Purpose of Review
Since recognition in 1975, Lyme disease has become the most common vector-borne illness in North America and Europe. The clinical features are well-characterized and treatment is usually curative, but misperceptions about morbidity persist. The purpose of this review is to examine advances in the diagnosis and treatment of Lyme disease, as well as ongoing management challenges.
It is useful to recognize that Lyme disease occurs in stages, with early- and late-stage disease. Clinical expression is in part determined by Borrelial variability. For example, some strains of Borrelia burgdorferi, the causative organism in North America, are particularly arthritogenic. Most patients with early Lyme disease can be cured with a single course of oral antibiotic therapy, in contrast to some patients with Lyme arthritis, a late-stage manifestation, who are more antibiotic refractory and require other treatment strategies.
Successful treatment of Lyme disease begins with successful diagnosis and with an understanding of the emergence, clinical features, and impact of Lyme disease over the past half century.
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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(1):7–17.
Asbrink E, Hovmark A, Olsson I. Clinical manifestations of acrodermatitis chronica atrophicans in 50 Swedish patients. Zentralbl Bakteriol Mikrobiol Hyg A. 1986;263(1–2):253–61.
Ogrinc K, Lusa L, Lotric-Furlan S, Bogovic P, Stupica D, Cerar T, et al. Course and outcome of early European Lyme neuroborreliosis (Bannwarth syndrome): clinical and laboratory findings. Clin Infect Dis. 2016;63(3):346–53.
Steere AC, Bartenhagen NH, Craft JE, Hutchinson GJ, Newman JH, Rahn DW, et al. The early clinical manifestations of Lyme disease. Ann Intern Med. 1983;99(1):76–82.
Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, Davis JP. Lyme disease-a tick-borne spirochetosis? Science. 1982;216(4552):1317–9.
Benach JL, Bosler EM, Hanrahan JP, Coleman JL, Habicht GS, Bast TF, et al. Spirochetes isolated from the blood of two patients with Lyme disease. N Engl J Med. 1983;308(13):740–2.
Steere AC, Grodzicki RL, Kornblatt AN, Craft JE, Barbour AG, Burgdorfer W, et al. The spirochetal etiology of Lyme disease. N Engl J Med. 1983;308(13):733–40.
• Mead PS. Epidemiology of Lyme disease. Infect Dis Clin North Am. 2015;29(2):187–210. This review provides a comprehensive discussion of Lyme disease epidemiology.
Margos G, Vollmer SA, Ogden NH, Fish D. Population genetics, taxonomy, phylogeny and evolution of Borrelia burgdorferi sensu lato. Infect Genet Evol. 2011;11(7):1545–63.
• Steere AC, Strle F, Wormser GP, Hu LT, Branda JA, Hovius JW, et al. Lyme borreliosis. Nat Rev Dis Primers. 2016;2:16090. This review is a thorough update by experts.
Grillon A, Scherlinger M, Boyer PH, De Martino S, Perdriger A, Blasquez A, et al. Characteristics and clinical outcomes after treatment of a national cohort of PCR-positive Lyme arthritis. Semin Arthritis Rheum. 2019;48(6):1105–12.
Maraspin V, Mrvic T, Ruzic-Sabljic E, Jurcic V, Strle F. Acrodermatitis chronica atrophicans in children: report on two cases and review of the literature. Ticks Tick Borne Dis. 2019;10(1):180–5.
Bacon RM, Kugeler KJ, Mead PS. Surveillance for Lyme disease--United States, 1992–2006. Morbidity and mortality weekly report surveillance summaries (Washington, DC : 2002). 2008;57(10):1–9.
Eisen RJ, Eisen L, Beard CB. County-scale distribution of Ixodes scapularis and Ixodes pacificus (Acari: Ixodidae) in the continental United States. J Med Entomol. 2016;53(2):349–86.
Centers for Disease Control. Data and surveillance Lyme disease 2019 [5/18/19]. Available from: https://www.cdc.gov/lyme/stats/index.html. Accessed 1 July 2019.
Reid MC, Schoen RT, Evans J, Rosenberg JC, Horwitz RI. The consequences of overdiagnosis and overtreatment of Lyme disease: an observational study. Ann Intern Med. 1998;128(5):354–62.
