345(2):85-92.
ξ
Krupp LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S,
Dattwyler R, Chandler B. Study and treatment of post Lyme disease
(STOP-LD): a randomized double masked clinical trial. Neurology.
2003 Jun 24;60(12):1923-30.
ξ
Fallon BA, Keilp JG, Corbera KM, Petkova E, Britton CB, Dwyer
E, Slavov I, Cheng J, Dobkin J, Nelson DR, Sackeim HA. A
randomized, placebo-controlled trial of repeated IV antibiotic therapy
for Lyme encephalopathy. Neurology. 2007 Oct 10; [Epub ahead of
print]
Krupp: Chronic Lyme Re-Treatment
ξ
ξ
55 chronic Lyme patients were randomized to
received 4 weeks ceftriaxone vs placebo
ξ Targeted Clinical Outcomes:
ξ Improvements in Fatigue & Cognitive Abilities
ξ Fatigue improved.
ξ 64% of ceftriaxone group vs 18.5% of placebo group.
ξ Cognition did not improve.
ξ “although the patients with Lyme disease showed
cognitive slowing compared to healthy controls, these
deficits were relatively mild, which may have contributed
to the lack of a treatment effect on cognition.”
Selection Bias:
ξ 42.9% of ceftriaxone treated patients had already failed a
mean of 6.3 weeks of prior ceftriaxone
Krupp: Chronic Lyme Re-Treatment
ξ
Ceftriaxone patients more often guessed their treatment
assignment.
ξ “placebo effect may explain the greater improvement”
ξ Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser
GP; Ad Hoc International Lyme Disease Group A critical appraisal of
"chronic Lyme disease".N Engl J Med. 2007 Oct 4;357(14):1422-30.
ξ
ξ
Evidence for lack of placebo effect:
ξ 80% of seropositives improved vs 13% of seronegatives
ξ Seropositive patients are not better at guessing treatment
assignment, but they have been shown to respond better
to treatment of active Lyme by Luft et al. (see slide #7)
ξ “Subgroup analyses suggest that patients who had only
received oral antibiotic therapy in the past were more
likely to experience improvement”
Subgroup analyses further support that there was selection
bias inherent to treatment of patients with ceftriaxone who
have already failed ceftriaxone.
Fallon: Chronic Lyme Re-Treatment
ξ
ξ
ξ
ξ
37 chronic Lyme patients were randomized to received 10
weeks ceftriaxone vs placebo.
There were 20 healthy controls.
ξ Patients had met CDC surveillance case criteria.
ξ Cognitive testing revealed deficits across all domains
with a marked difference in memory between chronic
Lyme patients and healthy controls.
Results at 12 week assessment:
ξ Ceftriaxone group had improvements in target clinical
outcomes, ie cognitive improvements, fatigue, body pain.
ξ Placebo group did not demonstrate improvements.
Results at 24 week assessment:
ξ Improvements persisted for fatigue and body pain, but
cognitive abnormalities recurred since having
discontinued antibiotics
Fallon: Chronic Lyme Re-Treatment
ξ
ξ
Selection bias:
ξ Patients had been ill for a mean of 1.7 years before the
diagnosis was made.
ξ Patients had been ill for a mean of 9 years total.
ξ Patients had previously been treated with a mean of 2.5
months of IV antibiotics
Despite selection bias:
ξ Improvements in cognition, fatigue, and body pain.
ξ Fallon study further supports the benefits seen in the
Krupp study and indicates that further benefits can be
achieved with longer term antibiotic therapy
Klempner: Chronic Lyme Re-Treatment
ξ
ξ
ξ
ξ
129 chronic Lyme patients-4 wks ceftriaxone then 2 months
doxycycline vs placebo
Study terminated early due to interim analysis indicating a likelihood
of no benefit to re-treatment with this regimen in this sub-population
Study deemed not generalizable due to selection bias.
ξ Patients had previously failed an average of 3 courses of abx
ξ 33% of the patients had failed previous IV abx for 30 days.
ξ Patients had been ill for an average of 4.7 years
Cameron DJ. Generalizability in two clinical trials of Lyme disease.
Epidemiol Perspect Innov. 2006 Oct 17;3:12.
ξ
Study criticized due to flaws in design.
