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Volume 22, Number 7—July 2016

CME ACTIVITY - Synopsis

Current Guidelines, Common Clinical Pitfalls, and Future Directions for Laboratory Diagnosis of Lyme Disease, United States

Andrew Moore1, Christina A. Nelson1, Claudia Molins, Paul S. Mead, and Martin SchrieferComments to Author 
Author affiliations: University of Virginia School of Medicine, Charlottesville, Virginia, USA (A. Moore); Centers for Disease Control and Prevention, Fort Collins, Colorado, USA (C. Nelson, C. Molins, P. Mead, M. Schriefer)

Main Article

Table

Sensitivity and specificity of serologic tests for patients with Lyme disease, United States*

Variable Standard 2-tiered algorithm with whole-cell sonicate EIA†
Standard 2-tiered algorithm with C6 EIA,‡ Wormser et al. (13) Two-EIA algorithm§
Molins et al. (CDC Lyme Repository) (14) Wormser et al. (15) Branda et al. (12) Branda et al. (12) Wormser et al. (13,15)
% Sensitivity (no. tested)
Early Lyme disease with EM¶
Acute phase 40 (40) 38 (298) 42 (114) 38 (298) 53 (114) 58 (298)
Convalescent phase
61 (38)
27 (105)
57 (63)#
26 (105)
89 (63)#
67 (105)
Noncutaneous manifestations 96 (46) 94 (142) 87 (55) 93 (142) 100 (55) 97 (144)
Early disseminated Lyme disease 88 (17) 80 (20) 73 (26) 80 (20) 100 (26) ND
Late disseminated Lyme disease
100 (29)
96 (122)
100 (29)
95 (122)
100 (29)
ND
% Specificity (no. tested)
Healthy controls
Endemic area 98 (101) 99 (1,329) 99 (1,146) 99 (1,329) 99 (1,146) >99 (1,329)**
Nonendemic area
100 (102)
100 (513)
100 (100)
100 (513)
100 (100)
>99 (513)**
Controls with selected other diseases
Syphilis or RPR positive†† 95 (20) 95 (20) ND 95 (20) ND >95 (20)**
Infectious mononucleosis or EBV/CMV positive†† 90 (30) 100 (40) ND 100 (40) ND 100 (20)
Helicobacter pylori
ND
95 (20)
ND
100 (20)
ND
100 (20)
All nonhealthy controls 97 (144)‡‡ 99 (366)§§ 100 (54)¶¶ 100 (366)§§ 100 (54)¶¶ 100 (366)

*All percentage values were rounded to the nearest whole number. C6, C6 peptide of Borrelia burgdorferi; CDC, Centers for Disease Control and Prevention; CMV, cytomegalovirus; EIA, enzyme immunoassay; EM, erythema migrans; EBV, Epstein-Barr virus; ND, not done; RPR, rapid plasma regain.
†Standard 2-tiered algorithm: whole-cell sonicate EIA, then IgG (+IgM if presenting within 1 month) Western immune blot if positive or equivocal result.
‡C6+ Western immunoblot algorithm: C6 EIA, then IgG (+IgM if presenting within 1 month) Western immunoblot if positive or equivocal result.
§Two-tiered EIA: whole-cell sonicate EIA, then C6 EIA if positive or equivocal result.
¶Patients with EM and epidemiologic risk can be given a diagnosis without serologic analysis (see Figure 3).
#Branda et al. (12) conducted only convalescent-phase serologic analysis on a well-characterized serum set of Lyme disease patients and controls. All other data points from this study include the data from well-characterized serum set and serum samples submitted to Massachusetts General Hospital (Boston, MA, USA) for routine testing.
**Minimum specificity reported by Wormser et al. (13,15).
††Molins et al. (14) tested samples from patients with syphilis or infectious mononucleosis. Wormser et al. (13,15) tested blood samples with positive results for RPR or CMV/EBV.
‡‡In the report by Molins et al. (14), 2-tiered testing had 100% specificity for all other diseases not mentioned above. Other conditions tested include fibromyalgia, severe periodontitis, rheumatoid arthritis, and multiple sclerosis.
§§Among patients tested by Wormser et al. (13,15) there was a single hemolyzed blood sample that showed positive results for all tests. However, both methods of 2-tiered testing had 100% specificity for all other conditions not mentioned above, including Mycoplasma pneumoniae infection; HIV; hepatitis A, B, and C; influenza vaccinations; antinuclear antibodies; lipemia; icterus; systemic lupus erythematosus; rheumatoid arthritis; and positive results for rheumatoid factor.
¶¶Includes 25 patients with chronic fatigue syndrome or fibromyalgia, 14 with rheumatic diseases, 9 with neurologic conditions, 5 with infections, and 1 with T-cell lymphoma.

