Feedback on difficulties raised by the interpretation of serological tests for the diagnosis of Lyme disease.

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Feedback on difficulties raised by the interpretation of serological tests for the diagnosis of Lyme disease Retour sur les difficultés d’interprétation des tests sérologiques pour le diagnostic de la maladie de Lyme Y. Hansmann a,∗,1 , C. Leyer a,2 , N. Lefebvre a,3 , M. Revest d,4 , C. Rabaud b,5 , S. Alfandari c,6 , D. Christmann a,7 , P. Tattevin d,8 a

Service des maladies infectieuses et tropicales, hôpitaux universitaires de Strasbourg, 1, place de l’Hôpital, BP 426, 67091 Strasbourg cedex, France b Service des maladies infectieuses et tropicales, hôpitaux de Brabois, CHU de Nancy, 54511 Vandœuvre-lès-Nancy cedex, France c Service des maladies infectieuses et réanimation médicale, hôpital Gustave-Dron, CHRU de Lille, 59208 Tourcoing cedex, France d Service des maladies infectieuses et réanimation médicale, université de Rennes-I, CHU Pontchaillou, 35033 Rennes cedex, France Received 6 May 2013; received in revised form 15 January 2014; accepted 26 March 2014

Abstract Objectives. – We had for objectives: i) to evaluate the accuracy of serologic testing for Lyme borreliosis performed in a private medical laboratory (PML); ii) to evaluate the impact of these tests on the practices of infectious diseases specialists (IDS). Patients and method. – This study was performed in two steps: i) retrospective study of patients followed in a university hospital infectious diseases outpatient clinic for suspected Lyme borreliosis, tested (ELISA and Western blot) by both the PML and the National Reference Center (NRC); ii) national survey on IDS practices concerning patients consulting for suspected Lyme borreliosis. Results. – Between July 2008 and July 2011, 128 patients consulting for suspected Lyme borreliosis were tested by both laboratories. Serological tests came back positive in 91% of cases from the PML versus 8% of cases from the NRC. Lyme borreliosis was the IDS’s final diagnosis for 3.6% of patients. The survey on practices revealed that: i) the modal duration of consultation for suspected Lyme borreliosis was 30–60 minutes; ii) for 33% of patients, serologic test results performed at the PML were the only reason to suspect Lyme borreliosis; iii) 60% of patients had no indication for antibiotics. Conclusion. – The serological test performed in the PML were positive most of the time, but were not confirmed by tests performed at the NRC. This discrepancy lead to multiple and prolonged consultations in infectious diseases clinics, and discordance in the indications for antibiotics. © 2014 Published by Elsevier Masson SAS. Keywords: Lyme disease; Borrelia; Lyme serology

Résumé Objectifs. – Les objectifs sont : i) évaluer la pertinence des diagnostics de maladie de Lyme établis à l’aide de tests réalisés par un laboratoire d’analyses médicales privé (AMP) ; ii) évaluer l’impact des diagnostics établis par ce laboratoire sur la pratique des infectiologues. ∗

Corresponding author. E-mail address: [email protected] (Y. Hansmann). 1 Yves Hansmann: initiation, analysis, and drafting of the part concerning the retrospective study; participation to consultations of patients included in the study 2 Caroline Leyer: designing and documenting of the Excel database for the retrospective study analysis 3 Nicolas Lefebvre: participation to consultations of patients included in the retrospective study, methodological assistance for the construction and the analysis of the database 4 Matthieu Revest: analysis of the practice survey 5 Christian Rabaud: initiation and management of the practice survey 6 Serge Alfandari: designing of the practice survey 7 Daniel Christmann: initiation of the retrospective survey analysis and participation to consultations of patients included in the retrospective study 8 Pierre Tattevin: initiation of the practice survey, analysis and drafting of the practice survey. http://dx.doi.org/10.1016/j.medmal.2014.03.009 0399-077X/© 2014 Published by Elsevier Masson SAS.

