Post-treatment Lyme disease symptoms score: Developing a new tool for research

Autoři: Siu P. Turk aff001;  Keith Lumbard aff002;  Kelly Liepshutz aff003;  Carla Williams aff003;  Linden Hu aff004;  Kenneth Dardick aff005;  Gary P. Wormser aff006;  Joshua Norville aff004;  Carol Scavarda aff006;  Donna McKenna aff006;  Dean Follmann aff007;  Adriana Marques aff001
Působiště autorů: Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America aff001;  Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America aff002;  Leidos Biomedical Research, Inc., Clinical Services Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America aff003;  Tufts University School of Medicine, Boston, Massachusetts, United States of America aff004;  Mansfield Family Practice, Storrs, Connecticut, United States of America aff005;  Infectious Diseases, New York Medical College, Valhalla, New York, United States of America aff006;  Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America aff007
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225012


Some patients have residual non-specific symptoms after therapy for Lyme disease, referred to as post-treatment Lyme disease symptoms or syndrome, depending on whether there is functional impairment. A standardized test battery was used to characterize a diverse group of Lyme disease patients with and without residual symptoms. There was a strong correlation between sleep disturbance and certain other symptoms such as fatigue, pain, anxiety, and cognitive complaints. Results were subjected to a Logistic Regression model using the Neuro-QoL Fatigue t-score together with Short Form-36 Physical Functioning scale and Mental Health component scores; and to a Decision Tree model using only the QoL Fatigue t-score. The Logistic Regression model had an accuracy of 97% and Decision Tree model had an accuracy of 93%, when compared with clinical categorization. The Logistic Regression and Decision Tree models were then applied to a separate cohort. Both models performed with high sensitivity (90%), but moderate specificity (62%). The overall accuracy was 74%. Agreement between 2 time points, separated by a mean of 4 months, was 89% using the Decision Tree model and 87% with the Logistic Regression model. These models are simple and can help to quantitate the level of symptom severity in post-treatment Lyme disease symptoms. More research is needed to increase the specificity of the models, exploring additional approaches that could potentially strengthen an operational definition for post-treatment Lyme disease symptoms. Evaluation of how sleep disturbance, fatigue, pain and cognitive complains interrelate can potentially lead to new interventions that will improve the overall health of these patients.

Klíčová slova:

Antibiotics – Decision trees – Emotions – Erythema – Fatigue – Lyme disease – Mental health and psychiatry – Sleep


1. 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. Epub 2002/03/20. doi: 10.7326/0003-4819-136-6-200203190-00005 11900494.

2. Nowakowski J, Nadelman RB, Sell R, McKenna D, Cavaliere LF, Holmgren D, et al. Long-term follow-up of patients with culture-confirmed Lyme disease. Am J Med. 2003;115(2):91–6. Epub 2003/08/02. doi: 10.1016/s0002-9343(03)00308-5 12893393.

3. Wormser GP, Ramanathan R, Nowakowski J, McKenna D, Holmgren D, Visintainer P, et al. Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138(9):697–704. Epub 2003/05/06. doi: 10.7326/0003-4819-138-9-200305060-00005 12729423.

4. 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(9):1089–134. Epub 2006/10/10. doi: 10.1086/508667 17029130.

5. Kowalski TJ, Tata S, Berth W, Mathiason MA, Agger WA. Antibiotic treatment duration and long-term outcomes of patients with early lyme disease from a lyme disease-hyperendemic area. Clin Infect Dis. 2010;50(4):512–20. Epub 2010/01/15. doi: 10.1086/649920 20070237.

6. Cerar D, Cerar T, Ruzic-Sabljic E, Wormser GP, Strle F. Subjective symptoms after treatment of early Lyme disease. Am J Med. 2010;123(1):79–86. Epub 2010/01/28. doi: 10.1016/j.amjmed.2009.05.011 20102996.

7. Tory HO, Zurakowski D, Sundel RP. Outcomes of children treated for Lyme arthritis: results of a large pediatric cohort. J Rheumatol. 2010;37(5):1049–55. Epub 2010/04/03. doi: 10.3899/jrheum.090711 20360182.

