Seronegative Borreliosis

The diagnostic accuracy of serological tests for Lyme borreliosis in Europe: a systematic review and meta-analysis

M. M. G. LeeflangC. W. AngJ. BerkhoutH. A. BijlmerW. Van BortelA. H. BrandenburgN. D. Van BurgelA. P. Van Dam,

R. B. DessauV. FingerleJ. W. R. HoviusB. JaulhacB. MeijerW. Van PeltJ. F. P. SchellekensR. SpijkerF. F. StelmaG. Stanek, F. Verduyn-LunelH. Zeller and H. Sprong 

BMC Infectious DiseasesBMC series – open, inclusive and trusted201616:140 DOI: 10.1186/s12879-016-1468-4 ©  Leeflang et al. 2016

 

 

Detection of Borrelia burgdorferi-specific antigen in antibody-negative cerebrospinal fluid in neurologic Lyme disease.

Coyle PK, Schutzer SE, Deng Z, Krupp LB, Belman AL, Benach JL, Luft BJ.

Neurology.1995 Nov;45(11):2010-5.

 

Isolation of live Borrelia burgdorferi sensu lato spirochetes from patients with undefined disorders and symptoms not typical for Lyme borreliosis

N. Rudenko, M. Golovchenko, M. Vancova, K. Clark, L. Grubhoffer, H. Oliver Jr.

 
Over 100 Articles on seronegativity and persistent infection of Borrelia 
Diagnosis: Laboratory Testing
False Seronegativity Extensively Documented
41 Patients with late Lyme disease confirmed by Positive Culture or Positive PCR
54% had been sick for more than 1 year
63.5% had a negative or borderline ELISA.
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.
– 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
Only 50% of patients with late Lyme frankly seropositive.
Late-phase ocular Lyme borreliosis is probably underdiagnosed because of weak seropositivity or seronegativity in ELISA assays.
-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.
240 hospitalized patients with diagnoses c/w late Lyme
32/240 (13.3 %) PCR positive
18/32 (56.3%) were seronegative.
-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.
…a patient with active Lyme disease may have a negative test result…
-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.
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
-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
-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.
– 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.
Seronegative Patients Worse Off
– 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.‖
-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.
Serologic status & PCR status inversely correlated
– 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.
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
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.
Lyme borreliosis patients who have live spirochetes in body fluids have low or negative levels of borrelial antibodies in their sera
-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
False Seronegativity Extensively Documented
– 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.
– 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.
…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.
Greater than 70% of patients with chronic Lyme disease were seronegative by CDC criteria
– Donta ST. Tetracycline therapy for chronic Lyme disease. Clin Infect Dis 1997 Jul;25 Suppl 1:S52-6.
– 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):552-5.
– 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.
Steere AC. Seronegative Lyme disease. JAMA. 1993 Sep 15;270(11):1369.
– 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.
– 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.
– 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.
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.
-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.
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 in red .
False Negative CSF (& Seronegative Also)
Of 35 patients with specific Lyme Antigen (Osp A) in CSF:
15 (43%) were antibody-negative in CSF.
Seven of these 15 (47%) had otherwise normal routine CSF analyses.
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):2010-5.
CSF False Negative Antibodies
…local antibody production in CSF is an inconsistent finding in American patients with late neurologic manifestations of the disorder.
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.
39%-54% of patients with late neurologic Lyme were antibody negative in CSF
– 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.
– 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.
– 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.
– 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.
– 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.
– 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.
– 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.
CSF PCR—Useful or Not?
In children with known Lyme meningitis, Lyme CSF-PCR had a sensitivity of 5% and a specificity of 99%
– 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.
Nested CSF PCR sensitivity in known Lyme neuroborreliosis was 35%.
– 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.
CDC Case Definition is Not for Diagnosis
CDC Surveillance Case Definition
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.
http://www.cdc.gov/ncphi/disss/nndss/casedef/lyme_disease_2008.htm