Please cite this article in press as: Hansmann Y, et al. Feedback on difficulties raised by the interpretation of serological tests for the diagnosis of Lyme disease. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.03.009

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Patients et méthode Deux étapes: i) étude rétrospective des patients consultants dans un service d’infectiologie de CHU pour suspicion de maladie de Lyme avec tests (ELISA, Western blot) par le laboratoire AMP et le Centre national de référence (CNR); ii) enquête de pratique auprès de médecins infectiologues à l’aide de questionnaires portant sur les patients vus pour suspicion de borréliose. Résultats. – Entre juillet 2008 et juillet 2011, 128 patients ayant consulté pour suspicion de maladie de Lyme ont fait réaliser une sérologie Lyme dans les 2 laboratoires. La sérologie était positive dans 91 % des cas pour le laboratoire AMP versus 8 % pour le CNR. Le diagnostic a été finalement retenu par l’infectiologue chez 3,6 % des patients. L’enquête de pratique a montré que i) la durée moyenne de consultation pour suspicion de maladie de Lyme était de 30 à 60 minutes ; ii) 33 % des patients avaient pour seule documentation la sérologie réalisée au laboratoire AMP ; iii) 60 % des patients n’avaient pas d’indication d’antibiotique. Conclusion. – Les sérologies de borréliose réalisées au laboratoire AMP un taux de séropositivité élevé, le plus souvent en désaccord avec les tests réalisés au CNR. Ces différences sont à l’origine de consultations spécialisées prolongées et de discordances dans les indications d’antibiothérapie. © 2014 Publié par Elsevier Masson SAS. Mots clés : Maladie de Lyme ; Borrelia ; Sérologie Lyme

1. Introduction The management of suspected Lyme disease is complicated by the proteiform aspect of described manifestations, by the abundant communication, not always relying on scientific data, which is given to the global population, as well as by the heterogeneousness of available diagnostic tests [1]. During the initial phase of Lyme borreliosis, clinical signs of erythema migrans are sufficient to make the diagnosis [2], serologic testing being positive in less than 50% of cases at this stage [3]. But detecting the specific antibody is required for the diagnosis of later stages of Lyme disease [4]. Screening for this antibody should be motivated by suggestive clinical signs: indeed, in endemic zones, the seroprevalence is high [5], and the detection of the antibody may correspond to an ongoing borreliosis, as well as to an older and cured borreliosis [6,7]. Symptoms are thus the central elements of the borreliosis diagnosis, serologic testing coming in as a diagnostic means of confirming the clinical hypothesis [4,8]. This position was well specified during the consensus conference on Lyme borreliosis in 2006 [4]: in case of symptoms suggesting neurological or articular borreliosis, a first “screening” test should be performed, then in case of positive result, a second “confirmation” test should be performed. These two tests should be positive to confirm the presence of the specific antibody. This approach is similar to the American [8,9], and Europeans Recommendations [10]. Between 2008 and 2012, most French hospital centers were confronted to difficulties related to interpretation of serologic testing performed in a private medical laboratory (PML). In this PML, amendments had been introduced in the interpretation of serologic testing results with immuno-enzymatic screening (ELISA, BioMérieux) and specifically noted on the final result sheet: • the threshold of positivity noted on the result sheet was decreased from 0.8 (manufacturer’s recommendation) to 0.5; • the result was considered positive (if the threshold > to 0.5) or equivocal (if the threshold < 0.5). The PML thus systematically performed a confirmation test by Western blot, justifying this by documents provided by the

manufacturer mentioning: “A negative or equivocal result did not rule out the diagnosis of borreliosis”. Furthermore, the reading of bands revealed by antigen-antibody type reactions could be performed without using the reading scanner provided by the manufacturer. The threshold of positivity set by the manufacturer being an indication only, the interpretation of the bands may be done subjectively without complying with the manufacturer’s recommendations. Lastly, the final results sent to the prescribing physician took into account a score complying with the one proposed by the test manufacturer [11,12], but to which was added a personal interpretation on the ongoing aspect or not of the infection and the pathogenicity of some species not mentioned in the notice provided by the manufacturer. The modifications made by the PML, not validated by the test manufacturer, resulted in a high rate of positive results for Lyme serologic testing, which some patients and prescribers considered to prove a better sensitivity of this test. We wanted to make things clear in 2 steps: • check the relevance of diagnosis for Lyme disease made according to serologic testing results provided by the PML, by systematically comparing to results provided in blind by the National Reference Center for borreliosis (NRC), completed by a final evaluation made by the infectious disease specialist (IDS) having conducted the medical consultation; • assess the impact of diagnosis of Lyme disease made according to serologic testing results with two practice surveys made on IDS practicing in France. 2. Patients and methods 2.1. Diagnostic value of serologic testing made at the PML We analyzed the files of patients with serologic testing performed at the NRC for borreliosis, among patients having consulted in the Strasbourg Teaching Hospital Infectious Diseases Department with two IDS responsible for outpatient consultations between July 2008 and July 2011, for a suspected Lyme borreliosis documented by serologic testing performed at the PML. The PML results were expressed in total Ig for