Schiffman EK, McLaughlin C, Ray JAE, Kemperman MM, Hinckley AF, Friedlander HG, et al. Underreporting of Lyme and other tick-borne diseases in residents of a high-incidence county, Minnesota, 2009. Zoonoses Public Health. 2018;65(2):230–7.
White J, Noonan-Toly C, Lukacik G, Thomas N, Hinckley A, Hook S, et al. Lyme disease surveillance in New York state: an assessment of case underreporting. Zoonoses Public Health. 2018;65(2):238–46.
Doyle TJ, Glynn MK, Groseclose SL. Completeness of notifiable infectious disease reporting in the United States: an analytical literature review. Am J Epidemiol. 2002;155(9):866–74.
Nelson CA, Saha S, Kugeler KJ, Delorey MJ, Shankar MB, Hinckley AF, et al. Incidence of clinician-diagnosed Lyme disease, United States, 2005-2010. Emerg Infect Dis. 2015;21(9):1625–31.
Steere AC. Lyme disease. N Engl J Med. 1989;321(9):586–96.
Schoen RT. A case revealing the natural history of untreated Lyme disease. Nat Rev Rheumatol. 2011;7(3):179–84.
Smith RP, Schoen RT, Rahn DW, Sikand VK, Nowakowski J, Parenti DL, et al. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med. 2002;136(6):421–8.
Matuschka FR, Ohlenbusch A, Eiffert H, Richter D, Spielman A. Antiquity of the Lyme-disease spirochaete in Europe. Lancet. 1995;346(8986):1367.
Keller A, Graefen A, Ball M, Matzas M, Boisguerin V, Maixner F, et al. New insights into the Tyrolean Iceman’s origin and phenotype as inferred by whole-genome sequencing. Nat Commun. 2012;3:698.
Poinar G. Spirochete-like cells in a Dominican amber Ambylomma tick (Arachnida: Ixodidae). Hist Biol. 2015;27(5):565–70.
Spielman A. The emergence of Lyme disease and human babesiosis in a changing environment. Ann N Y Acad Sci. 1994;740:146–56.
Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet. 2012;379(9814):461–73.
Clow KM, Leighton PA, Ogden NH, Lindsay LR, Michel P, Pearl DL, et al. Northward range expansion of Ixodes scapularis evident over a short timescale in Ontario. Canada PLoS One. 2017;12(12):e0189393.
Gasmi S, Ogden NH, Lindsay LR, Burns S, Fleming S, Badcock J, et al. Surveillance for Lyme disease in Canada: 2009-2015. Canada communicable disease report =. Releve des maladies transmissibles au Canada. 2017;43(10):194–9.
Schwartz AM, Hinckley AF, Mead PS, Hook SA, Kugeler KJ. Surveillance for Lyme disease - United States, 2008–2015. Morbidity and mortality weekly report surveillance summaries (Washington, DC : 2002). 2017;66(22):1–12.
Rand PW, Lubelczyk C, Lavigne GR, Elias S, Holman MS, Lacombe EH, et al. Deer density and the abundance of Ixodes scapularis (Acari: Ixodidae). J Med Entomol. 2003;40(2):179–84.
Centers for Disease Control. Lyme disease—confirmed cases by month of disease onset, United States, 2001-2017 2018 [Available from: https://www.cdc.gov/lyme/stats/graphs.html.
Nigrovic LE, Neville DN, Balamuth F, Bennett JE, Levas MN, Garro AC. A minority of children diagnosed with Lyme disease recall a preceding tick bite. Ticks Tick Borne Dis. 2019;10(3):694–6.
Nadelman RB, Nowakowski J, Fish D, Falco RC, Freeman K, McKenna D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med. 2001;345(2):79–84.
Steere AC, Sikand VK. The presenting manifestations of Lyme disease and the outcomes of treatment. N Engl J Med. 2003;348(24):2472–4.
Wormser GP, Sudhindra P, Lopez E, Patel L, Rezai S, Brumbaugh AD, et al. Fatigue in patients with erythema migrans. Diagn Microbiol Infect Dis. 2016;86(3):322–6.
Nadelman RB. Erythema migrans. Infect Dis Clin N Am. 2015;29(2):211–39.