ξ
Bransfield R, Brand S, Sherr V. Treatment of patients with
persistent symptoms and a history of Lyme disease. N Engl J Med.
2001 Nov 8;345(19):1424-5.
Donta ST. Treatment of patients with persistent symptoms and a
history of Lyme disease. N Engl J Med. 2001 Nov 8;345(19):1424.
McCaulley ME. Treatment of patients with persistent symptoms and
ξ
ξ
Re-Treatment Studies—Adverse Events
ξ
Krupp study
ξ 1 out of the 28 (3.5%) ceftriaxone treated patients had a serious
adverse event (anaphylaxis)
ξ
Klempner study
ξ 2 out of the 64 (3.1%) ceftriaxone treated patients had a serious
adverse event (pulmonary embolus in one and fever, anemia,
and GI bleed in the other)
ξ
Fallon study
ξ 6 out of the 23 (26.1%) ceftriaxone treated patients had an
adverse event (2 with DVT, 3 with allergy, 1 with cholecystitis
resulting in cholecystectomy)
ξ 4/23 (17.4%) in ceftriaxone group had a serious adverse event*
ξ *In the text, it was not specified if the allergies were mild or
serious, but based on personal communication with Dr. Fallon, 2
were mild, 1 was serious (allergy with FUO). Even the nonserious allergies were significant however in that they prompted
removal from study
ξ Clearly, a prudent risk benefit analysis must be made.
Adverse Events—Suggested Research
Primary and Secondary Prevention
ξ
ξ
ξ
ξ
ξ
Could some of the adverse events associated with IV
ceftriaxone in the Fallon, Krupp, and Klempner studies be
minimized by performing the following?
A baseline coagulopathy work up;
A baseline abdominal sonogram, and a screening abdominal
sonogram every 3 weeks of therapy;
A sonogram of the upper extremity to rule out IV line
induced DVT at 7 days of therapy and every 3 weeks
thereafter;
Weekly CBC with diff, ESR, CRP, and CMP
Risk vs. Benefit—Putting Things in Perspective
Antibiotics Are Far Safer than Many Medications
ξ
Lymphoma due to infliximab (Remicade)
ξ
Mackey AC, Green L, Liang LC, Dinndorf P, Avigan M. Hepatosplenic T cell
lymphoma associated with infliximab use in young patients treated for inflammatory
bowel disease. J Pediatr Gastroenterol Nutr. 2007 Feb;44(2):265-7.
ξ
Tuberculosis due to infliximab (Remicade)
ξ
Raychaudhuri S, Shmerling R, Ermann J, Helfgott S. Development of active
tuberculosis following initiation of infliximab despite appropriate prophylaxis.
Rheumatology (Oxford). 2007 May;46(5):887-8.
ξ
Death due to infliximab (Remicade)
ξ
de' Clari F, Salani I, Safwan E, Giannacco A. Sudden death in a patient without heart
failure after a single infusion of 200 mg infliximab: does TNF-alpha have protective effects
on the failing heart, or does infliximab have direct harmful cardiovascular effects?
Circulation. 2002 May 28;105(21):E183.
ξ
99.7% relapse rate upon discontinuation of infliximab
(Remicade) after 3 years of continuous use by IV infusion
ξ
Baraliakos X, Listing J, Brandt J, Zink A, Alten R, Burmester G, GromnicaIhle E, Kellner H, Schneider M, Sörensen H, Zeidler H, Rudwaleit M, Sieper J,
Braun J. Clinical response to discontinuation of anti-TNF therapy in patients with
ankylosing spondylitis after 3 years of continuous treatment with infliximab.
Arthritis Res Ther. 2005;7(3):R439-44.
Consequences of Withholding Antibiotic Treatment
ξ
ξ
Randomized retrospective case controlled study
100 patients: 24 treatment failures, 76 treatment successes
ξ Treatment delay results in treatment failure
ξ Steroid treatment results in treatment failure
ξ Retrospective design ethically required—cannot
purposefully withhold treatment
ξ
Cameron DJ. Consequences of treatment delay in Lyme disease. J
Eval Clin Pract. 2007 Jun;13(3):470-2.
ξ
“Antibiotic treatment resulted in transient improvement, but
the patient relapsed after the antibiotics were discontinued.”
Consequences of antibiotic discontinuation: Death.
“…prolonged antibiotic therapy may be necessary.”
