Lyme disease is the most common vector-borne infection in the United States. Recent dramatic increases in the number of reported cases reflect increased disease awareness, as well as spread of infected vectors and reservoirs into most geographic regions in the US. Currently, the only practical laboratory means of diagnosing Lyme disease is based on serologic tests. The demand for these tests has soared as more physicians and the lay public confront the protean clinical manifestations of Borrelia burgdorferi infection. Enzyme-linked immunosorbent analysis (ELISA) is the most useful serologic method currently available; nonetheless, this and other methods are hampered by false–positive and false–negative results. This article reviews the human immune response to B. burgdorferi, the various available Lyme disease serodiagnostic tests, the causes of false serologic test results, and prospects for improvements in Lyme disease diagnosis.
SteereA.C.MalawistaS.E.SnydmanD.R.ShopeR.E.AndimanW.A.RossM.R.SteeleF.M.Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum1977; 20, 7–17
2.
Centers for Disease Control. Lyme disease – United States, 1987 and 1988. MMWR 1989; 38, 668–72.
3.
GuyE.C.BatemanD.E.MartynC.N.HeckelsJ.E.LawtonN.F.Lyme disease: prevalence and clinical importance of Borrelia burgdorferi specific IgG in forestry workers. Lancet1989; 1, 484–486
4.
SchwartzB.S.GoldsteinM.D.Lyme disease in outdoor workers: risk factors, preventive measures, and tick removal methods. Am J Epidemiol1990; 131, 877–885
SchmidG.P.The global distribution of lyme disease. Rev Infect Dis1985; 7, 41–50
7.
CiesielskiC.A.MarkowitzL.E.HorsleyR.HightowerA.W.RussellH.BroomeC.V.Lyme disease surveillance in the United States, 1983–1986. Rev Infect Dis1989; 11(suppl 6), S1435–S1441
8.
BoslerE.M.OrmistonB.G.ColemanJ.L.HanrahanJ.P.BenachJ.L.Prevalence of the Lyme disease spirochete in populations of white-tailed deer and white-footed mice. Yale J Biol Med1984; 57, 651–659
9.
FalcoR.C.FishD.Prevalence of Ixodes dammini near the homes of Lyme disease patients in Westchester County, New York. Am J Epidemiol1988; 127, 826–830
10.
LaneR.S.LavoieP.E.Lyme borreliosis in California: acarological, clinical, and epidemiological studies. Ann N Y Acad Sci1988; 539, 192–203
11.
LastavicaC.C.WilsonM.L.BerardiV.P.SpielmanA.DeblingerR.D.Rapid emergence of a focal epidemic of Lyme disease in coastal Massachusetts. N Engl J Med1989; 320, 133–137
12.
BurgdorferW.BarbourA.G.HayesS.F.BenachJ.L.GrunwaldtE.DavisJ.P.Lyme disease – a tick-borne spirochetosis?. Science1982; 216, 1317–1319
13.
SteereA.C.GrodzickiR.L.KornblattA.N.CraftJ.E.BarbourA.G.BurgdorferW.SchmidG.P.JohnsonE.MalawistaS.E.The spirochetal etiology of Lyme disease. N Engl J Med1983; 308, 733–740
14.
BoslerE.M.ColemanJ.L.BenachJ.L.MasseyD.A.HanrahanJ.P.BurgdorferW.BarbourA.G.Natural Distribution of the Ixodes dammini spirochete. Science1983; 220, 321–322
15.
BarbourA.G.HayesS.F.Biology of Borrelia species. Microbiol Rev1986; 50, 381–400
16.
BarbourA.G.HeilandR.A.HoweT.R.Heterogeneity of major proteins in Lyme disease borreliae: a molecular analysis of North American and European isolates. J Infect Dis1985; 152, 478–484
17.
WilskeB.Preac-MursicV.SchierzG.KuhbeckR.BarbourA.G.KramerM.Antigenic variability of Borrelia burgdorferi. Ann N Y Acad Sci1988; 539, 126–143
18.
BissettM.L.HillW.Characterization of Borrelia burgdorferi strains isolated from Ixodes pacificus ticks in California. J Clin Microbiol1987; 25, 2296–2301
19.
