Contents

Search

Lyme disease

Etiology: 1) infection with Borrelia species - Borrelia burgdorferi - Borrelia mayonii 2) transmission by infected ixodid (deer) ticks - attachment of Ixodes scapularis for at least 36 hours [1] 3) recurrent Lyme disease represents reinfection with a different genotype of Borrelia burgdorferi rather than relapse [17] * images of ticks [49] Epidemiology: 1) greatest prevalence in: a) southern New England b) middle Atlantic states, southwestern Virginia [30] c) Wisconsin d) Minnesota e) Northern California & Oregon f) Borrelia mayonii identified in Minnesota, Wisconsin, North Dakota 2) factors contributing to increase in Lyme disease a) expansion of deer & tick populations b) spread by migrating birds? c) movement of people into endemic areas, especially new housing developments 3) 30,000 cases of Lyme disease are reported to the CDC annually; the actual number of annual cases is roughly 10 times higher [21] 4) 3 deaths due to Lyme carditis Nov 2012 - July 2013 (U.S.) [22] Genetics: - chronic joint disease associated with HLA-DR4, often in combination with HLA-DR2 Pathology: - obliterative endarteritis in synovium - a peptidoglycan in the cell envelope of Borrelia burgdorferi is released but not degraded when the bacterium dies [43] - the peptidoglycan lingers in synovial fluid & elicits an ongoing immune response* * systemic administration of the peptidoglycan ellicits acute arthritis in mice [43] Clinical manifestations: 1) early localized disease a) characteristic rash - erythema migrans (60-80%) - < 30 days after tick bite at site of tick attachment - confirms diagnosis [1] - case report shows image of periorbital erythema migrans [28] - macular skin rash noted for Borrelia mayonii [31] b) generally develops 3-20 days after tick bite c) viral-like illness d) may present as fever & headache without rash [25] e) images [33,34] 2) spirochetemia a) weeks to months after initial tick bite b) multiple sites of erythema migrans [49] c) fever, headache, myalgias d) syncope e) dizziness f) shortness of breath g) cardiac manifestations 1] substernal chest pain or palpitation 2] mild congestive heart failure 3] fluctuating AV nodal block - complete heart block may develop (usually transient) [2,15,49] 4] mild pericarditis h) neurological manifestations 1] lymphocytic meningitis 2] radiculitis radiculoneuritis a] often multifocal, polyradiculitis, meningoradiculitis [41] b] motor fibers & sensory fibers 3] cranial neuritis [11] (image) [33] a] most commonly facial (CN VII) palsy (Bell's palsy) [46] b] bilateral CN VII palsy in an endemic area is diagnostic 4] confused speech, somnolence, & visual impairment noted with Borrelia mayonii [31] i) acute, oligoarticular inflammatory arthritis [1] j) nausea/vomiting may be more common with Borrelia mayonii [31] 3) late disease a) may develop years after initial tick bite & without evidence of antecedent disease b) chronic neurological manifestations - encephalopathy or encephalomyelitis [1] c) chronic arthritis 1] generally monoarticular or oligoarticular involving large joints 2] knee is most commonly affected joint 3] minimally symptomatic despite large effusions 4] episodes may last days to months or may become chronic 5] image [33] d) late stage skin manifestations - acrodermatitis chronica atrophicans (Borrelia afzelii) e) severe fatigue is rare, less severe fatigue is uncommon [27] 4) fibromyalgia may be associated with previous Lyme disease 5) asymptomatic infection is uncommon (7% of all cases) * images of erythema migrans [49] Laboratory: 1) Borrelia burgdorferi antibody in serum a) IgM appears 