Persistent Lyme disease

Instructor

Elizabeth Maloney, MD
Education Co-Director, Invisible International

Description

The occurrence of persistent manifestations following antibiotic treatment of Lyme disease is well documented in the literature. This module uses a case discussion format to highlight: common ongoing manifestations of Lyme disease, potential pathophysiologic mechanisms for ongoing manifestations, the evaluation of patients who remain symptomatic and consideration of the trial evidence regarding antibiotic retreatment.

Learning objectives

1. Understand that manifestations of Lyme disease can persist following antibiotic therapy
2. Understand the evidence supporting the various proposed pathophysiologic mechanisms of persistent manifestations
3. Understand the general process for evaluating patients with persistent manifestations and selecting appropriate therapy

This session, Persistent Lyme disease, is approved for 1.0 enduring AAFP Prescribed credit.

AAFP Prescribed credit is accepted by the American Medical Association as equivalent to AMA PRA Category 1 credit(s)™ toward the AMA Physician’s Recognition Award. When applying for the AMA PRA, Prescribed credit earned must be reported as Prescribed, not as Category 1.

The AAFP has reviewed One Health Medical Education for a Changing Climate and deemed it acceptable for AAFP credit. Term of approval is from 01/02/2024 to 01/01/2025. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Evidence-based bibliography for further study

• Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med 1990; 323:1438-1444. 

• Maloney EL. Controversies in Persistent (Chronic) Lyme Disease. J Infus Nurs. 2016 Nov/Dec;39(6):369-375. 

• Steere AC, Malawista SE et al. The clinical spectrum and treatment of Lyme disease. Yale J Biol Med 1984; 57(4):453-464. 

• Asch ES, Bujak DI, Weiss M, Peterson MG, Weinstein A. Lyme disease: an infectious and postinfectious syndrome. J Rheumatol 1994;21(3):454-461. 

• Shadick NA, Phillips CB, Logigian EL et al. The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study. Ann Intern Med 1994;121(8):560-567. 

• Aucott JN, Rebman AW, Crowder LA, et al. Post-treatment Lyme disease syndrome symptomatology and the impact on life functioning: is there something here? Qual Life Res. 2013 Feb;22(1):75-84. 

• Cameron D, Johnson L, Maloney e. Evidence Assessments and Guideline Recommendations in Lyme disease: The Clinical Management of Known Tick Bites, Erythema Migrans Rashes and Persistent Disease. Expert Review Anti-infect Ther. 2014 Sep;12(9):1103-1135. doi: 10.1586/14787210.2014.940900. 

• Rebman AW, Bechtold KT, Yang T. The Clinical, Symptom, and Quality-of-Life Characterization of a Well-Defined Group of Patients with Posttreatment Lyme Disease Syndrome. Front Med (Lausanne). 2017 Dec 14;4:224. doi: 10.3389/fmed.2017.00224. eCollection 2017. 

• Shor S, Green C, Szantyr B, Phillips S, Liegner K, Burrascano JJ Jr, Bransfield R, Maloney EL. Chronic Lyme Disease: An Evidence-Based Definition by the ILADS Working Group. Antibiotics (Basel). 2019 Dec 16;8(4). pii: E269. doi: 10.3390/antibiotics8040269. 

• Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089-1134. 

• Eppes SC, Childs JA. Comparative study of cefuroxime axetil versus amoxicillin in children with early Lyme disease. Pediatrics 2002; 109:1173-1177. 

• Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ. Amoxicillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis. Lancet 1990; 336:1404-1406. 

• Dattwyler RJ, Luft BJ, Kunkel M, et al.. Ceftriaxone compared with doxycycline for the treatment of acute disseminated Lyme disease. N Engl J Med 1997; 337:289-294. 

• Nadelman RB, Luger SW, Frank E, et al. Comparison of cefuroxime axetil and doxycycline in the treatment of early Lyme disease. Ann Intern Med 1992; 117:273-280. 

