The Controversies, Challenges and Complexities of Lyme Disease: A Narrative Review
AbstractPurpose: Lyme disease has become an increasingly important global public health concern. Method: A narrative review was conducted and designed to present a broad perspective on Lyme disease, and describe its history and development in terms of clinical care and public health implications. A structured literature search was conducted based on the question; what is currently known about Lyme disease? Results: The narrative review is presented in chronological order in terms of a summary of the history of Lyme disease, the complexities of clinical diagnosis, the problematic interpretation of serologic testing, the conflicting guidelines for diagnosis, treatment and management of chronic Lyme, and benefits of antibiotic treatment. Conclusion: Despite growing global incidence of the Lyme disease, treatment has not attracted pharmaceutical investment, and the evidence base and international guidelines for treatment and management of chronic Lyme continue to be conflicting and controversial. The challenges of this immune mediated tick borne disease for public health policy and clinical practice are summarised, alongside directions for future research.
Koedel U, Fingerle V, Pfister HW. Lyme neuroborreliosis—epidemiology, diagnosis and management. Nat. Rev. Neurol 2015;11:446–56.
Luché-Thayer J, Ahern H, DellaSala D, Franklin S, Gilbert L, Horowitz R, et al. UPDATING ICD11 Borreliosis Diagnostic Codes. Edition One March 29, 2017. Global Network on Institutional Discrimination and Ad Hoc Committee for Health Equity in ICD11 Borreliosis Codes. 2017. Available from: http://www.lymeactionnetwork.org/wp-content/uploads/2017/04/Excerpt-for-LAN-hyperlink-3.2017-UPDATING-ICD11-DIAGNOSTIC-CODES-J.Luche-Thayer.pdf
Maloney EL. Controversies in Persistent (Chronic) Lyme Disease. J Infus Nur 2016;39:369–75.
Borchers AT, Keen CL, Huntley AC, Gershwin ME. Lyme disease: A rigorous review of diagnostic criteria and treatment. J. Autoimmun 2015;57:82–115.
Błaut-Jurkowska J, Olszowska M, Kaźnica-Wiatr M, Podolec P. Borelioza serca [Lyme carditis]. Pol Merkur Lekarski, 2015;39:111–15.
Coumou J, Hovius JW. De ziekte van Lyme. [Lyme disease]. Ned Tijdschr Tandheelkd, 2011;118:310–16.
Coumou J, van der Poll T, Speelman P, Hovius JW. Tired of Lyme borreliosis. Lyme borreliosis in the Netherlands. Neth J Med 2011;69:101–11.
European Centre for Disease Prevention and Control. CDC. (2016). Tick maps: tick species—distribution maps, http://ecdc.europa.eu/en/healthtopics/vectors/vector-maps/Pages/VBORNET-maps-tick-species.aspx; 2016 [accessed 18 May 2016].
Oliveira CR, Shapiro ED. Update on persistent symptoms associated with Lyme disease. Curr Opin Pediatr 2015;27:100–4.
Schwameis M, Kündig T, Huber G, von Bidder L, Meinel L, Weisser R, et al. Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial. Lancet Infect Dis 2017;17:322–29.
Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet 2012;379:461–73.
Pritt BS, Mead PS, Johnson DK, Neitzel DF, Respicio-Kingry LB, Davis JP, et al. Identification of a novel pathogenic Borrelia species causing Lyme borreliosis with unusually high spirochaetaemia: a descriptive study. Lancet Infect Dis 2016;16:556–64.
ESCMID. Tick tests for the detection of borrelia are not recommended by the ESCMID Study Group for Lyme borreliosis (ESGBOR). https://www.escmid.org/fileadmin/src/media/PDFs/3Research_Projects/ESGBOR/Tick_tests_discouragement_ESGBOR2013.pdf; 2016 [accessed June 20, 2016].
Rowe PM. Chronic Lyme disease: the debate goes on. Lancet 2000;355:1436.
Steere AC, Malawista SE, Snydman DR, Shope RE, Andiman WA, Ross MR, et al. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three connecticut communities. Arthritis Rheum 1977;20:7–17.