Cases reported to CDC are estimated to be 10 times less than the actual number of Lyme cases
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.
Early Lyme:
Objective Findings Poor-Subjective Findings Rich 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.
Objective Findings Subjective Symptoms
EM as Entry Criteria
No A-V Block
No Meningitis
No Cranial Neuritis
No encephalomyelitis
Joint swelling in 10.8%
Fatigue 56.8%
Myalgias 43.2%
Headache 39.2%
Chills 35.1%
Joint pain 35.1%
(without swelling)
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
18 patients with documented persistent infection by immuno-electron microscopy and PCR
50% had only non-specific subjective symptoms, nothing objective.
39% were seronegative initially
67% were seronegative on repeat testing.
50% had completely negative CSF for Lyme antibodies, chemistries, and cell count
– 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
120 Lyme patients evaluated vague, non-specific dental, facial or head pain, who present with a multisystemic, multi-treatment history, are suspect.
– 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.
… 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.
– 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.
27 Chronic Lyme patients evaluated
56% of the total had Brain lesions on MRI.
– 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
…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.
Patient #1: Severe weight loss and chronic headaches
Patient #2: Seizures and failure to thrive.
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
Short term antibiotics fail in 25%-71% of patients with late stage disease.
-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.
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.
– Dvorakova J, Celer V. [Pharmacological aspects of Lyme borreliosis]Ceska Slov
Farm. 2004 Jul;53(4):159-64.
– Kaiser R. Clinical courses of acute and chronic neuroborreliosis following treatment with ceftriaxone.Nervenarzt.2004 Jun;75(6):553-7.
– 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.
– 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.
– 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
mild and self-limiting subjective symptoms common, and some occur in more than 10% of the general population
– 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.
Base-line assessments documented severe impairment in the patients’ health-related quality of life
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.
marked levels of fatigue, pain, and impaired physical functioning. (which was NOT entry criteria for the study)
pain similar to post-surgery patients; fatigue similar multiple sclerosis patients; functional limitations comparable to CHF patients
– 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]
Animal Data Persistent Infection Despite ABX
Infected dogs received amoxicillin; azithromycin; ceftriaxone; or doxycycline for 30 days
PCR positvity despite antibiotic treatment
Corticosteroid treatment reactivated subclinical Lyme2
– 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.
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.
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.
Mice were divided into 2 groups by stage of infection:
Early disease–3 weeks duration & Late disease–4 months duration
All mice were treated with 30 days ceftriaxone, then examined for persistent infection at 1 and 3 months later.
Methods of examination were Culture, PCR, and Pathology as well as: 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.
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
– 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.
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 Not Done Neg 1/3(33%) Neg
Late infection
1 month p-tx. 3/8(38%) 1/8 Not Done 8/8(100%) 3/8(38%) Neg
Late infection
3 month p-tx. 1/5(20%) 2/5(40%) 2/5(40%) 1/5 (20%)
8/9 (89%) of SCID mice exposed to xenodiagnosis positive ticks became infected with B. burgdorferi, by either culture or PCR
– 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
30% Remained PCR Positive Despite Multiple Courses of ―Adequate Antibiotic Therapy
– 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.
….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.”
– 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.
74% Remained PCR Positive Despite Extended Antibiotic Therapy
– 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.
165 Lyme patients treated for at least 3 months
32 (19.4%) relapsed despite therapy
38% of relapsers were culture or PCR positive
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.
Retrospective cohort study: 38 patients, 43 controls
10/38 (26.3%) relapsed within 1 year of treatment
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 CSF Lyme antibody negative 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.
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 poly -merase 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.2001Feb;144(2):387-92.
Erythema migrans–Histopathology and PCR positive despite long term antibiotics
-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.