LeFebvreR.B.LaneR.S.PerngG.C.BrownJ.A.JohnsonR.C.DNA and protein analyses of tick-derived isolates of Borrelia burgdorferi from California. J Clin Microbiol1990; 28, 700–707
20.
SchwanT.G.BurgdorferW.Antigenic changes of Borrelia burgdorferi as a result of in vitro cultivation [letter]. J Infect Dis1987; 156, 852–853
21.
BarbourA.G.Plasmid analysis of Borrelia burgdorferi, the Lyme disease agent. J Clin Microbiol1988; 26, 475–478
22.
PiesmanJ.SinskyR.J.Ability of Ixodes scapularis, Dermacentor vaiabilis, and Amblyomma americanum (Acari: Ixodidae) to acquire, maintain, and transmit Lyme disease spirochetes (Borrelia burgdorferi). J Med Entomol1988; 25, 336–339
23.
BurgdorferW.GageK.L.Susceptibility of the black-legged tick, Ixodes scapularis, to the Lyme disease spirochete, Borrelia burgdorferi. Zentralbl Bakteriol Mikrobiol Hyg [a]1986; 263, 15–20
SteereA.C.BartenhagenN.H.CraftJ.E.HutchinsonG.J.NewmanJ.H.RahnD.W.SigalL.H.SpielerP.N.StennK.S.MalawistaS.E.The early clinical manifestations of Lyme disease. Ann Intern Med1983; 99, 76–82
MagnarelliL.A.AndersonJ.F.Ticks and biting insects infected with the etiologic agent of Lyme disease, Borrelia burgdorferi. J Clin Microbiol1988; 26, 1482–1486
29.
LugerS.W.Lyme disease transmitted by a biting fly. N Engl J Med1990; 322, 1752
30.
TelfordS.R.MatherT.N.MooreS.I.WilsonM.L.SpielmanA.Incompetence of deer as reservoirs of the Lyme disease spirochete. Am J Trop Med Hyg1988; 39, 105–109
31.
WeisbrodA.R.JohnsonR.C.Lyme disease the migrating birds in the Saint Croix River Valley. Appl Environ Microbiol1989; 55, 1921–1924
32.
PiesmanJ.MatherT.N.SinskyR.J.SpielmanA.Duration of tick attachment and Borrelia burgdorferi transmission. J Clin Microbiol1987; 25, 557–558
33.
AsbrinkE.HovmarkA.Early and late cutaneous manifestations in Ixodes-borne borreliosis (erythema migrans borreliosis, Lyme borreliosis). Ann N Y AcadSci1988; 539, 4–15
34.
SteereA.C.Lyme disease. N Engl J Med1989; 321, 586–596
35.
MalaneM.S.GrantK.J.FederH.J.LugerS.W.Diagnosis of Lyme disease based on dermatologic manifestations. Ann Intern Med1991; 114, 490–498
36.
McAlisterH.F.KlementowiczP.T.AndrewsC.FisherJ.D.FeldM.FurmanS.Lyme carditis: an important cause of reversible heart block [see comments]. Ann Intern Med1989; 110, 339–345
37.
KimballS.A.JansonP.A.LaRaiaP.J.Complete heart block as the sole presentation of Lyme disease. Arch Intern Med1989; 149, 1897–1898
38.
ClarkJ.R.CarlsonR.D.SasakiC.T.PachnerA.R.SteereA.C.Facial paralysis in Lyme disease. Laryngoscope1985; 95, 1341–1345
39.
HanrahanJ.P.BenachJ.L.ColemanJ.L.BoslerE.M.MorseD.L.CameronD.J.EdelmanR.KaslowR.A.Incidence and cumulative frequency of endemic Lyme disease in a community. J Infect Dis1984; 150, 489–496
40.
SteereA.C.TaylorE.WilsonM.L.LevineJ.F.SpielmanA.Longitudinal assessment of the clinical and epidemiological features of Lyme disease in a defined population. J Infect Dis1986; 154, 295–300
41.
The Medical LetterTreatment of Lyme disease. Medical Letter1989; 31, 57–59
42.
SpielmanA.Prospects for suppressing transmission of Lyme disease. Ann N Y Acad Sci1988; 539, 212–220
43.
