Understanding Lyme Disease Diagnosis: A Global Consensus on Guidelines

Table of Contents

• Key Points
• Background: The Challenge of Diagnosing Lyme Disease
• Study Methods: How the Guidelines Were Evaluated
• Quality Analysis of the Guidelines
• Diagnosing Early Localized Infection: Erythema Migrans
• Diagnosing Early Disseminated Infection
• Diagnosing Late Lyme Disease
• Clinical Implications: What This Means for Patients
• Limitations of the Study
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• A review of 16 international guidelines found strong consensus on Lyme disease diagnosis.
• Two-tier serology (ELISA then immunoblot) is the standard for most stages.
• Erythema migrans rash is diagnosed clinically; blood tests are not recommended early.
• Guidelines from recognized societies in Germany, France, and the US agree on diagnosis.
• The German Borreliosis Society's recommendations are not supported by other guidelines.

Background: The Challenge of Diagnosing Lyme Disease

Lyme disease is a tick-borne illness caused by spiral-shaped bacteria (spirochetes) belonging to the Borrelia burgdorferi sensu lato complex. In Europe, the primary carrier is the hard tick of the Ixodes genus, specifically Ixodes ricinus. The infection is mainly caused by three genospecies: B. burgdorferi sensu stricto, B. afzelii, and B. garinii. Thanks to advances in genotyping techniques, this complex now includes around 20 genomic species.

Since the disease was first described in Connecticut in the 1970s and its agent discovered in the 1980s, clinicians and microbiologists have faced several significant barriers to diagnosis. First, the infection is polymorphic, meaning it can involve various organs including the skin, neurological system, bones, eyes, and heart. This means physicians from many different medical specialties need to be trained to recognize the disease.

Second, despite this multisystemic nature, the bacteria are only transiently present in the blood after the primary infection, making isolation of B. burgdorferi sensu lato from blood samples almost impossible. Third, culturing the bacteria—the gold standard of microbiological diagnosis—requires special laboratory media and expertise that are not widely available.

As a result of these challenges, serology (blood testing for antibodies) has emerged as the cornerstone for diagnosing Lyme disease in routine practice. The most common approach is a two-tier testing strategy: an ELISA (enzyme-linked immunosorbent assay) as a screening test, followed by an immunoblot for confirmation. Molecular tools like PCR (polymerase chain reaction) have also emerged, but their sensitivity varies depending on the sample tested (blood, skin, synovial fluid, or cerebrospinal fluid).

In recent years, a flood of information about Lyme disease has appeared on the Internet and in other media, mostly in the form of patient testimonials. Many patients, patient associations, and even some physicians believe that laboratory diagnosis of Lyme disease in France and other European countries is not reliable. Some patients choose to be tested abroad, mainly in Germany, believing they will get more reliable results. This phenomenon has led to mistrust of the French medical community. For the general public and physicians unfamiliar with the subject, this volume of information can be confusing, making it difficult to know whom to trust.

To help clinicians navigate this complexity, guidelines on Lyme disease have been regularly developed to synthesize existing evidence and translate it into practical recommendations. This review aimed to provide an overview of existing guidelines from countries where the disease is prevalent, comparing evidence-based guidelines from North America and Europe, and evaluating their methodological quality.

Study Methods: How the Guidelines Were Evaluated

The researchers conducted a comprehensive search on Medline, Google, and Google Scholar in French, English, and German languages using the keywords "Guidelines," "Lyme disease," and "diagnosis." They paid special attention to German guidelines because patients in France often believe that German physicians have a different approach to the disease.

Articles published before 2004 were excluded from the analysis. When two guidelines from the same authors or organizations were found, only the most recent one was included. Guidelines that only dealt with treatment and not with diagnostic criteria were also excluded. In total, sixteen guidelines from seven countries were included in the final analysis.