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Table 1 Comparison of ELISA performed in the private medical laboratory (PML) and at the National Reference Center for borreliosis. Comparaisons des résultats de sérologies Elisa réalisées au laboratoire AMP et au « Centre national de référence (CNR) des borrélioses ». PML

National Reference Center (NRC) ELISA results

Equivocal Positive Total

Negative IgG– IgM–

Doubtful (±) IgG– IgG± IgM± IgM±

IgG± IgM–

Positive IgG– IgM+

IgG± IgM+

IgG+ IgM+

IgG+ IgM±

IgG+ IgM–

70 14a 84

7 10 17

4 2 6

0 2 2

0 1 1

0 2 2

1a 0 1

3a 5 8

4 3 7

Total(%)

89 (70) 39 (30) 128

The concordance coefficient K was calculated with the following values: PML: 39 positive, 89 negative; NRC: 44 positive (sum of all blood serum samples at least doubtful or positive for IgG or IgM), 84 negative. a Patients with completely discrepant results between the two laboratories.

the ELISA (BioMérieux laboratories, France). The Western blot confirmation test (Mikrogen, Germany), performed systematically for IgM and IgG, was considered as “equivocal” if the antigen band score was ≤ 6; “infection” if the score was > 6 and ≤ 10; or “late stage infection” if the score was > 10. The ELISA screening made at the NRC was expressed quantitatively for IgM and IgG: between 4 and 10 U/L, the test was considered as doubtful; it was positive if the rate of antibodies was superior to 10 U/L. In the context of this study (positivity of tests performed at the PML), the Western blot confirmation serologic testing was systematically performed at the NRC for IgG, and only in case of positive ELISA for IgM. After obtaining Western blot test results performed at the NRC, the patient was classified in three categories: < four bands among the significant bands = no serologic argument suggesting Borrelia burgdorferi infection; four significant bands = possible Borrelia burgdorferi infection; > four significant bands = Borrelia burgdorferi infection. We took into account the final interpretation of the biologist noted on the result sheet to compare the results obtained in each laboratory. The concordance was measured by calculating the Kappa coefficient [13]. We also documented, on the clinical level, the final diagnosis made by the consulting physician and the treatment(s) eventually proposed. The patients were classified in five categories: “probable evolutive Lyme disease”, “old non-evolutive Lyme disease”, “no Lyme disease but other diagnosis certain”, “no Lyme disease but other diagnosis possible”, “no Lyme disease and no other diagnosis (patient asymptomatic or paucisymptomatic)”.

2.2. Impact of serologic testing on practice for IDS in France A practice survey was made via the French infection-flash mailing list in two steps (from January 19 to February 12, 2011, then in April 2011). The first questionnaire included a description of the responder’s profile and four multiple choice questions (MCQ) focusing on the consultations for suspicion of secondary or tertiary presentations of Lyme disease (frequency, duration, mode, and role, Appendix A). The second questionnaire concerned patients having consulted for suspicion of Lyme disease during the four previous month, focusing on serologic testing