• Luger SW, Paparone P, Wormser GP, et al. Comparison of cefuroxime axetil and doxycycline in treatment of patients with early Lyme disease associated with erythema migrans. Antimicrob Agents Chemother 1995; 39:661-667. 

• Luft BJ, Dattwyler RJ, Johnson RC, et al. Azithromycin compared with amoxicillin in the treatment of erythema migrans: a double blind, randomized, controlled trial. Ann Intern Med 1996; 124:785-791. 

• Massarotti EM, Luger SW, Rahn DW, et al. Treatment of early Lyme disease. Am J Med 1992; 92:396-403. 

• Wormser GP, Ramanathan R, Nowakowski J, et al.. Duration of antibiotic therapy for early Lyme disease: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003; 138:697- 704. 

• Dattwyler RJ, Halperin JJ, Volkman DJ, Luft BJ. Treatment of late Lyme borreliosis–randomised comparison of ceftriaxone and penicillin. Lancet. 1988 May 28;1(8596):1191-1194. 

• Jowett N, Gaudin RA, Banks CA, Hadlock TA. Steroid use in Lyme disease-associated facial palsy is associated with worse long-term outcomes. Laryngoscope. 2017 Jun; 127(6):1451-1458. 

• 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):1728-1736. 

• Hodzic E, Imai D, Feng S, Barthold SW. Resurgence of persisting non-cultivable Borrelia burgdorferi following antibiotic treatment in mice. PLoS One. 2014 Jan 23;9(1):e86907. 

• Barthold SW, Hodzic E, Imai DM, Feng S, Yang X, Luft BJ. Ineffectiveness of Tigecycline Against Persistent Borrelia burgdorferi. Antimicrob. Agents Chemother 2010; 54(2):643-651. 

• Embers ME, Barthold SW, Borda JT, et al. Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection. PLoS One. 2012; 7(1): e29914. 

• Weber K , Wilske B , Preac-Mursic V , Thurmayr R . Azithromycin versus penicillin V for the treatment of early Lyme borreliosis. Infection. 1993; 21(6):367-372. 

• 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; 21(2):83-88. 

• Oksi J , Nikoskelainen J , Viljanen MK . Comparison of oral cefixime and intravenous ceftriaxone followed by oral amoxicillin in disseminated Lyme borreliosis . Eur J Clin Microbiol Infect Dis 1998;17(10):715-719. 

• Logigian EL, Kaplan RF, Steere AC. Successful treatment of Lyme encephalopathy with intravenous ceftriaxone. J Infect Dis 1999;180(2):377-383. 

• Marques A, Telford SR 3rd, Turk SP et al. Xenodiagnosis to detect Borrelia burgdorferi infection: a first-in-human study. Clin Infect Dis 2014 Apr;58(7):937-345. doi: 10.1093/cid/cit939. 

• Rupprecht TA. The pathogenesis of lyme neuroborreliosis: from infection to inflammation. Mol Med 2008; 14(3-4): 205-212. 

• Chandra A, Wormser GP, Klempner MS, Trevino RP, Crow MK, Latov N, Alaedini A. Anti-neural antibody reactivity in patients with a history of Lyme borreliosis and persistent symptoms. Brain Behav Immun 2010 Aug;24(6):1018-1024. 

• Jacek E, Fallon BA, Chandra A, Crow MK, Wormser GP, Alaedini A. Increased IFNα activity and differential antibody response in patients with a history of Lyme disease and persistent cognitive deficits. J Neuroimmunol 2013 Feb 15;255(1-2):85-91. 

• Londoño D, Cadavid D, Drouin EE, Strle K, McHugh G, Aversa JM, Steere AC. Antibodies to endothelial cell growth factor and obliterative microvascular lesions in the synovium of patients with antibiotic-refractory lyme arthritis. Arthritis Rheumatol 2014 Aug;66(8):2124-2133. 

• Reimers, C. D., J. de Koning, et al. (1993). “Borrelia burgdorferi myositis: report of eight patients.” J Neurol 240(5):278-283. 