Steere AC. Lyme disease. N Engl J Med. 2001;345(2):115–25.
Waddell LA, Greig J, Lindsay LR, Hinckley AF, Ogden NH. A systematic review on the impact of gestational Lyme disease in humans on the fetus and newborn. PLoS One. 2018;13(11):e0207067.
Robinson ML, Kobayashi T, Higgins Y, Calkins H, Melia MT. Lyme carditis. Infect Dis Clin N Am. 2015;29(2):255–68.
• Three sudden cardiac deaths associated with Lyme carditis - United States, November 2012–July 2013. MMWR morbidity and mortality weekly report. 2013;62(49):993–6. A report of 3 deaths attibutable to Lyme disease.
Stanek G, Klein J, Bittner R, Glogar D. Isolation of Borrelia burgdorferi from the myocardium of a patient with longstanding cardiomyopathy. N Engl J Med. 1990;322(4):249–52.
N’Guyen Y, Lesaffre F, Metz D, de Martino S, Jaulhac B, Andreoletti L. No serological evidence for Borrelia burgdorferi sensu lato infection in patients with dilated cardiomyopathy in Northern France. Infectious diseases (London, England). 2016;48(10):763–4.
Pachner AR. CNS Lyme disease. Neurology. 1992;42(9):1849–50.
Clark JR, Carlson RD, Sasaki CT, Pachner AR, Steere AC. Facial paralysis in Lyme disease. Laryngoscope. 1985;95(11):1341–5.
Wong K, Sequeira S, Bechtel K. Pediatric bilateral facial paralysis: an unusual presentation of Lyme disease. Pediatric emergency care. 2018.
Gaudin RA, Jowett N, Banks CA, Knox CJ, Hadlock TA. Bilateral facial paralysis: a 13-year experience. Plast Reconstr Surg. 2016;138(4):879–87.
Tseng YJ, DeMaria A, Jr., Goldmann DA, Mandl KD. Claims-based diagnostic patterns of patients evaluated for Lyme disease and given extended antibiotic therapy. Vector borne and zoonotic diseases (Larchmont, NY). 2017;17(2):116–22.
Marques AR. Lyme neuroborreliosis. Continuum (Minneap Minn). 2015;21(6 Neuroinfectious Disease):1729–44.
Halperin JJ. Lyme neuroborreliosis. Curr Opin Infect Dis. 2019;32(3):259–64.
Halperin JJ. Neuroborreliosis. Neurol Clin. 2018;36(4):821–30.
Patel K, Shah S, Subedi D. Clinical association: Lyme disease and Guillain-Barre syndrome. The American Journal of Emergency Medicine. 2017;35(10):1583.e1–2.
Monteventi O, Steinlin M, Regenyi M, Roulet-Perez E, Weber P, Fluss J. Pediatric stroke related to Lyme neuroborreliosis: data from the Swiss NeuroPaediatric Stroke Registry and literature review. Eur J Paediatr Neurol. 2018;22(1):113–21.
Visser AE, Verduyn Lunel FM, Veldink JH, van den Berg LH. No association between Borrelia burgdorferi antibodies and amyotrophic lateral sclerosis in a case-control study. Eur J Neurol. 2017;24(1):227–30.
Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med. 1990;323(21):1438–44.
Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med. 1987;107(5):725–31.
Schoen R. Musculoskeletal manifestations of Lyme disease. Waltham, MA2009-Present.
Li X, McHugh GA, Damle N, Sikand VK, Glickstein L, Steere AC. Burden and viability of Borrelia burgdorferi in skin and joints of patients with erythema migrans or Lyme arthritis. Arthritis Rheum. 2011;63(8):2238–47.
Steere AC, Angelis SM. Therapy for Lyme arthritis: strategies for the treatment of antibiotic-refractory arthritis. Arthritis Rheum. 2006;54(10):3079–86.
• Arvikar SL, Steere AC. Diagnosis and treatment of Lyme arthritis. Infect Dis Clin North Am. 2015;29(2):269–80. A review of the patterns of Lyme arthritis.
Jones KL, McHugh GA, Glickstein LJ, Steere AC. Analysis of Borrelia burgdorferi genotypes in patients with Lyme arthritis: high frequency of ribosomal RNA intergenic spacer type 1 strains in antibiotic-refractory arthritis. Arthritis Rheum. 2009;60(7):2174–82.