The breakdown of guidelines by country was as follows:

• Germany: 6 guidelines (5 issued by academic societies and available on the website of the Association of Scientific Medical Societies in Germany, plus 1 issued by an organization called the German Borreliosis Society, which is not officially recognized by German authorities as an academic society)
• France: 1 guideline
• United States: 1 guideline
• Canada: 1 guideline
• Switzerland: 1 guideline
• Belgium: 1 guideline
• Poland: 1 guideline
• United Kingdom: 2 guidelines
• Europe (pan-European): 2 guidelines

The methodological quality of each guideline was evaluated using a scoring system adapted from Siering et al. Each guideline received points based on six criteria:

1. Presence of reference citations in the guidelines (1 point)
2. Presence of a description of the methodology for searching evidence (1 point)
3. Systematic method for searching evidence (1 point)
4. Explicit link between recommendations and evidence (1 point)
5. Presence of a system of recommendation gradation (1 point)
6. Single or multiple learned societies involved in developing the guidelines (1 point)

The total score for each guideline was calculated by adding the points for each item, with a maximum possible score of 6.

Quality Analysis of the Guidelines

The quality scores varied considerably among the guidelines. The highest quality score of 6 was achieved by two sets of guidelines: the European Federation of Neurological Societies (EFNS) guidelines and the British National Institute for Health and Care Excellence (NICE) guidelines. Both of these scored full marks on all criteria, including having a systematic method for searching evidence and an explicit link between recommendations and evidence.

The German Borreliosis Society showed the lowest quality score, receiving only 1 point. This low score reflects significant methodological shortcomings: while it included reference citations, it lacked a described methodology for searching evidence, had no systematic search method, no explicit link between recommendations and evidence, no gradation system, and was developed by a single organization rather than multiple learned societies.

Other guidelines scored in the middle range. The ESGBOR (ESCMID Study Group for Lyme Borreliosis) 2017 guidelines scored 5 points, as did the German Rheumatology Society, German Neurology Society, German Society of Hygiene and Microbiology, and German Dermatology Society guidelines. The SPILF (French Infectious Diseases Society) 2006 guidelines scored 4 points. The IDSA (Infectious Diseases Society of America) 2006 guidelines, British Infection Association 2011 guidelines, and Belgian Society of Infectious Diseases and Clinical Microbiology 2016 guidelines each scored 3 points. The Swiss Infectious Diseases Society 2006, Canadian Public Health Laboratory Network 2006, Committee for Infectious Diseases and Vaccinations of the German Academy for Pediatrics and Adolescent Health 2012, and Polish Society of Epidemiology and Infectious Diseases 2015 guidelines each scored 2 points.

For each clinical presentation of Lyme disease, the researchers detailed the recommendations regarding diagnosis, specifying at the end of each section the consensual recommendations (included in the majority of guidelines) and the discordant points.

Diagnosing Early Localized Infection: Erythema Migrans

Clinical Description

Most guidelines describe erythema migrans (EM) as a cutaneous lesion that appears between a few days and several weeks after the tick bite, at the site of the bite. This is the first sign of localized infection with B. burgdorferi sensu lato. It is an erythematous (reddened) annular rash with centrifugal extension, meaning it expands outward from the center.

After several days, the center of the lesion tends to brighten while the borders become infiltrated. The rash can spread for several weeks, reaching up to 30 cm in diameter, and may spontaneously disappear after several months. The IDSA guidelines recommend tracing the borders of the lesion with ink to measure its extension. The German Academy for Pediatrics and Adolescent Health also recommends tracing the borders with a pen to confirm or rule out the extension of the lesion.

The German Dermatological Society guidelines emphasize that EM can be atypical in appearance. It may not be marginated, may appear infiltrated, centrally vesicular, hemorrhagic, or as irregular blotches. In some cases, it is only visible when heat is applied to the skin. The British Infection Association guidelines note that EM caused by B. garinii may be more erythematous and homogeneous than EM caused by B. afzelii.

Many guidelines state that a rash that appears less than 24–48 hours after the bite and disappears within a few days without extension should rule out the diagnosis of EM. This distinction is important because not every rash following a tick bite is Lyme disease.

Diagnosis of Erythema Migrans

Early serology is not sensitive enough to confirm Lyme diagnosis at the EM stage, with sensitivity ranging from only 40% to 60%. This means that up to 60% of patients with early infection would test negative. For this reason, the following guidelines do not recommend early blood sampling: SPILF (2006), IDSA (2006), British Infection Association (2011), Committee for Infectious Diseases and Vaccinations of the German Academy for Pediatrics and Adolescent Health (2012), Polish Society of Infectious Diseases (2015), Belgian Antibiotic Policy Coordination Committee (BAPCOC) (2016), ESGBOR (2017), German Dermatological Society, and German Society of Hygiene and Microbiology (2017).