• Wormser GP, Weitzner E, McKenna D, et al. Long-term assessment of fibromyalgia in patients with culture-confirmed Lyme disease [published online December 2, 2014]. Arthritis Rheumatol doi:10.1002/art.38972. 

• Schutzer SE, Angel TE, Liu T, et al. Distinct cerebrospinal fluid proteomes differentiate post- treatment Lyme disease from chronic fatigue syndrome. PLoS One 2011; 6(2): e17287. doi: 10.1371/ journal.pone.0017287. 

• Aliota MT, Dupuis AP 2nd, Wilczek MP, Peters RJ, Ostfeld RS, Kramer LD. The prevalence of zoonotic tick-borne pathogens in Ixodes scapularis collected in the Hudson Valley, New York State. Vector Borne Zoonotic Dis 2014 Apr;14(4):245-250. doi: 10.1089/vbz.2013.1475. 

• Johnson TL, Graham CB, Maes SE, et al. Prevalence and distribution of seven human pathogens in host-seeking Ixodes scapularis (Acari: Ixodidae) nymphs in Minnesota, USA. Ticks Tick Borne Dis. 2018 Jul 20. pii: S1877-959X(18)30182-1. doi: 10.1016/j.ttbdis.2018.07.009. 

• Embers ME, Hasenkampf NR, Jacobs MB, Tardo AC, Doyle-Meyers LA, Philipp MT, et al. Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding. PLoS One 2017 Dec 13;12(12):e0189071. doi: 10.1371/journal.pone.0189071. eCollection 2017. 

• Cerar D, Cerar T, Ruzić-Sabljić E, Wormser GP, Strle F. Subjective symptoms after treatment of early Lyme disease. Am J Med 2010 Jan;123(1):79-86. 

• Yang X, Coleman AS, Anguita J, Pal U (2009) A Chromosomally Encoded Virulence Factor Protects the Lyme Disease Pathogen against Host-Adaptive Immunity. PLoS Pathog 5(3): e1000326. doi:10.1371/journal.ppat.1000326. Published March 6, 2009. 

• Singh SK, Girschick HJ. Molecular survival strategies of the Lyme disease spirochete Borrelia burgdorferi. Lancet Infect Dis 2004;4(9):575-583. 

• Embers ME, Ramamoorthy R, Philipp MT. Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease Microbes and Infection 2004; 6:312-318. 

• Girschick HJ, Huppertz HI, Russmann H, Krenn V, Karch H. Intracellular persistence of Borrelia burgdorferi in human synovial cells. Rheumatol Int 1996; 16:125-132. 

• Klempner MS, Noring R, Rogers RA. Invasion of human skin fibroblasts by the Lyme disease spirochete, Borrelia burgdorferi. J Infect Dis 1993;167:1074-1081. 

• Brorson O, Brorson SH. In Vitro Conversion of Borrelia burgdorferi to Cystic Forms in Spinal Fluid and Transformation to Motile Spirochetes by Incubation in BSK-H Medium. Infection 1998;26(3):144-150. 

• Kersten A, Poitschek C, Rauch S, Aberer E. Effects of Penicillin, Ceftriaxone, and Doxycycline on Morphology of Borrelia burgdorferi. Antimicrob Agents Chemother 1995; 39(5):1127-1133. 

• Lazarus JJ, Kay MA, McCarter AL, Wooten RM. Viable Borrelia burgdorferi Enhances Interleukin- 10 Production and Suppresses Activation of Murine Macrophages. Infection Immunity 2008; 76(3):1153-1162. 

• Liang FT, Jacobs MB, Bowers LC, Philipp MT. An immune evasion mechanism for spirochetal persistence in Lyme borreliosis. J Exp Med 2002;195:415-422. 

• Kraiczy, P., Skerka, C., Kirschfink, M., Zipfel, P. F. and Brade, V. (2002). Immune evasion of Borrelia burgdorferi: insufficient killing of the pathogens by complement and antibody. Int J Med Microbiol 291 Suppl 33: 141-146. 