8. Nizic T, Velikanje E, Ruzic-Sabljic E, Arnez M. Solitary erythema migrans in children: comparison of treatment with clarithromycin and amoxicillin. Wien Klin Wochenschr. 2012;124(13–14):427–33. Epub 2012/07/05. doi: 10.1007/s00508-012-0194-1 22760494.

9. Stupica D, Lusa L, Ruzic-Sabljic E, Cerar T, Strle F. Treatment of erythema migrans with doxycycline for 10 days versus 15 days. Clin Infect Dis. 2012;55(3):343–50. Epub 2012/04/24. doi: 10.1093/cid/cis402 22523260.

10. Arnez M, Ruzic-Sabljic E. Azithromycin Is Equally Effective as Amoxicillin in Children with Solitary Erythema Migrans. Pediatr Infect Dis J. 2015;34(10):1045–8. Epub 2015/07/18. doi: 10.1097/INF.0000000000000804 26186104.

11. Bechtold KT, Rebman AW, Crowder LA, Johnson-Greene D, Aucott JN. Standardized Symptom Measurement of Individuals with Early Lyme Disease Over Time. Arch Clin Neuropsychol. 2017;32(2):129–41. Epub 2017/04/04. doi: 10.1093/arclin/acw098 28365751.

12. Borsic K, Blagus R, Cerar T, Strle F, Stupica D. Clinical Course, Serologic Response, and Long-Term Outcome in Elderly Patients with Early Lyme Borreliosis. J Clin Med. 2018;7(12). Epub 2018/12/06. doi: 10.3390/jcm7120506 30513820

13. Eliassen KE, Hjetland R, Reiso H, Lindbaek M, Tschudi-Madsen H. Symptom load and general function among patients with erythema migrans: a prospective study with a 1-year follow-up after antibiotic treatment in Norwegian general practice. Scand J Prim Health Care. 2017;35(1):75–83. Epub 2017/03/10. doi: 10.1080/02813432.2017.1288812 28277054

14. Batheja S, Nields JA, Landa A, Fallon BA. Post-treatment lyme syndrome and central sensitization. J Neuropsychiatry Clin Neurosci. 2013;25(3):176–86. Epub 2013/09/13. doi: 10.1176/appi.neuropsych.12090223 24026711.

15. Touradji P, Aucott JN, Yang T, Rebman AW, Bechtold KT. Cognitive Decline in Post-treatment Lyme Disease Syndrome. Arch Clin Neuropsychol. 2018. Epub 2018/06/27. doi: 10.1093/arclin/acy051 29945190.

16. Marques A, Telford SR 3rd, Turk SP, Chung E, Williams C, Dardick K, et al. Xenodiagnosis to detect Borrelia burgdorferi infection: a first-in-human study. Clin Infect Dis. 2014;58(7):937–45. Epub 2014/02/14. doi: 10.1093/cid/cit939 24523212

17. Chandra A, Wormser GP, Klempner MS, Trevino RP, Crow MK, Latov N, et al. Anti-neural antibody reactivity in patients with a history of Lyme borreliosis and persistent symptoms. Brain Behav Immun. 2010;24(6):1018–24. Epub 2010/03/17. doi: 10.1016/j.bbi.2010.03.002 20227484

18. 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(2):85–92. Epub 2001/07/14. doi: 10.1056/NEJM200107123450202 11450676.

19. 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(12):1923–30. Epub 2003/06/25. doi: 10.1212/01.wnl.0000071227.23769.9e 12821734.

20. 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(13):992–1003. Epub 2007/10/12. doi: 10.1212/01.WNL.0000284604.61160.2d 17928580.

21. Aucott JN, Crowder LA, Kortte KB. Development of a foundation for a case definition of post-treatment Lyme disease syndrome. Int J Infect Dis. 2013;17(6):e443–9. Epub 2013/03/07. doi: 10.1016/j.ijid.2013.01.008 23462300.