4 weeks after exposure b) IgG appears 6-8 weeks after exposure c) indicated for early disseminated & late Lyme disease, not indicated for acute (early) localized Lyme disease d) serologic testing for Lyme disease for hikers in edemic region presenting with monoarticular arthritis regardless of history of tick bite [1] e) ELISA now accepable alternatives to Western blot - false positives with - other spirochetal infection - bacterial endocarditis - parvovirus B19 - Epstein-Barr - rheumatoid arthritis - systemic lupus erythematosus f) Borrelia burgdorferi immunoblot IgG (Western blot) 1] confirmatory test (IgG) - more specific than ELISA 2] identifies IgG antibodies against specific components of Borrelia burgdorferi 3] negative immnoblot IgG when symptoms have been present for >= 1 month excludes Lyme disease (no further testing is indicated) [1] g) Borrelia burgdorferi-specific immune complexes [4] h) seroreactivity often positive for months after antibiotic treatment of early disease & for years after treatment of late infection - do not used serology to assess adequacy of treatment [1] i) serologic tests for Lyme disease yield disparate results [12] 2) Polymerase chain reaction for Borrelia Burgdorferi DNA a) used to detect Borrelia Burgdorferi DNA in: 1] blood 2] cerebrospinal fluid (CSF) sensitivity is poor [41] 3] urine 4] skin 5] synovial fluid b) more sensitive than culture - may detect Borrelia before antibody response c) more specific than ELISA d) offers no advantage over serologic testing [1] e) not widely available 3) lumbar puncture with CSF analysis for neuroborreliosis [1] a) lymphocytic pleocytosis b) elevated CSF protein c) oligoclonal immunoglobulins d) CSF glucose may be normal e) CSF/serum antibody index (ELISA not immunoblot) best method [41] f) CSF findings in Lyme meningitis indistinguishable from other forms of aseptic meningitis [1] 4) synovial fluid analysis - inflammatory with neutrophil predominance - Borrelia Burgdorferi DNA - less sensitive than Borrelia burgdorferi immunoblot IgG for late Lyme arthritis [1] - cultures tend to be negative [1] 5) see ARUP consult [14] 6) un-approved test using immunostaining enriched culture specimens with or without PCR, considered positive when either immunostaining or PCR is positive - CDC discourages use citing false positives [23] Diagnostic criteria: - erythema migrans coupled with compatible epidemiology sufficient for diagnosis in early disease [1] Special laboratory: - electrocardiogram - transient AV block due to Lyme carditis - lumbar puncture for suspected neuroborreliosis Radiology: - CT of head (neuroimaging) unnecessary for suspected neuroborreliosis - neuroborreliosis rarely associated with parenchymal brain lesions [1] Complications: - Lyme carditis, potentially fatal (sudden death) [22,26] - 1% of patients with Lyme disease - rarely fatal, mortality 0.002% - complete heart block is usually transient [49] - most patients with Lyme carditis are male [26] - 42% with erythema migrans [26] - patients with Lyme neuroborreliosis have increased risks for hematological cancer & skin cancers, otherwise similar long-term health outcomes to their unaffected peers - post Lyme disease syndrome (chronic Lyme disease) - non-specific but disabling symptoms - repeat episodes of erythema migrans in appropriately treated patients due to reinfection, not to relapse [35] Differential diagnosis: - southern tick-associated rash illness [1] (clinically indistinguishable from Lyme disease) - coinfection with Anaplasma phagocytophilum since tick vectors are the same - anaplasmosis associated with leukopenia & thrombocytopenia Management: 1) general a) risk of disease after tick bite is low - transmission of Borrelia from tick to person rarely occurs unless tick has attached & fed for at least 36 hours - see prophylaxis (after tick bite) below b) antibiotic therapy is generally curative 2) oral agents for treatment of early disease a) with manifestations of 1] isolated facial palsy 2] carditis (except 3rd degree heart block) 3] Lyme arthritis 4] acrodermatitis chronica atrophicans 5] erythema migrans b) may be too early for serologic confirmation c) 1st line antibiotics 1] doxycycline 100 mg PO BID for 10-21 days a] shortens duration of symptoms b] generally prevents sequelae c] 10 days is standard, 7 days may be adequate for erythema migrans [50] d] 28 days of therapy for Lyme disease arthritis (NEJM) [20,29,42,51] 2] amoxicillin 500 mg PO TID - if tetracyclines contraindicated: pregnant women; children < 8 years of age 3] cefuroxime 500 mg PO BID d) alternative agent: azithromycin 500 mg PO QD e) Jarisch-Herxheimer reaction (5-10%) 1] occurs within 1st days of treatment 2] reaction is mild, generally lasting < 1 day 3) intravenous antibiotics: a) indications 1] neurologic manifestations (except isolated facial palsy) 2] severe carditis (3rd degree AV block) a] 3rd degree AV block resolves in antibiotics b] hospitalize with cardiac monitoring during treatment [2,15] c] temporary cardiac pacemaker if indicated [2,15] 3] refractory arthritis 4] erythema migrans b) ceftriaxone 2 g IV QD for 14-28 days (1st line) c) alternative agents 1] Penicillin G 20 million units IV QD for 14-28 days 2] cefotaxime 2 g IV every 8 hours [1] d) 12 weeks of oral doxycycline or clarithromycin plus hydroxychloroquine following IV ceftriaxone no better than placebo [38] 4) late stage (incubation period months to years) a) some patients with late features are refractory to antibiotic therapy b) oral therapy for 28 days (confirmed Lyme arthritis) c) IV antibiotics to 14-28 days (confirmed Lyme encephalopathy) 5) post Lyme disease syndrome (do not diagnose chronic Lyme disease) - management is symptomatic - prolonged administration of antibiotics contraindicated [1] - retreatment of persistent Lyme disease controversial [15] - consider coinfection with anaplasmosis [36] 6) synovitis a) intra-articular corticosteroid injections b) disease-modifying antirheumatic drug (DMARD) [51] - hydroxychloroquine - methotrexate 20 mg weekly c) synovectomy 7) prophylaxis after tick bite a) risk of contracting Lyme disease from tick bite is low, thus prophylaxis is generally not recommended b) however, a single 200 mg oral dose of doxycycline within 72 hours is 87% effective [5,6] c) consider doxycycline prophylaxis in endemic areas [5,6] - tick is black-legged deer tick - tick attacthed > 36 hours, < 72 hours since tick removal [1] - not pregnant of lactating 8) Fibromyalgia associated with previous Lyme disease does not respond to antibiotic therapy 9) vaccination a) recombinant outer surface protein A (OspA) vaccine is well tolerated by human volunteers b) adequate levels of IgG against OspA to inhibit in vitro replication of Borrelia burgdorferi are obtained by vaccination 10) tick repellant (DEET) 11) prognosis: - 73% of children with confirmed Lyme disease with complete recovery - 27% with non-specific residual symptoms at 5 years allegedly not different from uninfected children [16] Notes: - unproven treatment for "chronic Lyme disease" can cause serious adverse events [39] - long courses of IV antibiotics or immunoglobulins - osteomyelitis - paraspinal abscess - C difficile colitis - septic shock - death