Steere AC, Klitz W, Drouin EE, Falk BA, Kwok WW, Nepom GT, et al. Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide. J Exp Med. 2006;203(4):961–71.
Borchers AT, Keen CL, Huntley AC, Gershwin ME. Lyme disease: a rigorous review of diagnostic criteria and treatment. J Autoimmun. 2015;57:82–115.
•• Lochhead RB, Strle K, Kim ND, Kohler MJ, Arvikar SL, Aversa JM, et al. MicroRNA expression shows inflammatory dysregulation and tumor-like proliferative responses in joints of patients with postinfectious Lyme arthritis. Arthritis Rheumatol (Hoboken, NJ). 2017;69(5):1100–10. MicroRNA expression in Lyme arthritis synovium changes with disease persistence.
Arvikar SL, Crowley JT, Sulka KB, Steere AC. Autoimmune arthritides, rheumatoid arthritis, psoriatic arthritis, or peripheral spondyloarthritis following Lyme disease. Arthritis Rheumatol (Hoboken, NJ). 2017;69(1):194–202.
Wormser GP, McKenna D, Carlin J, Nadelman RB, Cavaliere LF, Holmgren D, et al. Brief communication: hematogenous dissemination in early Lyme disease. Ann Intern Med. 2005;142(9):751–5.
Wormser GP, Shapiro ED, Strle F. Studies that report unexpected positive blood cultures for Lyme borrelia - are they valid? Diagn Microbiol Infect Dis. 2017;89(3):178–81.
Branda JA, Body BA, Boyle J, Branson BM, Dattwyler RJ, Fikrig E, et al. Advances in serodiagnostic testing for Lyme disease are at hand. Clin Infect Dis. 2018;66(7):1133–9.
Theel ES. The past, present, and (possible) future of serologic testing for Lyme disease. J Clin Microbiol. 2016;54(5):1191–6.
Alby K, Capraro GA. Alternatives to serologic testing for diagnosis of Lyme disease. Clin Lab Med. 2015;35(4):815–25.
Alasel M, Keusgen M. Promising alternatives for one-tier testing of Lyme borreliosis. Clinica chimica acta; international journal of clinical chemistry. 2018;479:148–54.
Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morbidity and mortality weekly report. 1995;44(31):590–1.
Marques AR. Laboratory diagnosis of Lyme disease: advances and challenges. Infect Dis Clin N Am. 2015;29(2):295–307.
Moore A, Nelson C, Molins C, Mead P, Schriefer M. Current guidelines, common clinical pitfalls, and future directions for laboratory diagnosis of Lyme disease, United States. Emerg Infect Dis. 2016;22(7).
Nigrovic LE, Lipsett SC, Molins CR, Wormser GP, Bennett JE, Garro AC, et al. Higher C6 enzyme immunoassay index values correlate with a diagnosis of noncutaneous Lyme disease. Diagn Microbiol Infect Dis. 2019;94(2):160–4.
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):585–9.
Markowicz M, Kivaranovic D, Stanek G. Testing patients with non-specific symptoms for antibodies against Borrelia burgdorferi sensu lato does not provide useful clinical information about their aetiology. Clin Microbiol Infect. 2015;21(12):1098–103.
Lee-Lewandrowski E, Chen Z, Branda J, Baron J, Kaufman HW. Laboratory blood-based testing for Lyme disease at a national reference laboratory. Am J Clin Pathol. 2019;152(1):91–6.
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.
Lantos PM, Branda JA, Boggan JC, Chudgar SM, Wilson EA, Ruffin F, et al. Poor positive predictive value of Lyme disease serologic testing in an area of low disease incidence. Clin Infect Dis. 2015;61(9):1374–80.
Connally NP, Hinckley AF, Feldman KA, Kemperman M, Neitzel D, Wee SB, et al. Testing practices and volume of non-Lyme tickborne diseases in the United States. Ticks Tick Borne Dis. 2016;7(1):193–8.
Webber BJ, Burganowski RP, Colton L, Escobar JD, Pathak SR, Gambino-Shirley KJ. Lyme disease overdiagnosis in a large healthcare system: a population-based, retrospective study. Clin Microbiol Infect. 2019.