• 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):60-68. 

• Feng J, Shi W, Zhang S, Sullivan D, Auwaerter PG, Zhang Y. A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library. Front Microbiol 2016 May 23;7:743. 

• Feng, Jie and PG Auwaerter and Ying Zhang. Drug combinatins against borrelia burgdorferi perissters in vitro:eradication achieved by using Daptomycin, Cefoperazone and Doxycycline. PLOS One 2015 DOI:10:1371/journal.pone.0117207. March 25, 2015. 

• Feng J, Li T, Yee R, Yuan Y, Bai C, Cai M, et al. Stationary phase persister/biofilm microcolony of Borrelia burgdorferi causes more severe disease in a mouse model of Lyme arthritis: implications for understanding persistence, Post-treatment Lyme Disease Syndrome (PTLDS), and treatment failure. Discov Med 2019 Mar;27(148):125-138. 

• Kannian P, McHugh G, Johnson B, Bacon R, Glickstein L, Steere A. Antibody Responses to Borrelia burgdorferi in Patients With Antibiotic-Refractory, Antibiotic-Responsive, or Non– Antibiotic-Treated Lyme Arthritis. Arthritis Rheumatism 2007; 56(12):4216-4225. 

• Rupprecht TA, Elstner M, Weil S, Pfister HW. Autoimmune-mediated polyneuropathy triggered by borrelial infection? Muscle Nerve 2008 Jun;37(6):781-785. 

• Glatz M, Golestani M, Kerl H, Müllegger RR. Clinical relevance of different IgG and IgM serum antibody responses to Borrelia burgdorferi after antibiotic therapy for erythema migrans: longterm follow-up study of 113 patients. Arch Dermatol 2006; 142(7):862-868. 

• Rebman AW, Crowder LA, Kirkpatrick A, Aucott JN. Characteristics of seroconversion and implications for diagnosis of post-treatment Lyme disease syndrome: acute and convalescent serology among a prospective cohort of early Lyme disease patients. Clin Rheumatol 2015; 34(3):585-589. 

• Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001;345(2):85-92. 

• Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003;60(12):1923-1930. 

• Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 2008;70:992-1003. 

• Berende A, ter Hofstede HJ, Vos FJ, van Middendorp H, Vogelaar ML, Tromp M, et al. Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease. N Engl J Med 2016 Mar 31;374(13):1209-1220. 

• Delong AK, Blossom B, Maloney EL, Phillips SE. Antibiotic retreatment of Lyme disease in patients with persistent symptoms: A biostatistical review of randomized, placebo-controlled, clinical trials. Contemp Clin Trials 2012; 33(6):1132-1142. 

• Fallon BA, Petkova E, Keilp JG, Britton CB. A reappraisal of the U.S. Clinical trials of post- treatment lyme disease syndrome. Open Neurol J 2012;6:79-87. 

• Donta ST. Macrolide therapy of chronic Lyme Disease. Med Sci Monit. 2003 Nov;9(11): PI136-42. 

• Horowitz R. Precision medicine: retrospective chart review and data analysis of 200 patients on dapsone combination therapy for chronic Lyme disease/post-treatment Lyme disease syndrome: part 1.Int J Gen Med 2019 Feb 18;12:101-119. doi: 10.2147/IJGM.S193608. eCollection 2019. 

• Liegner KB. Disulfiram (Tetraethylthiuram Disulfide) in the Treatment of Lyme Disease and Babesiosis: Report of Experience in Three Cases. Antibiotics (Basel) 2019 May 30;8(2). pii: E72. doi: 10.3390/antibiotics8020072. 

• Institute of Medicine (Committee on Quality of Health Care in America). Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academies Press; 2001: http://www.nap.edu/openbook.php?isbn=0309072808. 

• AMA Code of Medical Ethics accessed from https://www.ama-assn.org/about/publications- newsletters/ama-principles-medical-ethics on April 10, 2019.