ξ
ξ
ξ
Waniek C, Prohovnik I, Kaufman MA, Dwork AJ. Rapidly
progressive frontal-type dementia associated with Lyme disease. J
Neuropsychiatry Clin Neurosci 1995 Summer;7(3):345-7.
Chronic Lyme Disease—Brain Tissue
How Do We Define “Adequate” Treatment?
ξ
Case #1-Lyme fatality
ξ Brain lesions; Multiple CNS symptoms; Seronegative in
serum and CSF; CSF cultured B. burgdorferi;
ξ Treated with ceftriaxone and then doxycycline for 8
months with relapse while still on oral antibiotics;
ξ Despite treatment, plasma & bone marrow PCR positive;
ξ Intravenous ceftriaxone re-started;
ξ Patient died of Lyme despite 10 months of antibiotics;
ξ Autopsy of Brain tissue: B. burgdorferi PCR positive.
ξ
Oksi J, Kalimo H, Marttila RJ, Marjamaki M, Sonninen P,
Nikoskelainen J, Viljanen MK. Inflammatory brain changes in Lyme
borreliosis. A report on three patients and review of literature. Brain
1996 Dec; 119 ( Pt 6): 2143-54.
Chronic Lyme Disease—BrainTissue
Success Only After Extremely Aggressive Antibiotics
ξ
Case #2-Lyme, success only after aggressive treatment
ξ Brain lesions; Multiple CNS symptoms; Serologies-IgM pos,
IgG neg (first pre-treatment sample only, thereafter both neg);
ξ CSF Ab Neg, CSF PCR Neg; Brain biopsy PCR Pos;
ξ Ceftriaxone x 3 wks, then amox/prob x 3 wks; New brain
lesion, CSF PCR neg;
ξ Ceftriaxone x 4 wks with azithro & rifampin x 3 wks;
ξ 3 new brain lesions; cefixime/prob x 100 days;
ξ Lesions getting smaller & no new ones; stopped antibiotics;
ξ 6 mos later, new brain lesion; CSF PCR neg.; doxy 150mg tid x
4 months;
ξ Off abx x 4 months; New brain lesions; Plasma PCR positive;
ξ Ceftriaxone x 100 days; All lesions resolved. Plasma PCR neg
x 3. End of tx.
ξ
Oksi J, Kalimo H, Marttila RJ, Marjamaki M, Sonninen P, Nikoskelainen J, Viljanen
MK. Inflammatory brain changes in Lyme borreliosis. A report on three patients and review
of literature. Brain 1996 Dec; 119 ( Pt 6): 2143-54.
Treatment Studies—Late Lyme
Large Study-Short vs. Long Term Antibiotics
ξ
100 patients with late Lyme were treated as follows:
Treatment
Ceftriaxone-14 days single agent
Ceftriaxone-14 days+Amox/Proben 100 days
Ceftriaxone-14 days+cephadroxil 100 days
Success
30.7%
89.3%
82.6%
ξ
“Short periods of treatment were not generally
effective.”
ξ
Wahlberg P, Granlund H, Nyman D, Panelius J, Seppälä I.
Treatment of late Lyme borreliosis. J Infect. 1994 Nov;29(3):255-61.
Treatment Studies:
Mixed Population of Disseminated Lyme
ξ
ξ
ξ
152 patients received 3 weeks of ceftriaxone followed by either
100 days of amoxicillin or placebo
Did not find adjunctive amoxicillin to be beneficial
“The number of enrolled patients did not reach the target to
have sufficient power to make a definite conclusion about
the lack of efficacy of the adjunctive treatment.”
ξ Outcome measures were clinical impression—Not as well
standardized as SF-36, or cognitive testing,
ξ Not a chronic Lyme population—Characteristics of a mixed
population are different
ξ
“No serious adverse effects of antibiotic treatment(s)
occurred in any of the 145 patients.”
ξ
Oksi J, Nikoskelainen J, Hiekkanen H, Lauhio A, Peltomaa M, Pitkäranta A, Nyman D,
Granlund H, Carlsson SA, Seppälä I, Valtonen V, Viljanen M. Duration of antibiotic
treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled,
multicenter clinical study. Eur J Clin Microbiol Infect Dis. 2007 Aug;26(8):571-81.