Main Article

References
  1. Stanek  G, Wormser  GP, Gray  J, Strle  F. Lyme borreliosis. Lancet. 2012;379:461–73. DOIPubMedGoogle Scholar
  2. Pritt  BS, Mead  PS, Johnson  DK, Neitzel  DF, Respicio-Kingry  LB, Davis  JP, Identification of a novel pathogenic Borrelia species causing Lyme borreliosis with unusually high spirochataemia: a descriptive study. Lancet Infect Dis. 2016;Feb 5:pii: S1473-3099(15)00464-8.
  3. Adams  DA, Jajosky  RA, Ajani  U, Kriseman  J, Sharp  P, Onwen  DH, Summary of notifiable diseases—United States, 2012. MMWR Morb Mortal Wkly Rep. 2014;61:1–121.PubMedGoogle Scholar
  4. Nelson  CA, Saha  S, Kugeler  KJ, Delorey  MJ, Shankar  MB, Hinckley  AF, Incidence of clinician-diagnosed Lyme disease, United States, 2005–2010. Emerg Infect Dis. 2015;21:1625–31. DOIPubMedGoogle Scholar
  5. Kugeler  KJ, Farley  GM, Forrester  JD, Mead  PS. Geographic distribution and expansion of human Lyme disease, United States. Emerg Infect Dis. 2015;21:1455–7. DOIPubMedGoogle Scholar
  6. Wormser  GP, Dattwyler  RJ, Shapiro  ED, Halperin  JJ, Steere  AC, Klempner  MS, 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. DOIPubMedGoogle Scholar
  7. Centers for Disease Control and Prevention. Recommendations for test performance and interpretation from the Second National Conference on serologic diagnosis of Lyme disease. MMWR Morb Mortal Wkly Rep. 1995;44:590–1.PubMedGoogle Scholar
  8. Seltzer  EG, Shapiro  ED. Misdiagnosis of Lyme disease: when not to order serologic tests. Pediatr Infect Dis J. 1996;15:762–3. DOIPubMedGoogle Scholar
  9. Centers for Disease Control and Prevention. Notice to readers: caution regarding testing for Lyme disease. MMWR Morb Mortal Wkly Rep. 2005;54:125 [cited 2016 Mar 14]. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5405a6.htm
  10. Aguero-Rosenfeld  ME, Wang  G, Schwartz  I, Wormser  GP. Diagnosis of Lyme borreliosis. Clin Microbiol Rev. 2005;18:484–509. DOIPubMedGoogle Scholar
  11. Craven  RB, Quan  TJ, Bailey  RE, Dattwyler  R, Ryan  RW, Sigal  LH, Improved serodiagnostic testing for Lyme disease: results of a multicenter serologic evaluation. Emerg Infect Dis. 1996;2:136–40. DOIPubMedGoogle Scholar
  12. Branda  JA, Linskey  K, Kim  YA, Steere  AC, Ferraro  MJ. Two-tiered antibody testing for Lyme disease with use of 2 enzyme immunoassays, a whole-cell sonicate enzyme immunoassay followed by a VlsE C6 peptide enzyme immunoassay. Clin Infect Dis. 2011;53:541–7. DOIPubMedGoogle Scholar
  13. Wormser  GP, Schriefer  M, Aguero-Rosenfeld  ME, Levin  A, Steere  AC, Nadelman  RB, Single-tier testing with the C6 peptide ELISA kit compared with two-tier testing for Lyme disease. Diagn Microbiol Infect Dis. 2013;75:9–15. DOIPubMedGoogle Scholar
  14. Molins  CR, Sexton  C, Young  JW, Ashton  LV, Pappert  R, Beard  CB, Collection and characterization of samples for establishment of a serum repository for Lyme disease diagnostic test development and evaluation. J Clin Microbiol. 2014;52:3755–62. DOIPubMedGoogle Scholar