However, several guidelines recommend obtaining a baseline serum sample to allow for the diagnosis of seroconversion (the appearance of antibodies in the blood) later. The German Dermatological Society also recommends a serological test in case of atypical EM. The Canadian Public Health Laboratory Network Guidelines differentiate two situations: they do not recommend serology for EM with a compatible seasonal occurrence in an established tick area with a compatible history of tick bite. In that case, the diagnosis of EM is purely clinical. However, if the rash occurs out of season or in an area without ticks, a two-tier serology should be performed and repeated four weeks after symptom onset, with treatment at the physician's discretion.

PCR on a skin biopsy of EM is suggested by some guidelines as an option, mainly in cases of atypical EM. Its sensitivity is around 70%. In cases of atypical EM with negative serology, the German Dermatological Society states that patients should be referred to a dermatologist and a biopsy should be performed for PCR and culture.

The German Borreliosis Society guidelines state that serology may be "falsely negative" in cases of EM. However, they are the only guidelines to recommend one-tier serology (IgM antibodies, IgG antibodies by enzymatic immunoassay, or IgM blot, IgG blot) and a lymphocyte transformation test for Borrelia in cases of "early infection with or without EM." This latter test is not recommended in any other guideline because of a lack of standardization and reproducibility.

Consensual recommendation: No serology in case of EM suspicion (15 out of 16 guidelines).

Discordant recommendation: The German Borreliosis Society recommends (as a relative indication) a one-tier serology in case of early infection suspicion with or without EM, plus a lymphocyte transformation test (1 out of 16 guidelines).

Diagnosing Early Disseminated Infection

Multiple Erythema Migrans

Multiple EM is considered rare according to the SPILF guidelines. The IDSA and British Infection Association guidelines state that secondary hematogenous lesions (lesions spread through the bloodstream) are usually smaller and more irregular in patients presenting with multiple EM than in those with the initial localized EM. The Swiss Infectious Diseases Society guidelines specify that multiple EM is rarer in Europe than in the United States.

The Belgian guidelines describe multiple EM as "secondary lesions" appearing several days or weeks after the bite. They are frequently associated with systemic symptoms such as fever, myalgia (muscle pain), and lymphadenitis (swollen lymph nodes), and represent 4% to 20% of EM cases.

The German Dermatological Society guidelines have a more detailed section about multiple EM than other guidelines. Multiple EM is described as a hematogenous dissemination of B. burgdorferi sensu lato, noticeable by sharp, marginated, asymptomatic lesions of various sizes. Children can present symmetrical erythema on their face mimicking fifth disease (Parvovirus B19 infection). There is no associated epidermal change, and it can be associated with systemic or acute neurological symptoms.

For most guidelines, multiple EM is not differentiated from typical isolated EM in terms of diagnostic strategy. The diagnostic approach remains the same: clinical diagnosis without the need for serological confirmation.

Lymphocytoma

Borreliosis-associated lymphocytoma is a less common cutaneous manifestation of early disseminated Lyme disease. The German Academy for Pediatrics and Adolescent Health guidelines state that serology can be negative in lymphocytoma, and the diagnosis may be established by clinical means, as is the case for EM.

Most guidelines recommend performing a biopsy at this stage for histological analysis and PCR. The Swiss Infectious Diseases Society guidelines recommend a biopsy of the lesion only if there is no improvement after treatment or if there is an atypical localization, to rule out cutaneous lymphoma. The Belgian guidelines also suggest a biopsy only in cases of atypical lymphocytoma (optional). The German Dermatological Society stresses that in rare cases, early Borrelial lymphocytoma may be disseminated, and biopsy should be performed to differentiate it from malignant cutaneous lymphomas.

The German Borreliosis Society guidelines are the only ones to recommend performing one-tier serology and a lymphocyte transformation test, and they do not mention whether a biopsy is required.

Consensual recommendation: To perform a two-tier serology (10 out of 16 guidelines).

Discordant recommendation: German Borreliosis Society: to perform a one-tier serology and a lymphocyte transformation test (1 out of 16 guidelines).