Biesiada G, Czepiel J, Lesniak MR, Garlicki A, Mach T. Lyme disease: review. Arch Med Sci 2012;8:978–982.
Centers for Disease Control and Prevention. Lyme disease: Two-step laboratory testing process. Atlanta, GA: Centers for Disease Control and Prevention; 2011 Available from: http://www.cdc.gov/lyme/diagnosistreatment/LabTest/TwoStep/.
Centers for Disease Control and Prevention. Lyme disease frequently asked questions. Atlanta, GA: Centers for Disease Control and Prevention; 2015 Available from: http://www.cdc.gov/lyme/faq/index.html.
Hamer SA, Tsao JI, Walker ED, Hickling GJ. Invasion of the lyme disease vector Ixodes scapularis: implications for Borrelia burgdorferi endemicity. EcoHealth 2010;7:47–63.
Mandell G, Bennett J, Dolin R. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Elsevier Churchill Livingstone, 2009.
Margos G, Tsao JI, Castillo-Ramirez S, Girard YA, Hamer SA, Hoen AG, et al. Two boundaries separate Borrelia burgdorferi populations in North America. Appl Environ Microbiol 2012;78:6059–67.
Wright WR. Borrelia: Molecular Biology, Host Interaction and Pathogenesis. Norfolk: Caister Academic Press; 2010.
Wright WF, Riedel DJ, Talwani R, Gilliam BL. Diagnosis and management of Lyme disease. Am Fam Physician 2012;85:1086–93.
van den Wijngaard CC, Hofhuis A, Harms MG, Haagsma JA, Wong A, de Wit GA, et al. The burden of Lyme borreliosis expressed in disability-adjusted life years. Eur J Pub Health 2015;25:1071–78.
Tibbles CD, Edlow JA. Does this patient have erythema migrans? JAMA 2007;297:2617–27.
Scheffold N, Herkommer B, Kandolf R, May AE. Lyme Carditis—Diagnosis, Treatment and Prognosis. Dtsch Arztebl Int 2015;112:202–08.
Lewandrowski K, Prisco L. The Challenges of Lyme Disease: From Clinical Diagnosis to Testing Methodology. Prussia, PA: Advance Healthcare Network for Laboratory; 2015.
Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, 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;43:1089–134.
Albert S, Schulze J, Riegel H, Brade V. Lyme arthritis in a 12-year-old patient after a latency period of 5 years. Infection 1999;27:286–288.
Garcia-Monco JC, Villar BF, Alen JC, Benach JL. Borrelia burgdorferi in the central nervous system: experimental and clinical evidence for early invasion. J Infect Dis 1990;161:1187–93.
Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med 1990;323:1438–44.
Hyde JA. Borrelia burgdorferi Keeps Moving and Carries on: A Review of Borrelial Dissemination and Invasion. Front Immunol 2017;8:114.
Tumminello R, Glaspey L, Bhamidipati A, Sheehan P, Patel S. Early Disseminated Lyme Disease Masquerading as Mononucleosis: A Case Report. J Emerg Med 2017;53:e133–e135.
Centers for Disease Control and Prevention (CDC). Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep 1995;44:590–91.
Reed KD. Laboratory testing for Lyme disease: possibilities and practicalities. J Clin Microbiol 2002;40:319–24.
Branda JA, Strle K, Nigrovic LE, Lantos PM, Lepore TJ, Damle NS. Evaluation of Modified 2-Tiered Serodiagnostic Testing Algorithms for Early Lyme Disease. Clin Infect Dis 2017;64:1074–80.
Waddell LA, Greig J, Mascarenhas M, Harding S, Lindsay R, Ogden N. The Accuracy of Diagnostic Tests for Lyme Disease in Humans, A Systematic Review and Meta-Analysis of North American Research. PloS one 2016;11:e0168613.
Cook MJ, Puri BK. Commercial test kits for detection of Lyme borreliosis: a meta-analysis of test accuracy. Int J Gen Med 2016;9:427–40.
Leeflang MM, Ang CW, Berkhout J, Bijlmer HA, Van Bortel W, Brandenburg AH, et al. The diagnostic accuracy of serological tests for Lyme borreliosis in Europe: a systematic review and meta-analysis. BMC Infect Dis 2016;16:140.