22. Aucott JN, Rebman AW, Crowder LA, Kortte KB. Post-treatment Lyme disease syndrome symptomatology and the impact on life functioning: is there something here? Qual Life Res. 2013;22(1):75–84. Epub 2012/02/02. doi: 10.1007/s11136-012-0126-6 22294245

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 (Lausanne). 2017;4:224. Epub 2018/01/10. doi: 10.3389/fmed.2017.00224 29312942

24. CDC. Lyme Disease (Borrelia burgdorferi) 2017 Case Definition 2017 [

25. Ware JE Jr. SF-36 health survey update. Spine (Phila Pa 1976). 2000;25(24):3130–9. Epub 2000/12/22. doi: 10.1097/00007632-200012150-00008 11124729.

26. Ware JE., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473–83. Epub 1992/06/11. 1593914.

27. Ware JJ, Kosinski M, Dewey J. How to score version 2 of the SF-36 Health Survey (standard and acute forms). QualityMetric, Inc.; 2005.

28. 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. Epub 2016/03/31. doi: 10.1093/cid/ciw189 27025825

29. Hays RD, Sherbourne CD, Mazel RM. The RAND 36-Item Health Survey 1.0. Health Econ. 1993;2(3):217–27. Epub 1993/10/01. doi: 10.1002/hec.4730020305 8275167.

30. HealthMeasures. NeuroQoL Interpretation [

31. Gershon RC, Lai JS, Bode R, Choi S, Moy C, Bleck T, et al. Neuro-QOL: quality of life item banks for adults with neurological disorders: item development and calibrations based upon clinical and general population testing. Qual Life Res. 2012;21(3):475–86. Epub 2011/08/30. doi: 10.1007/s11136-011-9958-8 21874314

32. Cella D, Lai JS, Nowinski CJ, Victorson D, Peterman A, Miller D, et al. Neuro-QOL: brief measures of health-related quality of life for clinical research in neurology. Neurology. 2012;78(23):1860–7. Epub 2012/05/11. doi: 10.1212/WNL.0b013e318258f744 22573626

33. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46(10):1121–3. doi: 10.1001/archneur.1989.00520460115022 2803071

34. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Hauser W, Katz RL, et al. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. 2016;46(3):319–29. Epub 2016/12/06. doi: 10.1016/j.semarthrit.2016.08.012 27916278.

35. Newcombe R. Two-Sided Confidence Intervals for the Single Proportion: Comparison of Seven Methods. Statistics in Medicine. 1998;17:857–72. doi: 10.1002/(sici)1097-0258(19980430)17:8<857::aid-sim777>;2-e 9595616

36. Schwartz JE, Jandorf L, Krupp LB. The measurement of fatigue: a new instrument. J Psychosom Res. 1993;37(7):753–62. doi: 10.1016/0022-3999(93)90104-n 8229906

37. Scoggins JF, Patrick DL. The use of patient-reported outcomes instruments in registered clinical trials: evidence from Contemp Clin Trials. 2009;30(4):289–92. Epub 2009/03/12. doi: 10.1016/j.cct.2009.02.005 19275948

38. Geebelen L, Lernout T, Kabamba-Mukadi B, Saegeman V, Sprong H, Van Gucht S, et al. The HUMTICK study: protocol for a prospective cohort study on post-treatment Lyme disease syndrome and the disease and cost burden of Lyme borreliosis in Belgium. Arch Public Health. 2017;75:42. Epub 2017/08/11. doi: 10.1186/s13690-017-0202-z 28794875

39. Djukic M, Schmidt-Samoa C, Nau R, von Steinbuchel N, Eiffert H, Schmidt H. The diagnostic spectrum in patients with suspected chronic Lyme neuroborreliosis—the experience from one year of a university hospital’s Lyme neuroborreliosis outpatients clinic. Eur J Neurol. 2011;18(4):547–55. Epub 2010/10/28. doi: 10.1111/j.1468-1331.2010.03229.x 20977545.

40. 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. Epub 2016/03/31. doi: 10.1056/NEJMoa1505425 27028911.