Treatment of Lyme disease. Jama. 2016;315(22):2461–2.
• Sanchez E, Vannier E, Wormser GP, Hu LT. Diagnosis, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: a review. JAMA. 2016;315(16):1767–77. A review focusing on Lyme disease treatment.
Strle F, Stupica D, Bogovic P, Visintainer P, Wormser GP. Is the risk of early neurologic Lyme borreliosis reduced by preferentially treating patients with erythema migrans with doxycycline? Diagn Microbiol Infect Dis. 2018;91(2):156–60.
Cadavid D, Auwaerter PG, Rumbaugh J, Gelderblom H. Antibiotics for the neurological complications of Lyme disease. The Cochrane database of systematic reviews. 2016;12:Cd006978.
Dersch R, Freitag MH, Schmidt S, Sommer H, Rauer S, Meerpohl JJ. Efficacy and safety of pharmacological treatments for acute Lyme neuroborreliosis - a systematic review. Eur J Neurol. 2015;22(9):1249–59.
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;127(6):1451–8.
Wormser GP, McKenna D, Scavarda C, Karmen C. Outcome of facial palsy from Lyme disease in prospectively followed patients who had received corticosteroids. Diagn Microbiol Infect Dis. 2018;91(4):336–8.
Lantos PM. Chronic Lyme disease. Infect Dis Clin N Am. 2015;29(2):325–40.
Aguero-Rosenfeld ME, Wormser GP. Lyme disease: diagnostic issues and controversies. Expert Rev Mol Diagn. 2015;15(1):1–4.
Dersch R, Sarnes AA, Maul M, Hottenrott T, Baumgartner A, Rauer S, et al. Quality of life, fatigue, depression and cognitive impairment in Lyme neuroborreliosis. J Neurol. 2015;262(11):2572–7.
Weitzner E, McKenna D, Nowakowski J, Scavarda C, Dornbush R, Bittker S, et al. Long-term assessment of post-treatment symptoms in patients with culture-confirmed early Lyme disease. Clin Infect Dis. 2015;61(12):1800–6.
Wills AB, Spaulding AB, Adjemian J, Prevots DR, Turk SP, Williams C, et al. Long-term follow-up of patients with Lyme disease: longitudinal analysis of clinical and quality-of-life measures. Clin Infect Dis. 2016;62(12):1546–51.
Berende A, Nieuwenhuis L, Ter Hofstede HJM, Vos FJ, Vogelaar ML, Tromp M, et al. Cost-effectiveness of longer-term versus shorter-term provision of antibiotics in patients with persistent symptoms attributed to Lyme disease. PLoS One. 2018;13(4):e0195260.
• 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;374(13):1209–20. A study demonstrating lack of benefit for long-term antibiotic therapy.
Aucott JN. Posttreatment Lyme disease syndrome. Infect Dis Clin N Am. 2015;29(2):309–23.
Rebman AW, Bechtold KT, Yang T, Mihm EA, Soloski MJ, Novak CB, et al. The clinical, symptom, and quality-of-life characterization of a well-defined group of patients with posttreatment Lyme disease syndrome. Front Med. 2017;4:224.
Wormser GP, Weitzner E, McKenna D, Nadelman RB, Scavarda C, Nowakowski J. Long-term assessment of fatigue in patients with culture-confirmed Lyme disease. Am J Med. 2015;128(2):181–4.
Wormser GP, Weitzner E, McKenna D, Nadelman RB, Scavarda C, Molla I, et al. Long-term assessment of health-related quality of life in patients with culture-confirmed early Lyme disease. Clin Infect Dis. 2015;61(2):244–7.
Adrion ER, Aucott J, Lemke KW, Weiner JP. Health care costs, utilization and patterns of care following Lyme disease. PLoS One. 2015;10(2):e0116767.
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Dr. Schoen has no conflicts of interest to disclose.
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Schoen, R.T. Challenges in the Diagnosis and Treatment of Lyme Disease. Curr Rheumatol Rep 22, 3 (2020). https://doi.org/10.1007/s11926-019-0857-2
- Lyme disease
- Lyme arthritis
- Lyme disease treatment