Treatment Studies—Lyme Arthritis
ξ
ξ
ξ
7 prospectively studied patients:
ξ Responses to antibiotics; Relapses off treatment;
ξ Ultimate responses to longer term antibiotic therapy
ξ PCR positives were seen in some patients treated > 4
weeks
“All 38 laboratory controls were negative by PCR.”
“Polymerase chain reaction was done four times with
identical results…”
ξ
Bradley JF, Johnson RC, Goodman JL. The persistence of spirochetal nucleic
acids in active Lyme arthritis. Ann Intern Med. 1994 Mar 15;120(6):487-9
ξ
Repeated courses of antibiotics can be beneficial for Lyme.
A second month can be better than 1 month
A third month can be better than 2 months
Steere AC, Angelis SM. Therapy for Lyme arthritis:
Strategies for the treatment of antibiotic-refractory arthritis.
Arthritis Rheum. 2006;54:3079–3086.
ξ
ξ
ξ
Treatment Studies: Suggested Future Research
Study Drugs Other Than Beta-Lactams
ξ
ξ
Two open label trials have shown progressive benefits over
time in a chronic Lyme sub-population treated with long
term antibiotics that are not beta-lactams.
Long term tetracycline
ξ
Donta ST. Tetracycline therapy for chronic Lyme disease. Clin Infect Dis 1997
Jul;25 Suppl 1:S52-6.
ξ
Long term macrolide with hydroxychloroquine
ξ
Donta ST. Macrolide therapy of chronic Lyme Disease. Med Sci Monit. 2003
Nov;9(11):PI136-42.
ξ
Hydroxychloroquine kills B. burgdorferi cystic forms in vitro
ξ
Brorson O, Brorson SH. An in vitro study of the susceptibility of mobile and cystic
forms of Borrelia burgdorferi to hydroxychloroquine. Int Microbiol. 2002
Mar;5(1):25-31.
B. Burgdorferi Spheroplasts/Cysts: In Vitro
ξ
In regard to B. burgdorferi cyst forms Dr. Feder states:
ξ “there is no evidence that this phenomenon has any
clinical relevance.”
ξ Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere AC, Wormser
GP; Ad Hoc International Lyme Disease Group. A critical appraisal of
"chronic Lyme disease".N Engl J Med. 2007 Oct 4;357(14):1422-30.
ξ
“they may represent a strategy that facilitates the survival of
B. burgdorferi”
ξ
Alban PS; Johnson PW; Nelson DR. Serum-starvation-induced changes in protein
synthesis and morphology of Borrelia burgdorferi. Microbiology Jan 2000;146 (Pt
1):119-27.
ξ
Other authors believe cyst forms to be critical to the
relapsing nature of the disease
ξ
Zajkowska JM; Hermanowska-Szpakowicz T; Pancewicz SA; Kondrusik M.
Selected aspects of immunopathogenesis in Lyme disease. Pol Merkuriusz Lek,
2000 9(50):579-83.
Hermanowska-Szpakowicz T, Zajkowska JM, Pancewicz SA, Kondrusik M,
Grygorczuk SS, Swierzbinska R. Pathogenetic-clinical problems of Lyme
borreliosis Neurol Neurochir Pol. 2003;37 Suppl 2:29-38.
ξ
B. Burgdorferi Spheroplasts/Cysts: In Vitro
ξ
ξ
ξ
ξ
ξ
ξ
ξ
ξ
ξ
Aberer E; Kersten A; Klade H; Poitschek C; Jurecka W. Heterogeneity of Borrelia
burgdorferi in the skin. American Journal of Dermatopathology, 1996;18(6):571-9.
Angelov L; Dimova P; Berbencova W. Clinical and laboratory evidence of the
importance of the tick D. marginatus as a vector of B. burgdorferi in some areas of
sporadic Lyme disease in Bulgaria. European Journal of Epidemiology. 1996;12(5):499502.
Schaller M; Neubert Ultrastructure of Borrelia burgdorferi after exposure to
benzylpenicillin. Infection, 1994 22(6):401-406.
Bruck DK; Talbot ML; Cluss RG; Boothby JT. Ultrastructural characterization of the
stages of spheroplast preparation of Borrelia burgdorferi. J Microbiol. Methods, 1995
(23):219-228.