CostelloC.M.SteereA.C.PinkertonR.E.FederH.J.A prospective study of tick bites in an endemic area for Lyme disease. J Infect Dis1989; 159, 136–139
44.
RahnD.W.MalawistaS.E.Lyme disease: recommendations for diagnosis and treatment. Ann Intern Med1991; 114, 472–481
45.
BarbourA.G.Laboratory aspects of Lyme borreliosis. Clin Microbiol Rev1988; 1, 399–414
46.
de KoningJ.Hoogkamp-KorstanjeJ.A.A.van der LindeM.R.CrijnsH.J.G.M.Demonstration of spirochetes in cardiac biopsies of patients with Lyme disease. J Infect Dis1989; 160, 150–153
47.
AtlasE.NovakS.N.DurayP.H.SteereA.C.Lyme myositis: muscle invasion by Borrelia burgdorferi. Ann Intern Med1988; 109, 245–246
48.
HydeF.W.JohnsonR.C.WhiteT.J.ShelburneC.E.Detection of antigens in urine of mice and humans infected with Borrelia burgdorferi, etiologic agent of Lyme disease. J Clin Microbiol1989; 27, 58–61
49.
BenachJ.L.BoslerE.M.HanrahanJ.P.ColemanJ.L.HabichtG.S.BastT.F.CameronD.J.ZieglerJ.L.BarbourA.G.BurgdorferW.EdelmanR.KaslowR.A.Spirochetes isolated from the blood of two patients with Lyme disease. N Engl J Med1983; 308, 740–742
50.
SnydmanD.R.SchenkeinD.P.BerardiV.P.LastavicaC.C.PariserK.M.Borrelia burgdorferi in joint fluid in chronic Lyme arthritis. Ann Intern Med1986; 104, 708–800
51.
StanekG.KleinJ.BittnerR.GlogarD.Isolation of Borrelia burgdorferi from the myocardium of a patient with longstanding cardiomyopathy. N Engl J Med1990; 322, 249–252
52.
NadelmanR.B.PaviaC.S.MagnarelliL.A.WormserG.P.Isolation of Borrelia burgdorferi from the blood of seven patients with Lyme disease. Am J Med1990; 88, 21–26
53.
KarlssonM.HovindH.K.SvenungssonB.StiernstedtG.Cultivation and characterization of spirochetes from cerebrospinal fluid of patients with Lyme borreliosis. J Clin Microbiol1990; 28, 473–479
CraftJ.E.FischerD.K.ShimamotoG.T.SteereA.C.Antigens of Borrelia burgdorferi recognized during Lyme disease. Appearance of a new immunoglobulin M response and expansion of the immunoglobulin G response late in the illness. J Clin Invest1986; 78, 934–939
56.
DattwylerR.J.LuftB.J.Immunodiagnosis of Lyme borreliosis. Rheum Dis Clin North Am1989; 15, 727–734
57.
WallichR.MoterS.E.SimonM.M.EbnetK.HeilbergerA.KramerM.D.The Borrelia burgdorferi flagellum-associated 41-kilodalton antigen (flagellin): molecular cloning, expression, and amplification of the gene. Infect Immun1990; 58, 1711–1719
58.
MoffatC.M.SigalL.H.SteereA.C.FreemanD.H.DwyerJ.M.Cellular immune findings in Lyme disease. Correlation with serum IgM and disease activity. Am J Med1984; 77, 625–632
59.
LuftB.J.JiangW.MunozP.DattwylerR.J.GorevicP.D.Biochemical and immunological characterization of the surface proteins of Borrelia burgdorferi. Infect Immun1989; 57, 3637–3645
60.
SimpsonW.J.SchrumpfM.E.SchwanT.G.Reactivity of human Lyme borreliosis sera with a 39-kilodalton antigen specific to Borrelia burgdorferi. J Clin Microbiol1990; 28, 1329–1337
61.
SchaibleU.E.KramerM.D.EichmannK.ModolellM.MuseteanuC.SimonM.M.Monoclonal antibodies specific for the outer surface protein A (OspA) of Borrelia burgdorferi prevent Lyme borreliosis in severe combined immunodeficiency (scid) mice. Proc Natl Acad Sci USA1990; 87, 3768–3772
62.