made upstream, its consequence, and possible confirmation by a reference laboratory (Appendix B). 3. Results 3.1. Diagnostic value of serologic testing performed at the PML One hundred and twenty-eight (74.0%) of the 173 patients having consulted in the Strasbourg Teaching Hospital Infectious Diseases Department for a suspected Lyme disease between July 2008 and July 2011 were included. These were 90 females (70%) and 38 males (30%) patients, with a mean age of 45.8 years (SD ± 17.9), including 11 children less than 15 years of age. The main reasons for no-inclusion were: 18 incomplete files (10.4%), or 27 serologic testing results not available in one of the two laboratories (15.6%). PML ELISA results were: 39 tests (30%) considered as “equivocal” and 89 (70%) as “positive”. Only 17 tests (13.3%) would have been “positive” with the threshold recommended by the manufacturer (0.8). The NRC results for “ELISA” were negative for 84 patients (66%) for IgG and IgM, positive for IgM only for two patients (1.5%), positive in IgG only for eight patients (6%), and positive in IgM and IgG for two patients (1.5%). Table 1 presents the comparative data between the two laboratories for the interpretation of ELISA results. The kappa concordance coefficient between the results of the two laboratories, calculated in the most favourable manner, by considering that doubtful results at the NRC were equivalent to positive results at the PML, was only 0.418. Most patients (118, 91%) had a “positive” Western blot test at the PML, with only four tests (3%) considered as “negative”. At the NRC, 97 patients (76%) had a test considered as “negative”, and 11 (8%) a test considered as “positive”, the test was “doubtful” for the others. The kappa concordance coefficient calculated with these values was null. Western blot tests were totally discordant between the two laboratories for 86 patients (67%) (Table 2). Table 3 lists the detailed data of serologic testing interpretation by the biologist in the 2 laboratories, and the final diagnosis made by the physician managing the patient: only 7 patients (3.6%) were considered as presenting with an ongoing Lyme borreliosis. The diagnosis of Lyme disease was not made for 115 patients (either because of


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Table 2 Comparison of Western Blot serological tests performed in the private medical laboratory (PML) and at the National Reference Center for borreliosis. Comparaisons des résultats de sérologies Western Blot réalisées au laboratoire APM et au « Centre national de référence (CNR) des borrélioses ». National Reference Center (NRC)

PML score

Western Blot results

Negative(< 4 significant bands)

Doubtful(4 significant bands)

Positive(> 4 significant bands)

Total (%)

Negative (< 6) Doubtful (6) Positive (> 6) Total (%)

4 7 86a 97 (76)

0 0 20 20 (16)

0 1 10 11 (8)

4 (3) 8 (6) 116 (91) 128

The concordance coefficient K was calculated with the following values: PML: 116 positive and 12 negative; NRC: 33 positive and 97 negative. a Patients with completely discrepant results between the two laboratories.

another diagnosis, or because there was no diagnosis); serologic testing at the NRC was negative for 96 patients (83.5%), doubtful for 18 (15.6%), and positive for only 1 (0.9%), whereas it was positive for 108 patients (93.9%) and negative or equivocal for 7 patients (6.1%) at the PML. In the sub-group of patients for whom the diagnosis of Lyme borreliosis was not made, the kappa concordance coefficient was calculated at 0.025, by comparing the number of patients with a positive interpretation at the PML to those of the NRC. The three patients for whom another diagnosis explaining the symptoms was made all had negative serologic testing for Lyme at the NRC and positive at the PML. More than half (55%) of the patients without any specific diagnosis at the end of consultation were pauci or asymptomatic, and the only reason for consulting in the infectious diseases department (IDD) was requiring an expert advice after systematic testing at the PML. 3.2. Impact of serologic testing on the practices of IDS in France Ninety-three (16%) of the 595 physicians, having subscribed to the infection-flash letter, answered the 1st stage questionnaire. The M/F sex ratio was 1.3; 50% of answerers were between 40 and 55 years of age; 59% practiced in a teaching hospital (TH) and 82% in IDDs. They estimated the frequency of consultation for suspicion of Lyme disease at 1/week (9% of answers), 1 to