Related

Borrelia burgdorferi erythema chronicum migricans (erythema migrans) Jarisch-Herxheimer reaction

Specific

neuroborreliosis; Lyme Disease - Neurologic

General

borreliosis (relapsing fever) tick borne infection

References

  1. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  2. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 314, 509
  3. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 657-58, 879-80
  4. Schutzer SE, Coyle PK, Reid P, Holland B Borrelia burgdorferi-specific immune complexes in acute Lyme disease. JAMA. 1999 Nov 24;282(20):1942-6. PMID: 10580460
  5. Prescriber's Letter 8(7):39 2001
  6. Journal Watch 21(14):111, 2001 Nadelman et al, N Engl J Med 345:79, 2001 Shapiro, N Engl J Med 345:113, 2001
  7. Journal Watch 23(19):152, 2003 Steere AC et al, Clin Infect Dis 37:528, 2003
  8. Halperin JJ, Shapiro ED, Logigian E, Belman AL, Dotevall L, Wormser GP, Krupp L, Gronseth G, Bever CT Jr. Practice Parameter: Treatment of nervous system Lyme disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2007 May 23; [Epub ahead of print] PMID: 17522387 http://www.neurology.org/cgi/rapidpdf/01.wnl.0000265517.66976.28v1.pdf
  9. Prescriber's Letter 14(7): 2007 Detail-Document#: 230711 PATIENT HANDOUT: Lyme Disease Prevention and Treatment CHART: IDSA Guidelines for Treatment of Lyme Disease (subscription needed) http://www.prescribersletter.com
  10. Halperin JJ et al, Practice Parameter: Treatment of nervous system Lyme disease (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology> Neurology 2007, 69:91 PMID: 17522387
  11. Nigrovic LE et al. Clinical predictors of Lyme disease among children with a peripheral facial palsy at an emergency department in a Lyme disease-endemic area. Pediatrics 2008 Nov; 122:e1080 PMID: 18931349 http://dx.doi.org/10.1542/peds.2008-1273
  12. Ang CW et al. Large differences between test strategies for the detection of anti-Borrelia antibodies are revealed by comparing eight ELISAs and five immunoblots. Eur J Clin Microbiol Infect Dis 2011 Aug; 30:1027. PMID: 21271270
  13. Prescriber's Letter 19(6): 2012 CHART: IDSA Guidelines for Treatment of Lyme Disease PATIENT EDUCATION HANDOUT: Lyme Disease Prevention and Treatment Detail-Document#: 280615 (subscription needed) http://www.prescribersletter.com
  14. ARUP Consult: Borrelia Species - Lyme Disease and Borrelia hermsii The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/borrelia-species - Tick-Borne Testing ARUP Consult: The Physician's Guide to Laboratory Test Selection & Interpretation. http://www.arupconsult.com/Algorithms/LymeDz.pdf
  15. Delong AK et al Antibiotic retreatment of Lyme disease in patients with persistent symptoms: A biostatistical review of randomized, placebo-controlled, clinical trials Contemporary Clinical Trials Volume 33, Issue 6, November 2012, Pages 1132-1142 PMID: 22922244 http://www.sciencedirect.com/science/article/pii/S1551714412002030 - Wormser GP 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 Clinical Infectious Diseases Volume 43, Issue 9Pp. 1089-1134 PMID: 17029130 http://cid.oxfordjournals.org/content/43/9/1089.full corresponding NGC guideline withdrawn Feb 2016
  16. Skogman BH et al. Long-term clinical outcome after Lyme neuroborreliosis in childhood. Pediatrics 2012 Aug; 130:262 PMID: 22802606
  17. Physician's First Watch, Nov 15, 2012 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Nadelman RB et al. Differentiation of reinfection from relapse in recurrent Lyme disease. N Engl J Med 2012 Nov 15; 367:1883 - Steere AC. Reinfection versus relapse in Lyme disease. N Engl J Med 2012 Nov 15; 367:1950
  18. 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 Aug 11;44(31):590-1. PMID: 7623762