Miraglia CM. A Review of the Centers for Disease Control and Prevention's Guidelines for the Clinical Laboratory Diagnosis of Lyme Disease. J Chiropr Med 2016;15:272–80.
Robert Koch Institute. Lyme-Borreliose. [Lyme borreliosis]. https://www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/Ratgeber_LymeBorreliose.html; 2013 [accessed May 14, 2016].
Ruzic-Sabljic E, Cerar T. Progress in the molecular diagnosis of Lyme disease. Expert Rev Mol Diagn 2017;17:19–30.
Stanek G, Fingerle V, Hunfeld KP, Jaulhac B, Kaiser R, Krause A, et al. Lyme borreliosis: Clinical case definitions for diagnosis and management in Europe. Clin Microbiol Infect 2011;17:69–79.
Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme Disease. Dissociation of T- and B-Lymphocyte Responses to Borrelia burgdorferi. N Engl J Med 1988;319:1441–46.
Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev Anti Infect Ther 2014;12:1103–35.
Stricker RB. Counterpoint: long-term antibiotic therapy improves persistent symptoms associated with lyme disease. Clin Infect Dis 2007;45:149–57.
Knauer J, Krupka I, Fueldner C, Lehmann J, Straubinger RK. Evaluation of the preventive capacities of a topically applied azithromycin formulation against Lyme borreliosis in a murine model. J Antimicrob Chemother 2011;66:2814–22.
Lode H. The pharmacokinetics of azithromycin and their clinical significance. Eur J Clin Microbiol Infect Dis 1991;10:807–12.
Piesman J, Hojgaard A, Ullmann AJ, Dolan MC. Efficacy of an experimental azithromycin cream for prophylaxis of tick-transmitted Lyme disease spirochete infection in a murine model. Antimicrob Agents Chemother 2014;58:348–51.
German Borreliosis Society. (2010). Diagnosis and Treatment of Lyme borreliosis (Lyme disease). Jena: German Borreliosis Society. Available from: http://www.borreliose-gesellschaft.de/Texte/guidelines.pdf#
Marques A. Chronic Lyme Disease: An appraisal. Infect Dis Clin North Am 2008;22:341–60.
Lantos PM. Chronic Lyme Disease. Infect Dis Clin North Am 2015;29:325–40.
Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994;121:953–59.
Prins JB, van der Meer JW, Bleijenberg G. Chronic fatigue syndrome. Lancet 2006;367:346–55.
Clauw D.J. Fibromyalgia: a clinical review. Jama 2014;311:1547–55.
Feder HM, Johnson BJ, O’Connell S, Shapiro ED, Steere AC, Wormser GP, et al. A critical appraisal of “chronic Lyme disease”. N Engl J Med 2007;357,:1422–30.
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;33:1132–42.
Auwaerter PG, Bakken JS, Dattwyler RJ, Dumler JS, Halperin JJ, McSweegan E, et al. Antiscience and ethical concerns associated with advocacy of Lyme disease. Lancet Infect Dis 2011;11:713–19.
Stricker RB, Lautin A, Burrascano JJ. Lyme disease: point/counterpoint. Expert Rev Anti Infect Ther 2005;3:155–65.
Bockenstedt LK, Wormser GP. Review: Unraveling LymeDdisease. Arthritis Rheum 2014;66:2313–23.
Shapiro ED. Clinical practice. Lyme disease. N Engl J Med 2014;370:1724–31.
Fallon BA, Petkova E, Keilp JG, Britton CB. A reappraisal of the u.s. Clinical trials of post-treatment lyme disease syndrome. Open Microbiol J 2012;6:79–7.
Asch ES, Bujak DI, Weiss M, Peterson MG, Weinstein A. Lyme disease: an infectious and postinfectious syndrome. J Rheumatol 1994;21:454–461.
Logigian EL, Kaplan RF, Steere AC. Successful treatment of Lyme encephalopathy with intravenous ceftriaxone. J Infect Dis 1999;180:377–83.