41. Eikeland R, Mygland A, Herlofson K, Ljostad U. European neuroborreliosis: quality of life 30 months after treatment. Acta Neurol Scand. 2011;124(5):349–54. Epub 2011/02/10. doi: 10.1111/j.1600-0404.2010.01482.x 21303350.

42. Eikeland R, Mygland A, Herlofson K, Ljostad U. Risk factors for a non-favorable outcome after treated European neuroborreliosis. Acta Neurol Scand. 2013;127(3):154–60. Epub 2012/06/14. doi: 10.1111/j.1600-0404.2012.01690.x 22690926.

43. Shadick NA, Phillips CB, Sangha O, Logigian EL, Kaplan RF, Wright EA, et al. Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease. Ann Intern Med. 1999;131(12):919–26. Epub 1999/12/28. doi: 10.7326/0003-4819-131-12-199912210-00003 10610642.

44. Seltzer EG, Gerber MA, Cartter ML, Freudigman K, Shapiro ED. Long-term outcomes of persons with Lyme disease. JAMA. 2000;283(5):609–16. Epub 2000/02/09. doi: 10.1001/jama.283.5.609 10665700.

45. Kowalski TJ, Berth WL, Mathiason MA, Agger WA. Oral antibiotic treatment and long-term outcomes of Lyme facial nerve palsy. Infection. 2011;39(3):239–45. Epub 2011/04/28. doi: 10.1007/s15010-011-0107-7 21523405.

46. Jares TM, Mathiason MA, Kowalski TJ. Functional outcomes in patients with Borrelia burgdorferi reinfection. Ticks Tick Borne Dis. 2014;5(1):58–62. Epub 2013/11/13. doi: 10.1016/j.ttbdis.2013.09.002 24215678.

47. 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. Epub 2015/04/19. doi: 10.1093/cid/civ277 25888674.

48. 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. Epub 2016/08/25. doi: 10.1016/j.diagmicrobio.2016.07.026 27553702

49. Corporation R. 36-Item Short Form Survey (SF-36) 2008 [cited 2019 2/8/2019].

50. Petrie KJ, Faasse K, Crichton F, Grey A. How common are symptoms? Evidence from a New Zealand national telephone survey. BMJ Open. 2014;4(6):e005374. Epub 2014/06/15. doi: 10.1136/bmjopen-2014-005374 24928596

51. Nijrolder I, Leone SS, van der Horst HE. Explaining fatigue: an examination of patient causal attributions and their (in)congruence with family doctors’ initial causal attributions. Eur J Gen Pract. 2015;21(3):164–9. Epub 2015/07/03. doi: 10.3109/13814788.2015.1055556 26134092.

52. Koffel E, Kroenke K, Bair MJ, Leverty D, Polusny MA, Krebs EE. The bidirectional relationship between sleep complaints and pain: Analysis of data from a randomized trial. Health Psychol. 2016;35(1):41–9. Epub 2015/06/16. doi: 10.1037/hea0000245 26076002

53. Krause AJ, Prather AA, Wager TD, Lindquist MA, Walker MP. The pain of sleep loss: A brain characterization in humans. J Neurosci. 2019. Epub 2019/01/30. doi: 10.1523/JNEUROSCI.2408-18.2018 30692228.

54. Smith MT, Haythornthwaite JA. How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature. Sleep Med Rev. 2004;8(2):119–32. Epub 2004/03/23. doi: 10.1016/S1087-0792(03)00044-3 15033151.

55. Krause AJ, Simon EB, Mander BA, Greer SM, Saletin JM, Goldstein-Piekarski AN, et al. The sleep-deprived human brain. Nat Rev Neurosci. 2017;18(7):404–18. Epub 2017/05/19. doi: 10.1038/nrn.2017.55 28515433

56. Weinstein ER, Rebman AW, Aucott JN, Johnson-Greene D, Bechtold KT. Sleep quality in well-defined Lyme disease: a clinical cohort study in Maryland. Sleep. 2018;41(5). Epub 2018/02/17. doi: 10.1093/sleep/zsy035 29452400.

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