  19. Murray TS, Shapiro ED. Lyme disease. Clin Lab Med. 2010 Mar;30(1):311-28 PMID: 20513553
  20. Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet. 2012 Feb 4;379(9814):461-73. PMID: 21903253
  21. Centers for Disease Control and Prevention (CDC) Press Release. August 19, 2013 CDC provides estimate of Americans diagnosed with Lyme disease each year. http://www.cdc.gov/media/releases/2013/p0819-lyme-disease.html
  22. Centers for Disease Control and Prevention (CDC) Three Sudden Cardiac Deaths Associated with Lyme Carditis - United States, November 2012-July 2013 MMWR. December 13, 2013 / 62(49);993-996 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6249a1.htm
  23. Nelson C et al for the 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 Weekly. April 18, 2014 / 63(15);333-333 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6315a4.htm
  24. Prescriber's Letter 21(7): 2014 ALGORITHM: Stepwise Approach to Lyme Disease: From Tick Bite to Treatment CHART: IDSA Guidelines for Treatment of Lyme Disease PATIENT EDUCATION HANDOUT: Lyme Disease Prevention and Treatment PATIENT EDUCATION HANDOUT SPANISH VERSION: Enfermedad de Lyme Prevencion y Tratamiento Detail-Document#: 300704 (subscription needed) http://www.prescribersletter.com
  25. Redig AJ et al Interactive medical case. A Chilly Fever. N Engl J Med 2014; 371:e24O. ctober 16, 2014 PMID: 25317891 http://www.nejm.org/doi/full/10.1056/NEJMimc1315897
  26. Forrester JD et al Notes from the Field: Update on Lyme Carditis, Groups at High Risk, and Frequency of Associated Sudden Cardiac Death - United States. MMWR. Weekly October 31, 2014 / 63(43);982-983 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6343a4.htm
  27. Wormser GP et al. Long-term assessment of fatigue in patients with culture- confirmed Lyme disease. Am J Med 2015 Feb; 128:181 PMID: 25447620
  28. Regelin N, Montaruli E Images in clinical medicine. Disseminated Lyme Disease. N Engl J Med 2015; 372:2136. May 28, 2015 PMID: 26017824 http://www.nejm.org/doi/full/10.1056/NEJMicm1408084
  29. Hu LT In the clinic. Lyme disease. Ann Intern Med. 2012 Aug 7;157(3):ITC2-2 - ITC2-16 PMID: 22868858
  30. Lantos PM et al. Geographic expansion of Lyme disease in the southeastern United States, 2000-2014. Open Forum Infect Dis 2015 Sep 27 PMID: 26550580
  31. Pritt BS, Mead PS, Johnson DK et al Identification of a novel pathogenic Borrelia species causing Lyme borreliosis with unusually high spirochaetaemia: a descriptive study. Lancet Infectious Diseases. Feb 5, 2016 PMID: 26856777 http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2815%2900464-8/abstract - Wilhelmsson P, Lindgren PE Lancet Infectious Diseases. Feb 5, 2016 PMID: 26856776 http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2815%2900483-1/abstract
  32. DeBiasi RL A concise critical analysis of serologic testing for the diagnosis of lyme disease. Curr Infect Dis Rep. 2014 Dec;16(12):450. PMID: 25351855
  33. Centers for Disease Control and Prevention (CDC) (images) Signs and Symptoms of Untreated Lyme Disease. http://www.cdc.gov/lyme/signs_symptoms/
  34. DermNet NZ: Lyme disease (images) http://www.dermnetnz.org/bacterial/lyme.html
  35. Nadelman RB, Hanincova K, Mukherjee P et al Differentiation of reinfection from relapse in recurrent Lyme disease. N Engl J Med. 2012 Nov 15;367(20):1883-90. PMID: 23150958 Free PMC Article
  36. Horowitz HW, Aguero-Rosenfeld ME, Holmgren D et al Lyme disease and human granulocytic anaplasmosis coinfection: impact of case definition on coinfection rates and illness severity. Clin Infect Dis. 2013 Jan;56(1):93-9. PMID: 23042964 Free Article