CruzM.H.HansenK.FaarvangK.L.LinkH.Intrasynovial production of oligoclonal specific antibodies in Lyme arthritis. N Engl J Med1990; 322, 1889–1890
63.
WilskeB.SchierzG.Preac-MursicV.vonBuschK.KuhbeckR.PfisterH.W.EinhauplK.Intrathecal production of specific antibodies against Borrelia burgdorferi in patents with lymphocytic meningoradiculitis (Bannwarth's Syndrome). J Infect Dis1986; 153, 304–314
64.
DattwylerR.J.VolkmanD.J.HalperinJ.J.LuftB.J.ThomasJ.GolightlyM.G.Specific immune responses in Lyme borreliosis. Characterization of T cell and B cell responses to Borrelia burgdorferi. Ann N Y Acad Sci1988; 539, 93–102
65.
SigalL.H.SteereA.C.FreemanD.H.DwyerJ.M.Proliferative responses of mononuclear cells in Lyme disease. Arthritis Rheum1986; 29, 761–769
66.
PachnerA.R.SteereA.C.SigalL.H.JohnsonC.J.Antigen-specific proliferation of CSF lymphocytes in Lyme disease. Neurology1985; 35, 1642–1644
67.
DattwylerR.J.VolkmanD.J.LuftB.J.HalperinJ.J.ThomasJ.GolightlyM.G.Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med1988; 319, 1441–1446
68.
DuffyJ.MertzL.E.WobigG.H.KatzmannJ.A.Diagnosing Lyme disease: the contribution of serologic testing. Mayo Clin Proc1988; 63, 1116–1121
69.
MagnarelliL.A.Serologic diagnosis of Lyme disease. Ann N Y Acad Sci1988; 539, 154–161
70.
MagnarelliL.A.Laboratory diagnosis of Lyme disease. Rheum Dis Clin North Am1989; 15, 735–745
71.
EichenfieldA.H.AthreyaB.H.Lyme disease: of ticks and titers. J Pediatr1989; 114, 328–333
72.
RussellH.SampsonJ.S.SchmidG.P.WilkinsonH.W.PlikaytisB.Enzyme-linked immunosorbent assay and indirect immunofluorescence assay for Lyme disease. J Infect Dis1984; 149, 465–470
73.
CraftJ.E.GrodzickiR.L.SteereA.C.Antibody response in Lyme disease: evaluation of diagnostic tests. J Infect Dis1984; 149, 789–795
74.
PennellR.WandP.J.SchellR.F.Evaluation of a quantitative fluorescence immuno- assay (FIAX) for detection of serum antibody to Borrelia burgdorferi. J Clin Microbiol1987; 25, 2218–2220
75.
SchmidliJ.HunzikerT.GerberH.Immunoperoxidase slide test for detecting antibodies to Borrelia burgdorferi. J Infect Dis1988; 157, 218–219
76.
ShresthaM.GrodzickiR.L.SteereA.C.Diagnosing early Lyme disease. Am J Med1985; 78, 235–240
77.
MagnarelliL.A.AndersonJ.F.Enzyme-linked immunosorbent assays for the detection of class-specific immunoglobulins to Borrelia burgdorferi. Am J Epidemiol1988; 127, 818–825
78.
BerardiV.P.WeeksK.E.SteereA.C.Serodiagnosis of early Lyme disease: analysis of IgM and IgG antibody responses by using an antibody-capture enzyme immunoassay. J Infect Dis1988; 158, 754–760
79.
SteereA.C.BerardiV.P.WeeksK.E.LogigianE.L.AckermannR.Evaluation of the intrathecal antibody response to Borrelia burgdorferi as a diagnostic test for Lyme neuroborreliosis. J Infect Dis1990; 161, 1203–1209
80.
HalperinJ.J.LuftB.J.AnandA.K.RoqueC.T.AlvarezO.VolkmanD.J.DattwylerR.J.Lyme neuroborreliosis: central nervous system manifestations. Neurology1989; 39, 753–759
81.
ColemanJ.L.BenachJ.L.Isolation of antigenic components from the Lyme disease spirochete: their role in early diagnosis. J Infect Dis1987; 155, 756–765
82.
MagnarelliL.A.AndersonJ.F.BarbourA.G.Enzyme-linked immunosorbent assays for Lyme disease: reactivity of subunits of Borrelis burgdorferi. J Infect Dis1989; 159, 43–49
83.