Shadick NA, Phillips CB, Logigian EL, Steere AC, Kaplan RF, Berardi VP, et al. The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study. Ann Intern Med 1994;121:905–8.
National Institute of Health and Care Excellence (NICE). Lyme disease. London: NICE; 2018. Expected publication date: 04 April 2018. Available from: https://www.nice.org.uk/guidance/indevelopment/gid-ng10007
Public Health England. Lyme Disease: Diagnosis and Treatment: UK: Public Health England; 2014. Available from: https://www.gov.uk/government/publications/lyme-disease-diagnosis-and-treatment.
Donta ST. Tetracycline therapy for chronic Lyme disease. Clin Infect Dis 1997;25:S52–56.
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;17:715–719.
Wahlberg P, Granlund H, Nyman D, Panelius J, Seppälä I. Treatment of late Lyme borreliosis. J Infect 1994;29:255–61.
Fallon BA, Keilp JG, Corbera KM, Petkova E, Britton CB, Dwyer E, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 2008;70:992–1003.
Klempner MS, Hu LT, Evans J, Schmid CH, Johnson GM, Trevino RP, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001;345:85–2.
Krupp LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003;60:1923–30.
Grygorczuk S, Zajkowska J, Kondrusik M, Moniuszko A, Pancewicz S, Pawlak-Zalewska W. [Failures of antibiotic treatment in Lyme arthritis]. [Article in Polish] Przegl Epidemiol 2008;62:581–88.
Hill D, Holmes T. Provider knowledge, attitudes, and practices regarding Lyme disease in Arkansas. J Community Health 2015;40(2):339–46.
Aguero-Rosenfeld ME, Nowakowski J, Bittker S, Cooper D, Nadelman RB, Wormser GP. Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans. J Clin Microbiol 1996;34:1–9.
Aucott J, Morrison C, Munoz B, Rowe PC, Schwarzwalder A, West SK. Diagnostic challenges of early Lyme disease: lessons from a community case series. BMC Infect Dis 2009;9:79.
Beard BB, Schriefer M, Gerald N. HHS federal research update on Lyme disease diagnostics activities. Washington DC: US Department of Health and Human Services; 2012. Available from: https://www.cdc.gov/lyme/resources/webinar/09242012_diagnosticswebinartranscript.pdf
Dressler F, Whalen JA, Reinhardt BN, Steere AC. Western blotting in the serodiagnosis of Lyme disease. J Infect Dis 1993;167:392–400.
Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol 1995;33:419–27.
Johnson B. Laboratory diagnostic testing for Borrelia burgdorferi infection. In: Halperin J, editor. Lyme Disease. An evidence-based approach Cambridge: CAB International; 2011, p. 73–88.
Nelson C, Hojvat S, Johnson B, Petersen J, Schriefer M, Beard CB, Centers for Disease Control and Prevention (CDC). Concerns regarding a new culture method for Borrelia burgdorferi not approved for the diagnosis of Lyme disease. MMWR Morb Mortal Wkly Rep 2014;63:333.
Tokarz R, Tagliafierro T, Cucura DM, Rochlin I, Sameroff S, Lipkin I. Detection of Anaplasma phagocytophilum, Babesia microti, Borrelia burgdorferi, Borrelia miyamotoi, and Powassan Virus in Ticks by a Multiplex Real-Time Reverse Transcription-PCR Assay. Clin Sci Epidem 2017;2:e00151–17.
Perronne C. Lyme disease antiscience. Lancet 2012;12:361–62.
Perea AE, Hinckley AF, Mead PS. Tick bite prophylaxis: Results from a 2012 survey of healthcare providers. Zoonoses Public Health 2015;62:388–92.
Brett ME, Hinckley AF, Zielinski-Gutierrez EC, Mead PS. U.S. healthcare providers experience with Lyme and other tick-borne diseases. Ticks Tick Borne Dis 2014;5:404–8.
Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 4th ed. New York, NY: Oxford University Press; 1994.
Committee on Quality of Health Care in America; Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academies Press; 2001.
Informed Medical Decisions Foundation. Why shared decision making? http://www.informedmedicaldecisions.org/what-is-shared-decision-making; 2016 [accessed 15 August 2016].
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