  37. Shapiro ED. Clinical practice. Lyme disease. N Engl J Med. 2014 May 1;370(18):1724-31. PMID: 24785207 Free PMC Article
  38. Berende A, ter Hofstede HJ, Vos FJ et al Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease. N Engl J Med 2016; 374:1209-1220. March 31, 2016 PMID: 27028911 http://www.nejm.org/doi/full/10.1056/NEJMoa1505425 - Melia MT, Auwaerter PG. Time for a Different Approach to Lyme Disease and Long-Term Symptoms. N Engl J Med 2016; 374:1277-1278. March 31, 2016 PMID: 27028918 http://www.nejm.org/doi/full/10.1056/NEJMe1502350
  39. Marzec NS, Nelson C, Waldron PR, et al. Serious Bacterial Infections Acquired During Treatment of Patients Given a Diagnosis of Chronic Lyme Disease - United States. MMWR Morb Mortal Wkly Rep 2017;66:607-609 https://www.cdc.gov/mmwr/volumes/66/wr/mm6623a3.htm
  40. Obel N, Dessau RB, Krogfelt KA et al Long term survival, health, social functioning, and education in patients with European Lyme neuroborreliosis: nationwide population based cohort study. BMJ 2018;361:k1998 PMID: 29848547 Free full text https://www.bmj.com/content/361/bmj.k1998
  41. Rothaus C A Woman with Paresthesia and Weakness of the Foot and Abdominal Wall. NEJM Resident 360. Nov 07, 2018 https://resident360.nejm.org/content_items/a-woman-with-paresthesia-and-weakness-of-the-foot-and-abdominal-wall
  42. Arvikar SL, Steere AC. Diagnosis and treatment of Lyme arthritis. Infect Dis Clin North Am. 2015 Jun;29(2):269-80. Review. PMID: 25999223 PMCID: PMC4443866 Free PMC Article
  43. IDSA/AAN/ACR Draft Lyme Disease Guidelines. June 2019 https://www.idsociety.org/practice-guideline/Lyme-Disease-Guideline-Public-Comments/
  44. Jutras BL, Lochhead RB, Kloos ZA et al. Borrelia burgdorferi peptidoglycan is a persistent antigen in patients with Lyme arthritis. Proc Natl Acad Sci U S A 2019 Jul 2; 116:13498. PMID: 31209025 Free PMC Article https://www.pnas.org/content/116/27/13498
  45. Mead P, Petersen J, Hinckley A. Updated CDC Recommendation for Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep 2019;68:703 https://www.cdc.gov/mmwr/volumes/68/wr/mm6832a4.htm
  46. Pacheco A et al. Positive tests for Lyme disease and emergency department visits for Bell's palsy patients. J Emerg Med 2020 Sep 22; [e-pub]. PMID: 32978030 https://www.jem-journal.com/article/S0736-4679(20)30725-3/fulltext
  47. Lantos PM et al. Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the prevention, diagnosis and treatment of Lyme Disease. Clin Infect Dis 2020 Nov 30 http://fdslive.oup.com/www.oup.com/pdf/production_in_progress.pdf
  48. Pitrak D, Nguyen CT, Cifu AS. Diagnosis of Lyme Disease. JAMA. 2022;327(7):676-677. February 15. PMID: 35166814 https://jamanetwork.com/journals/jama/fullarticle/2789046
  49. Steele RW Lyme disease Medscape. June 15, 2022 https://reference.medscape.com/slideshow/tick-borne-illnesses-6006369
  50. Slomski A Shorter Duration of Antibiotics Noninferior for Lyme Disease. JAMA. 2022;328(20):2004 https://jamanetwork.com/journals/jama/fullarticle/2798743 - Stupica D, Collinet-Adler S, Blagus R et al Treatment of erythema migrans with doxycycline for 7 days versus 14 days in Slovenia: a randomised open-label non-inferiority trial. Lancet Infect Dis. 2022 Oct 6:S1473-3099(22)00528-X PMID: 36209759 https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00528-X/fulltext
  51. NEJM Knowledge+ Complex Medical Care - Lantos PM, Rumbaugh J, Bockenstedt LK et al Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease. Clin Infect Dis. 2021 Jan 23;72(1):e1-e48. PMID: 33417672
  52. National Institute of Allergy and Infectious Diseases (NIAID) Lyme Disease https://www.niaid.nih.gov/diseases-conditions/lyme-disease