Erythema migrans–Culture positive oral antibiotic failure
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.
Skin–Culture positive despite repeated antibiotic treatments
-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. 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.
-Lawrence C, Lipton RB, Lowy FD, Coyle PK Seronegative chronic relapsing neuroborreliosis. Eur. Neurol. 1995;35(2):113-7.
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.
– Battafarano DF, Combs JA, Enzenauer RJ, Fitzpatrick JE. Chronic septic arthritis caused by Borrelia burgdorferi. Clin Orthop 1993 Dec(297): 238-41.
– 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
30% of Lyme patients who fail a short course of antibiotics meet diagnostic criteria for fibromyalgia.
– Bujak DI, Weinstein A, Dornbush RL. Clinical and neurocognitive features of the post Lyme syndrome. J Rheumatol. 1996 Aug;23(8):1392-7.
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 Disease
Verified Persistence of Infection Despite Antibiotics
– 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.
– 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.
– 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.
– 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.
– 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.
– 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.
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.
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
– 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.
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.‖
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):1074- 81.
Documented immunosuppression due to B. burgdorferi
– 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.
B. Burgdorferi-Antibiotic Resistance
Erythromycin
resistance is increased by pre-exposure to the antibiotic
– Terekhova D, Sartakova ML, Wormser GP, Schwartz I, Cabello FC. Erythromycin resistance in Borrelia burgdorferi. Antimicrob Agents Chemother. 2002 Nov;46(11):3637-40
Amoxicillin, Doxycycline, & Cefuroxime
10% of isolates cefuroxime resistant without pre-exposure
Pre-exposure to amoxicillin, cefuroxime & doxycycline increased resistance
– 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.
Pre-exposure to erythromycin, cefoxitin and tetracycline caused resistance to those drugs and drugs of the same family
– 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.
Macrolide-Lincosamide-Streptogramin A (MLS(A))
– 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]
Fluoroquinolones
– 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.
Aminoglycosides & Spectinomycin
– 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.
Penicillin G—clinical case
-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
The extracellular matrix appears to provide a protective niche for the spirochete.
– Cabello FC, Godfrey HP, Newman SA. Hidden in plain sight: Borrelia burgdorferi and the extracellular matrix. Trends Microbiol. 2007 Aug;15(8):350-4.
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…
– 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
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.
– 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.
– 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
55 chronic Lyme patients were randomized to received 4 weeks ceftriaxone vs placebo
Targeted Clinical Outcomes:
Improvements in Fatigue & Cognitive Abilities
Fatigue improved.
64% of ceftriaxone group vs 18.5% of placebo group.
Cognition did not improve.
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:
42.9% of ceftriaxone treated patients had already failed a mean of 6.3 weeks of prior ceftriaxone
-Krupp: Chronic Lyme Re-Treatment
Ceftriaxone patients more often guessed their treatment assignment.
placebo effect may explain the greater improvement
– 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.
Evidence for lack of placebo effect:
80% of seropositives improved vs 13% of seronegatives
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.
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
37 chronic Lyme patients were randomized to received 10 weeks ceftriaxone vs placebo.
There were 20 healthy controls.
Patients had met CDC surveillance case criteria.
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:
Ceftriaxone group had improvements in target clinical outcomes, ie cognitive improvements, fatigue, body pain.
Placebo group did not demonstrate improvements.
Results at 24 week assessment:
Improvements persisted for fatigue and body pain, but cognitive abnormalities recurred since having discontinued antibiotics
Fallon: Chronic Lyme Re-Treatment
Selection bias:
Patients had been ill for a mean of 1.7 years before the diagnosis was made.
Patients had been ill for a mean of 9 years total.
Patients had previously been treated with a mean of 2.5 months of IV antibiotics
Despite selection bias:
Improvements in cognition, fatigue, and body pain.
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
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.
Patients had previously failed an average of 3 courses of abx