Mursic VP; Wanner G; Reinhardt S; Wilske B; Busch U; Marget W. Formation and
cultivation of Borrelia burgdorferi spheroplast L-form variants. Infection 1996;
24(3):218-26.
Cluss RG; Goel AS; Rehm HL; Schoenecker JG; Boothby JT. Coordinate synthesis
and turnover of heat shock proteins in Borrelia burgdorferi: degradation of DnaK during
recovery from heat shock. Infection & Immunity, May1996;64(5):1736-43.
Kersten A; Poitschek C; Rauch S; Aberer E. Effects of penicillin, ceftriaxone, and
doxycycline on the morphology of Borrelia burgdorferi. Antimicrobial Agents &
Chemotherapy 1995;39(5):1127-33.
Aberer E; Koszik F; Silberer M. Why is chronic Lyme borreliosis chronic? Clinical
Infectious Diseases, 25 (Suppl 1), 1997 S64-S70.
Benach JL. Functional heterogeneity in the antibodies produced to Borrelia burgdorferi.
Wiener Klinische Wochenschrift, Dec1999;10;111(22-23):985-9.
B. Burgdorferi Spheroplasts/Cysts: In Vivo
ξ
ξ
ξ
ξ
ξ
ξ
Mursic VP; Wanner G; Reinhardt S; Wilske B; Busch U; Marget
W. Formation and cultivation of Borrelia burgdorferi spheroplast Lform variants. Infection 1996; 24(3):218-26.
Phillips SE; Mattman LH; Hulinska D; Moayad H. A proposal for
the reliable culture of Borrelia burgdorferi from patients with chronic
Lyme disease, even from those previously aggressively treated.
Infection 1998; 26(6):364-7.
Hulinska D; Jirous J; Valesova M; Hercogova J. Ultrastructure of
Borrelia burgdorferi in tissues of patients with Lyme disease. J Basic
Microbiol, 1989 29:73-83.
MacDonald AB. Concurrent neocortical borreliosis and Alzheimer's
disease: Demonstration of a spirochetal cyst form. Annals of the New
York Academy of Sciences, 1988 539:468-470.
Mursic VP; Wanner G; Reinhardt S; Wilske B; Busch U; Marget
W. Formation and cultivation of Borrelia burgdorferi spheroplast Lform variants. Infection 1996; 24(3):218-26.
Hulinska D; Bartak P; Hercogova J; Hancil J; Basta J;
Schramlova J. Electron microscopy of Langerhans cells and Borrelia
burgdorferi in Lyme disease patients. Zbl Bakt 1994;280:348-349.
Legend for Evidence Based Recommendations
ξ
ξ
ξ
Recommendations are based on two criteria:
The strength of the evidence (denoted by categories A–E)
The quality of the data (denoted by Roman numerals I–III)
Criteria
Support of Recommendations
Recommendations rated ‘A’
Recommendations rated ‘B’
Recommendations rated ‘C’
Recommendations rated ‘D’
Recommendations rated ‘E’
Rating of I
Good evidence to support
Moderate evidence to support
Considered optional
Generally should not be offered
Contraindicated
At least one randomized
controlled trial
At least one well-designed
non-randomized clinical trial
Expert opinion
Rating of II
Rating of III
Evidence Based Recommendations
Recommendations
Seronegativity Common in
Active Lyme Patients Even
After 8 weeks of Illness
Evidence Based Rating
A-1 (Luft) & A-2 (Too
numerous to Annotate)
Chronic Lyme Responds to
Antibiotic Re-treatment
A-1 (Krupp & Fallon) & A-2
(Too numerous to annotate)
Chronic Lyme Disease is
Due to Persistent Infection
Antecedent EM in Small
Minority of Late Lyme
A-2 (Too numerous to
annotate)
A-2 (Qureshi)
Only Non-Specific Symptoms
Common in Active Late Lyme
A-2 (Too numerous to
annotate)
CT Attorney General Investigates IDSA
Investigation Begun
ξ
“The attorney general of Connecticut has
begun an unprecedented antitrust investigation
of the Infectious Diseases Society of
America…”
ξ
Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED,
Steere AC, Wormser GP; Ad Hoc International Lyme
Disease Group. A critical appraisal of "chronic Lyme
disease".N Engl J Med. 2007 Oct 4;357(14):1422-30.