  15. Wormser  GP, Levin  A, Soman  S, Adenikinju  O, Longo  MV, Branda  JA. Comparative cost-effectiveness of two-tiered testing strategies for serodiagnosis of Lyme disease with noncutaneous manifestations. J Clin Microbiol. 2013;51:4045–9. DOIPubMedGoogle Scholar
  16. Food and Drug Administration. Database: search on product code LSR [cited 2015 Jul 17]. http://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm
  17. Bacon  RM, Biggerstaff  BJ, Schriefer  ME, Gilmore  RD Jr, Philipp  MT, Steere  AC, Serodiagnosis of Lyme disease by kinetic enzyme-linked immunosorbent assay using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi compared with 2-tiered testing using whole-cell lysates. J Infect Dis. 2003;187:1187–99. .DOIPubMedGoogle Scholar
  18. Liang  FT, Steere  AC, Marques  AR, Johnson  BJ, Miller  JN, Philipp  MT. Sensitive and specific serodiagnosis of Lyme disease by enzyme-linked immunosorbent assay with a peptide based on an immunodominant conserved region of Borrelia burgdorferi VlsE. J Clin Microbiol. 1999;37:3990–6.PubMedGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. Nelson  C, Elmendorf  S, Mead  P. Neoplasms misdiagnosed as “chronic Lyme disease.”. JAMA Intern Med. 2015;175:132–3. DOIPubMedGoogle Scholar
  21. Steere  AC, Berardi  VP, Weeks  KE, Logigian  EL, Ackermann  R. Evaluation of the intrathecal antibody response to Borrelia burgdorferi as a diagnostic test for Lyme neuroborreliosis. J Infect Dis. 1990;161:1203–9. DOIPubMedGoogle Scholar
  22. Babady  NE, Sloan  LM, Vetter  EA, Patel  R, Binnicker  MJ. Percent positive rate of Lyme real-time polymerase chain reaction in blood, cerebrospinal fluid, synovial fluid, and tissue. Diagn Microbiol Infect Dis. 2008;62:464–6. .DOIPubMedGoogle Scholar
  23. Molloy  PJ, Persing  DH, Berardi  VP. False-positive results of PCR testing for Lyme disease. Clin Infect Dis. 2001;33:412–3. DOIPubMedGoogle Scholar
  24. Nocton  JJ, Bloom  BJ, Rutledge  BJ, Persing  DH, Logigian  EL, Schmid  CH, Detection of Borrelia burgdorferi DNA by polymerase chain reaction in cerebrospinal fluid in Lyme neuroborreliosis. J Infect Dis. 1996;174:623–7. DOIPubMedGoogle Scholar
  25. Molloy  PJ, Telford  SR III, Chowdri  HR, Lepore  TJ, Gugliotta  JL, Weeks  KE, Borrelia miyamotoi disease in the northeastern United States: a case series. Ann Intern Med. 2015;163:91–8. DOIPubMedGoogle Scholar
  26. Hilton  E, DeVoti  J, Benach  JL, Halluska  ML, White  DJ, Paxton  H, Seroprevalence and seroconversion for tick-borne diseases in a high-risk population in the northeast United States. Am J Med. 1999;106:404–9. DOIPubMedGoogle Scholar
  27. Kalish  RA, McHugh  G, Granquist  J, Shea  B, Ruthazer  R, Steere  AC. Persistence of immunoglobulin M or immunoglobulin G antibody responses to Borrelia burgdorferi 10–20 years after active Lyme disease. Clin Infect Dis. 2001;33:780–5. DOIPubMedGoogle Scholar