4/month (17%), and less than 1/month (61%), with a duration of 30 to 60 minutes for 63% of responding physicians. Most of the consultations (79%) were made in three steps according to responding physicians: • review patient history to rule out the differential diagnosis; • explain it was useless to undergo multiple examinations and receive many treatments; • collect samples for serologic testing to be sent to a local laboratory. No antibiotic prescription was written out during these consultations in 60% of cases. This rate should be compared with the fact that 33% of patients believed prolonged antibiotic therapy could be useful. For most of responding physicians (83%), the IDS was to assume his status as an expert to put an end to a long series of consultations, of examinations, and of useless treatments. No significant difference was found according to age, sex, practice site, or specialty of the answering physician. Forty-nine physicians answered the 2nd survey stage including 34 individually and 15 for the whole department where they practiced. Two hundred and seventeen (33%) of the 651 patients having consulted during the previous four last months for suspicion of Lyme disease, had for sole documentation a positive serologic test result at the PML. Two hundred and one (93%) of these 217 patients with a positive serologic test result in this

Table 3 Correlation between the final clinical diagnosis and results of serological tests performed for borreliosis in the private medical laboratory (PML) and at the National Reference Center. Corrélations entre le diagnostic clinique final, et les résultats sérologiques rendus par le laboratoire AMP et par le « Centre national de référence des borrélioses ». Result PML serologic testing

Result serologic testing National Reference Center (NRC)

Final clinical diagnosis

Positive “late”

Positive “infection”

Equivocal or negative

Probable ongoing Lyme disease (n = 7) Previous non-evolutive Lyme disease (n = 6) No Lyme disease/other diagnosis certaina (n = 3) No Lyme disease/other diagnosis probableb (n = 37) No Lyme disease/no other diagnosisc (n = 75)

3 3 2 23 41

4 3 1 11 30

0 0 0 3 4

Total

72

49

7

Positive

Doubtful

Negative

6 4 0 1 0

1 1 0 5 13

0 1 3 31 62

11

20

97

a

The other certain diagnosis were patients presenting with confirmed multiple sclerosis. Other probable diagnosis: mechanical rachialgia (intervertebral disorders, herniated disk), degenerative articular diseases (arthrosis), systemic diseases (systemic inflammatory disease, lupus, Gougerot, primitive immune deficit), muscular skeletal disorders, and reactive arthritis. c Patients pauci or asymptomatic. b


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laboratory, had at least one negative serologic test result from another laboratory. Answering physicians thought that 42 patients (21%) of the 201 patients with a positive serologic test for Lyme disease at the PML and negative in another laboratory, needed antibiotic therapy, because the Lyme disease diagnosis could be possible. Nevertheless, most of these patients (n = 142, 71%) had already received one or several courses of antibiotic therapy targeting Lyme disease. 4. Discussion The objective of the reported studies was scientific and two fold: • assess the concordance of results provided by the PML with those of the NRC; • estimate the impact of these diagnostic tests for the patients and on medical practice, at the national level. The results obtained could be summarized as follows. First, there were major discrepancies between the results provided by the PML and those provided by NRC. This was true for the interpretation of ELISA as well as of Western Blot tests. For the latter, for a same population of patients tested in both labs, the results were positive in 91% of cases for the PML versus 8% of cases for the NRC, whereas the final diagnosis of Lyme borreliosis was made by physicians managing the medical consultation of these patients in only 3.6% of cases. It should be noted, as proven by the questionnaire on practice (2nd part of our study), that obtaining a written documentation for the diagnosis (with positive serologic test results provided by the PML) not only resulted in useless antibiotic therapies targeting Lyme disease (71% of patients for whom the diagnosis of Lyme disease was finally not made), but also failed to solve the patient’s problems, since they continued consulting specialists for an effective treatment. Indeed, the authors of several randomized double blind trials reported that repeating and/or prolonging antibiotic therapy was not more effective than placebo for patients presenting with symptoms attributed to Lyme disease [1,8,9]. No survey on the practice of IDS for a suspicion of Lyme disease had ever been made, as far as we know. This survey provided interesting data considering that several specialties were potentially involved. Even if these consultations for suspicion of a secondary or tertiary presentation of Lyme disease are only a small part of their activity, IDSs believe they can use their expertise to put an end to long series of investigations, specialized consultations, and of the useless or deleterious antibiotic therapies. There was a good homogeneousness of practices reported in this questionnaire, which is not always the case in this type of survey [14]. The PML results were the reason for 1/3 of consultations in the IDD for suspicion of Lyme disease, as expected given the high rate of positivity for serologic testing at the PML, in 2011. Our study has several limitations. First of all, the sample of patients tested both at the NRC and at the PML was not necessarily representative of all the patients having undergone serologic