HansenK.HinderssonP.PedersenN.S.Measurement of antibodies to the Borrelia burgdorferi flagellum improves serodiagnosis in Lyme disease. J Clin Microbiol1988; 26, 338–346
84.
HansenK.AsbrinkE.Serodiagnosis of eyrthema migrans and acrodermatitis chronica atrophicans by the Borrelia burgdorferi flagellum enzyme-linked immunosorbent assay. J Clin Microbiol1989; 27, 545–551
85.
GrodzickiR.L.SteereA.C.Comparison of immunoblotting and indirect enzyme-linked immunosorbent assay using different antigen preparations for diagnosing early Lyme disease. J Infect Dis1988; 157, 790–797
86.
NelsonJ.A.BankowskiM.J.NewtonB.J.BensonC.A.KaplanR.LandauW.TrenholmeG.M.PeeplesM.E.Detection of antibodies in late lyme disease. J. Infect Dis1990; 161, 1034–1035
87.
KarlssonM.StiernstedtG.GranstromM.AsbrinkE.WretlindB.Comparison of flagellum and sonicate antigens for serological diagnosis of Lyme borreliosis. Eur J Clin Microbiol Infect Dis1990; 9, 169–177
88.
KarlssonM.Western immunoblot and flagellum enzyme-linked immunosorbent assay for serodiagnosis of Lyme borreliosis. J Clin Microbiol1990; 28, 2148–2150
89.
SchwartzB.S.GoldsteinM.D.RibeiroJ.M.SchulzeT.L.ShahiedS.I.Antibody testing in Lyme disease. A comparison of results in four laboratories. JAMA1989; 262, 3431–3434
90.
SigalL.H.Summary of the first 100 patients seen at a Lyme disease referral center. Am J Med1990; 88, 577–581
91.
MagnarelliL.A.AndersonJ.F.JohnsonR.C.Cross-reactivity in serological tests for Lyme disease and other spirochetal infections. J Infect Dis1987; 156, 183–188
92.
RaoultD.HechemyK.E.BarantonG.Cross-reaction with Borrelia burgdorferi antigen of sera from patients with human immunodeficiency virus infection, syphilis, and leptospirosis. J Clin Microbiol1989; 27, 2152–2155
93.
MagnarelliL.A.MillerJ.N.AndersonJ.F.RiviereG.R.Cross-reactivity of nonspecific treponemal antibody in serologic tests for Lyme disease. J Clin Microbiol1990; 28, 1276–1279
94.
HedbergC.W.OsterholmM.T.MacDonaldK.L.WhiteK.E.An interlaboratory study of antibody to Borrelia burgdorferi. J Infect Dis1987; 155, 1325–1327
MagnarelliL.A.Quality of Lyme disease tests. JAMA1989; 262, 3464–3465
97.
SchutzerS.E.CoyleP.K.BelmanA.L.GolightlyM.G.DrulleJ.Sequestration of antibody to Borrelia burgdorferi in immune complexes in seronegative Lyme disease. Lancet1990; 335, 312–315
98.
RosaP.A.SchwanT.G.A specific and sensitive assay for the Lyme disease spirochete Borrelia burgdorferi using the polymerase chain reaction. J. Infect Dis1989; 160, 1018–1029
99.
PersingD.H.TelfordS.R.SpielmanA.BartholdS.W.Detection of Borrelia burgdorferi infection in Ixodes dammini ticks with the polymerase chain reaction. J Clin Microbiol1990; 28, 566–572
100.
MalloyD.C.NaumanR.K.PaxtonH.Detection of Borrelia burgdorferi using the polymerase chain reaction. J Clin Microbiol1990; 28, 1089–1093
101.
GoodmanJ.L.JurkovichP.KramberJ.M.JohnsonR.C.Molecular detection of persistent Borrelia burgdorferi in the urine of patients with active Lyme disease. Infect Immun1991; 59, 269–278
102.
JaulhacB.NicoliniP.PiemontY.MonteilH.Detection of Borrelia burgdorferi in cerebrospinal fluid of patients with Lyme borreliosis [letter]. N Engl J Med1991; 324, 1440