CT Attorney General Investigates IDSA
Investigation Complete
ξ
ξ
ξ
ξ
ξ
ξ
GENERAL RESULTS
“Attorney General's Investigation Reveals Flawed Lyme
Disease Guideline Process, IDSA Agrees To Reassess
Guidelines, Install Independent Arbiter”
OFFICIAL DETAILED FINDINGS
“The IDSA failed to conduct a conflicts of interest review
for any of the panelists prior to their appointment to the
2006 Lyme disease guideline panel;”
“Subsequent disclosures demonstrate that several of the
2006 Lyme disease panelists had conflicts of interest;”
Official Findings from the CT Attorney General
Investigation of the IDSA, released 5/1/08
CT Attorney General Investigates IDSA
Investigation Complete
ξ
ξ
ξ
ξ
OFFICIAL DETAILED FINDINGS
“The IDSA failed to follow its own procedures for
appointing the 2006 panel chairman and members, enabling
the chairman, who held a bias regarding the existence of
chronic Lyme, to handpick a likeminded panel without
scrutiny by or formal approval of the IDSA's oversight
committee;”
“The IDSA's 2000 and 2006 Lyme disease panels refused to
accept or meaningfully consider information regarding the
existence of chronic Lyme disease, once removing a panelist
from the 2000 panel who dissented from the group's
position on chronic Lyme disease to achieve "consensus";”
Official Findings from the CT Attorney General
Investigation of the IDSA, released 5/1/08
CT Attorney General Investigates IDSA
Investigation Complete
ξ
ξ
ξ
ξ
OFFICIAL DETAILED FINDINGS
“The IDSA blocked appointment of scientists and
physicians with divergent views on chronic Lyme who
sought to serve on the 2006 guidelines panel by informing
them that the panel was fully staffed, even though it was
later expanded;”
“The IDSA portrayed another medical association's Lyme
disease guidelines as corroborating its own when it knew
that the two panels shared several authors, including the
chairmen of both groups, and were working on guidelines at
the same time. In allowing its panelists to serve on both
groups at the same time, IDSA violated its own conflicts of
interest policy.”
Official Findings from the CT Attorney General
Investigation of the IDSA, released 5/1/08
IDSA—Independent Corroboration? Same Authors
ξ
ξ
ξ
ξ
ξ
IDSA Guidelines Authors
Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere
AC, Klempner MS, Krause PJ, Bakken JS, Strle F, Stanek
G, Bockenstedt L, Fish D, Dumler JS, Nadelman RB.
Feder HM Jr, Johnson BJ, O'Connell S, Shapiro ED, Steere
AC, Wormser GP; Ad Hoc International Lyme Disease
Group (Bockenstedt LK, Dattwyler RJ, Nadelman RB,
Halperin JJ, Klempner MS, Krause PJ, Dumler JS, Bakken
JS, et al).
American Academy of Neurology Authors
Halperin JJ, Shapiro ED, Logigian E, Belman AL, Dotevall
L, Wormser GP, Krupp L, Gronseth G, Bever CT Jr
Chronic Lyme Disease—The Standard of Care
Clinical Experience, or Lack Thereof
Year
2005
2004
2003
2002
ξ
ξ
ξ
ξ
Reported Number of Lyme Cases By
Westchester Medical Center
19
14
30
13
Source: Westchester County Department of Health, Division of Disease Control.
http://www.westchestergov.com/health/statistics.htm
ILADS physicians have extensive clinical experience in
successfully treating chronic Lyme patients with long term
antibiotics.
How can academic physicians dictate the standard of care when
their clinical experience is less than that of treating physicians?
Chronic Lyme Disease—The Standard of Care
ξ
“For chronic Lyme disease, 57% of responders treat
3 months or more.”
ξ
Ziska MH, Donta ST, Demarest FC. Physician preferences in the
diagnosis and treatment of Lyme disease in the United States.
Infection 1996 Mar-Apr;24(2):182-6.
ξ
Two equally legitimate but divergent standards of
care currently exist for the diagnosis and treatment
of Lyme disease.
ξ
Johnson L, Stricker RB. Treatment of Lyme disease: a medicolegal
assessment. Expert Rev Anti Infect Ther. 2004 Aug;2(4):533-57.
For More Information Visit
ξ
ILADS.ORG