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testing in these laboratories, since only patients having consulted in the Strasbourg teaching hospital IDD were included. This was a probable selection bias, since the patients for whom the diagnosis was adequate and the treatment effective had no reason to consult later. Second, no patient with a negative serologic test at the PML was examined in consultation. Third, the surveys made on IDS presented multiple potential bias, since: • the IDS were not representative of all specialties concerned by this disease; • the low percentage of answering physicians, even if it was in the average for this type of survey [14], did not allow projecting results; • as in all declarative surveys, the answers did not truly reflect reality. Finally, the interpretation of serologic test results for Lyme disease is complex: ELISA are rather well standardized and automated, but the diagnostic value of various identified antibodies in the Western-blot technique is uncertain since there are American recommendations, but no European consensus [15,16]. Nevertheless, in our comparative study the 2 Western-blot tests relied on Borrelia strain antigens of European origin. Despite these limitations, the great discrepancy of results between the two laboratories, and the correlation study with the diagnosis finally made by clinicians suggest that the results and especially their interpretation by the PML were wrong. The survey of practices made on a national level allowed determining the consequences of these discrepancies in terms of potentially deleterious treatments, specialized consultations, and useless complementary investigations. Finally, it is likely that the discrepancy of serological test results induced mistrust of biological test results for physicians prescribing these tests, or for all physicians. This mistrust could lead to refusing necessary care, or conversely to using potentially dangerous alternative treatments. This is why it was important to be able to rely on objective data by taking as reference recommendations made by International Expert Societies [4,8,10]. Our study was integrated in this observation policy by trying to minimize the confounding factors related to the intuitive experience of all physicians involved. Medicine cannot be an exact science but should remain an objective one, to prevent running astray. 5. Conclusion The positive serologic test results for Lyme disease performed at the PML until Spring 2012 for patients sampled all over in France were abnormally high by Western Blot (91% for a sample of patients having consulted at the Strasbourg teaching hospital), with a very high rate of discrepancy compared to negative results provided by the NRC for borreliosis on the same patients in 67% of cases. The results of serologic testing interpreted as proving the disease caused an excess of antibiotic prescription and of other inappropriate treatments targeting Lyme disease, longer specialized consultations, especially in IDD, and useless investigations.


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Disclosure of interest The following authors report no conflict of interest for this article: P. Tattevin, Y. Hansmann, C. Leyer, N. Lefebvre, M. Revest, C. Rabaud, S Alfandari, D. Christmann. Appendix A. Questionnaire on the practices of French infectious diseases physicians concerning consultations for suspected Lyme disease. Questionnaire de pratiques des infectiologues exerçant en France sur les consultations « suspicions de maladie de Lyme ». 1. Are you frequently requested to conduct this type of consultation? yes no If no, the survey is over for you! If yes, how many: • • • •

never (systematic refusal) at least 1 consultation/week 1 to 4 consultations/month less than 1 consultation/month 2. What is the average duration of these consultations?

• less than half an hour • half an hour to 1 hour • more than 1 hour 3. What are your main actions during these consultations (several answers possible) • take history from “scratch” to avoid missing another organic disease • try to explain that undergoing multiple examinations and treatments is useless • sample blood for serologic testing which will be sent to a trusted laboratory • suggest antibiotherapy (if yes, specify the agent and duration) • refer the patient to another physician (if yes, specify the specialty) 4. What is your opinion on antibiotic use for “chronic” Lyme disease • should not be used since the authors of several randomized studies have demonstrated that no anti-infectious treatment is useful at this stage • a prolonged antibiotic therapy may be useful in many wellselected cases 5. What is your opinion on the contribution of IDSs to the management of “chronic” Lyme disease • not necessary, because ID consultation is usually only one step in a long series of procedures