33% of the patients had failed previous IV abx for 30 days.
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.
Study criticized due to flaws in design.
– 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 a history of Lyme disease. N Engl J Med. 2001 Nov 8;345(19):1424
Re-Treatment Studies—Adverse Events
– Krupp study
1 out of the 28 (3.5%) ceftriaxone treated patients had a serious adverse event (anaphylaxis)
– Klempner study
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)
– Fallon study
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)
4/23 (17.4%) in ceftriaxone group had a serious adverse event*
*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
Clearly, a prudent risk benefit analysis must be made
Adverse Events—Suggested Research
Primary and Secondary Prevention
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
Lymphoma due to infliximab (Remicade)
– 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.
– Tuberculosis due to infliximab (Remicade)
– 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.
– Death due to infliximab (Remicade)
– 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.
99.7% relapse rate upon discontinuation of infliximab (Remicade) after 3 years of continuous use by IV infusion
– 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
Randomized retrospective case controlled study
100 patients: 24 treatment failures, 76 treatment successes
Treatment delay results in treatment failure
Steroid treatment results in treatment failure
Retrospective design ethically required—cannot purposefully withhold treatment
– Cameron DJ. Consequences of treatment delay in Lyme disease. J Eval Clin Pract. 2007 Jun;13(3):470-2.
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.
– 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?
Case #1-Lyme fatality
Brain lesions; Multiple CNS symptoms; Seronegative in serum and CSF; CSF cultured B. burgdorferi;
Treated with ceftriaxone and then doxycycline for 8 months with relapse while still on oral antibiotics;
Despite treatment, plasma & bone marrow PCR positive;
Intravenous ceftriaxone re-started;
Patient died of Lyme despite 10 months of antibiotics;
Autopsy of Brain tissue: B. burgdorferi PCR positive.
– 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.
Success Only After Extremely Aggressive Antibiotics
Case #2-Lyme, success only after aggressive treatment
Brain lesions; Multiple CNS symptoms; Serologies-IgM pos, IgG neg (first pre-treatment sample only, thereafter both neg);
CSF Ab Neg, CSF PCR Neg; Brain biopsy PCR Pos;
Ceftriaxone x 3 wks, then amox/prob x 3 wks; New brain lesion, CSF PCR neg;
Ceftriaxone x 4 wks with azithro & rifampin x 3 wks;
3 new brain lesions; cefixime/prob x 100 days;
Lesions getting smaller & no new ones; stopped antibiotics;
6 mos later, new brain lesion; CSF PCR neg.; doxy 150mg tid x 4 months;
Off abx x 4 months; New brain lesions; Plasma PCR positive;
Ceftriaxone x 100 days; All lesions resolved. Plasma PCR neg x 3. End of tx.
– 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
100 patients with late Lyme were treated as follows:
―Short periods of treatment were not generally effective.‖
– Wahlberg P, Granlund H, Nyman D, Panelius J, Seppälä I.
Treatment of late Lyme borreliosis. J Infect. 1994 Nov;29(3):255-61.
Mixed Population of Disseminated Lyme
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.‖
Outcome measures were clinical impression—Not as well standardized as SF-36, or cognitive testing,
Not a chronic Lyme population—Characteristics of a mixed population are different
No serious adverse effects of antibiotic treatment(s) occurred in any of the 145 patients.
– 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
7 prospectively studied patients:
Responses to antibiotics; Relapses off treatment;
Ultimate responses to longer term antibiotic therapy
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…‖
– 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
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.
Treatment Studies: Suggested Future Research
Study Drugs Other Than Beta-Lactams
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
– Donta ST. Tetracycline therapy for chronic Lyme disease. Clin Infect Dis 1997 Jul;25 Suppl 1:S52-6.
Long term macrolide with hydroxychloroquine
– Donta ST. Macrolide therapy of chronic Lyme Disease. Med Sci Monit. 2003 Nov;9(11):PI136-42.
Hydroxychloroquine kills B. burgdorferi cystic forms in vitro
– 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
In regard to B. burgdorferi cyst forms -they may represent a strategy that facilitates the survival of B. burgdorferi
– 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.
Other authors believe cyst forms to be critical to the relapsing nature of the disease
– 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.
B. Burgdorferi Spheroplasts/Cysts: In Vitro
– 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):499- 502.
– 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.
– 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.
Information taken from Dr Steven Phillips slides that he presented to IDSA review