  28. Nadelman  RB, Wormser  GP. Reinfection in patients with Lyme disease. Clin Infect Dis. 2007;45:1032–8. DOIPubMedGoogle Scholar
  29. Lantos  PM, Branda  JA, Boggan  JC, Chudgar  SM, Wilson  EA, Ruffin  F, Poor positive predictive value of Lyme disease serologic testing in an area of low disease incidence. Clin Infect Dis. 2015;61:1374–80. DOIPubMedGoogle Scholar
  30. Masters  EJ, Grigery  CN, Masters  RW. STARI, or Masters disease: Lone Star tick–vectored Lyme-like illness. Infect Dis Clin North Am. 2008;22:361–76. DOIPubMedGoogle Scholar
  31. Forrester  JD, Brett  M, Matthias  J, Stanek  D, Springs  CB, Marsden-Haug  N, Epidemiology of Lyme disease in low-incidence states. Ticks Tick Borne Dis. 2015;6:721–3. DOIPubMedGoogle Scholar
  32. Steere  AC, Dhar  A, Hernandez  J, Fischer  PA, Sikand  VK, Schoen  RT, Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease. Am J Med. 2003;114:58–62. DOIPubMedGoogle Scholar
  33. Nelson  C, Johnson  B, Petersen  J, Schriefer  M, Beard  CB, Petersen  L, 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..PubMedGoogle Scholar
  34. Fallon  BA, Pavlicova  M, Coffino  SW, Brenner  C. A comparison of Lyme disease serologic test results from 4 laboratories in patients with persistent symptoms after antibiotic treatment. Clin Infect Dis. 2014;59:1705–10. DOIPubMedGoogle Scholar
  35. Johnson  BJ, Pilgard  MA, Russell  TM. Assessment of new culture method for detection of Borrelia species from serum of Lyme disease patients. J Clin Microbiol. 2014;52:721–4. DOIPubMedGoogle Scholar
  36. Klempner  MS, Schmid  CH, Hu  L, Steere  AC, Johnson  G, McCloud  B, Intralaboratory reliability of serologic and urine testing for Lyme disease. Am J Med. 2001;110:217–9. DOIPubMedGoogle Scholar
  37. Marques  A, Brown  MR, Fleisher  TA. Natural killer cell counts are not different between patients with post-Lyme disease syndrome and controls. Clin Vaccine Immunol. 2009;16:1249–50. DOIPubMedGoogle Scholar
  38. Molins  CR, Ashton  LV, Wormser  GP, Hess  AM, Delorey  MJ, Mahapatra  S, Development of a metabolic biosignature for detection of early Lyme disease. Clin Infect Dis. 2015;60:1767–75. DOIPubMedGoogle Scholar
  39. Schnell  G, Boeuf  A, Westermann  B, Jaulhac  B, Lipsker  D, Carapito  C, Discovery and targeted proteomics on cutaneous biopsies infected by Borrelia to investigate Lyme disease. Mol Cell Proteomics. 2015;14:1254–64. DOIPubMedGoogle Scholar
  40. Halpern  MD, Molins  CR, Schriefer  M, Jewett  MW. Simple objective detection of human Lyme disease infection using immuno-PCR and a single recombinant hybrid antigen. Clin Vaccine Immunol. 2014;21:1094–105. DOIPubMedGoogle Scholar

Main Article

1These authors contributed equally to this article.

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Page updated: November 30, 2016
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