• the IDS may use his expert advice to put an end to a long series of consultations, of useless or deleterious examinations and treatments Appendix B. Questionnaire on the practices of French infectious diseases physicians concerning serological tests for Lyme disease. Questionnaire de pratiques des infectiologues exerçant en France sur les diagnostics sérologiques de la maladie de Lyme. 1. How many patients with suspected Lyme disease did you see in consultation or in hospitalization during the first 4 months of 2011? 2. How many of these patients had for sole documentation positive test results provided by a private laboratory? 3. How many of these patients had negative test results provided by another laboratory (before or after your consultation)? 4. How many of these patients seemed to present with Lyme disease and require antibiotic treatment? 5. How many, among patients who did presented with Lyme disease and for whom you did not recommend antibiotic therapy, had previously been prescribed antibiotic therapy? 6. How many, among patients who did presented with Lyme disease and for whom you did not recommend antibiotic therapy, had previously been prescribed another treatment they were told was adequate for Lyme disease? References [1] Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet 2012;379(9814):461–73. [2] Wormser GP. Clinical practice. Early Lyme disease. N Engl J Med 2006;354(26):2794–801. [3] Hansmann Y, Jaulhac B, Lipsker D, Christmann D. Diagnosing Lyme disease: the role of clinical and complementary examination. Med Mal Infect 2004;34(Suppl. 1):S88–91. [4] Société de Pathologie Infectieuse de langue Française. Lyme borreliose: diagnostic, therapeutic and preventive approaches – long text. Med Mal Infect 2007;37(Suppl. 3):S153–74. [5] Fahrer H, van der Linden SM, Sauvain MJ, Gern L, Zhioua E, Aeschlimann A. The prevalence and incidence of clinical and asymptomatic Lyme borreliosis in a population at risk. J Infect Dis 1991;163(2):305–10. [6] Fahrer H, Sauvain MJ, Zhioua E, Van Hoecke C, Gern LE. Longterm survey (7 years) in a population at risk for Lyme borreliosis: what happens to the seropositive individuals? Eur J Epidemiol 1998;14(2):117–23. [7] Mullegger RR, Glatz M. Is serological follow-up useful for patients with cutaneous Lyme borreliosis? Curr Probl Dermatol 2009;37:178–82. [8] 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. [9] Lantos PM, Charini WA, Medoff G, Moro MH, Mushatt DM, Parsonnet J, et al. Final report of the Lyme disease review panel of the Infectious Diseases Society of America. Clin Infect Dis 2010;51(1):1–5. [10] Stanek G, Fingerle V, Hunfeld KP, Jaulhac B, Kaiser R, Krause A, et al. Lyme borreliosis: clinical case definitions for diagnosis and management in Europe. Clin Microbiol Infect 2011;17(1):69–79. [11] Goettner G, Schulte-Spechtel U, Hillermann R, Liegl G, WiAMPke B, Fingerle V. Improvement of Lyme borreliosis serodiagnosis by a newly


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developed recombinant immunoglobulin G (IgG) and IgM line immunoblot assay and addition of VlsE and DbpA homologues. J Clin Microbiol 2005;43(8):3602–9. [12] Wilske B, Habermann C, Fingerle V, Hillenbrand B, Jauris-Heipke S, Lehnert G, et al. An improved recombinant IgG immunoblot for serodiagnosis of Lyme borreliosis. Med Microbiol Immunol 1999;188(3):139–44. [13] Guggenmoos Holzmann I, Vonk R. Kappa-like indices of observer agreement viewed from a latent class perspective. Stat Med 1998;17(8):797–812.

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[14] Tattevin P, Chapplain JM, Lesprit P, Billy C, Roblot F, Alfandari S, et al. Tuberculosis treatment duration in France: from guidelines to daily practice. Eur J Intern Med 2006;17(6):427–9. [15] Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol 1995;33(2): 419–27. [16] Dressler F, Whalen JA, Reinhardt BN, Steere AC. Western blotting in the serodiagnosis of Lyme disease. J Infect Dis 1993;167(2):392–400.


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Surface immunofluorescence assay for diagnosis of Lyme disease.

The diagnostic efficiency of some serological tests for bovine brucellosis.

Comparison of counter-immunoelectrophoresis with other serological tests in the diagnosis of human brucellosis.

Evaluation of eight serological tests in the diagnosis of human echinococcosis and follow-up.

A review of serological tests to assist diagnosis of reactive arthritis: critical appraisal on methodologies.