Neuroborreliosis

Neuroborreliosis, the neurological manifestation of Lyme disease, requires careful diagnostic evaluation. The guidelines consistently recommend examining cerebrospinal fluid (CSF) for evidence of inflammation and specific antibody production.

The standard diagnostic approach for early neuroborreliosis includes a CSF cell count and protein measurement, along with serology in both CSF and blood to detect intrathecal antibody synthesis (antibodies produced within the central nervous system). This is a key diagnostic feature that distinguishes neuroborreliosis from other neurological conditions.

PCR may be useful but is noted as not very sensitive in CSF samples. The German Neurology Society guidelines additionally mention that the CXCL13 chemokine should be better evaluated as a potential diagnostic marker, though this is not yet a standard recommendation.

The German Borreliosis Society guidelines again diverge, recommending one-tier serology and/or lymphocyte transformation tests, with PCR in CSF and culture in CSF as options.

Consensual recommendation: CSF cell count and protein analysis, two-tier serology in CSF and blood with detection of intrathecal antibody synthesis (15 out of 16 guidelines).

Diagnosing Late Lyme Disease

Lyme Arthritis

Lyme arthritis is a late manifestation of the disease, typically affecting the knees and other large joints. The diagnostic approach for Lyme arthritis involves two-tier serology, which is highly sensitive at this stage of infection. Most patients with Lyme arthritis will have strongly positive antibody responses.

In addition to serology, some guidelines recommend examining synovial fluid (joint fluid) for cell count and performing PCR on the fluid. The sensitivity of PCR on synovial fluid is variable, and a negative result does not rule out Lyme arthritis. The German Society of Hygiene and Microbiology guidelines recommend synovial fluid cell count as a primary criterion, with PCR as a useful but low-sensitivity adjunct.

The German Borreliosis Society recommends one-tier serology and/or lymphocyte transformation tests, with Borrelia PCR on biopsy as an option.

Consensual recommendation: Two-tier serology (15 out of 16 guidelines).

Cardiac Manifestations

Lyme carditis is a rare but potentially serious manifestation of disseminated Lyme disease. The guidelines recommend two-tier serology for diagnosis, consistent with the approach for other disseminated forms. The German Borreliosis Society again recommends one-tier serology and/or lymphocyte transformation tests.

Consensual recommendation: Two-tier serology (15 out of 16 guidelines).

Ocular Manifestations

Ocular involvement in Lyme disease can include conjunctivitis, uveitis, and other inflammatory conditions of the eye. The guidelines recommend two-tier serology for diagnosis, with some guidelines suggesting a biopsy for histological analysis in atypical cases.

Consensual recommendation: Two-tier serology (15 out of 16 guidelines).

Acrodermatitis Chronica Atrophicans

Acrodermatitis chronica atrophicans (ACA) is a late cutaneous manifestation of Lyme disease, primarily caused by B. afzelii. It typically presents as a bluish-red discoloration and swelling of the extremities, progressing to atrophy (thinning) of the skin over time.

The diagnostic approach for ACA includes two-tier serology, which is almost always strongly positive at this stage. Some guidelines also recommend a skin biopsy for histological analysis and PCR. The German Society of Hygiene and Microbiology guidelines mention intrathecal synthesis and CSF cell count as possible secondary criteria, along with oligoclonal bands.

Consensual recommendation: Two-tier serology and biopsy for histology (15 out of 16 guidelines).

Late Neuroborreliosis

Late neuroborreliosis requires the same diagnostic approach as early neuroborreliosis: CSF cell count and protein analysis, serology in CSF and blood with detection of intrathecal antibody synthesis. PCR may be useful but has very low sensitivity in this context.

Consensual recommendation: CSF cell count and protein analysis, two-tier serology in CSF and blood with intrathecal antibody synthesis detection (15 out of 16 guidelines).

Chronic Polyorganic Symptoms

The German Borreliosis Society guidelines uniquely recommend one-tier serology and/or lymphocyte transformation tests for chronic polyorganic symptoms. This recommendation is not supported by any other guideline and reflects the low methodological quality of this particular document.

Consensual recommendation: No test for Lyme borreliosis (15 out of 16 guidelines).

Discordant recommendation: German Borreliosis Society: one-tier serology and/or lymphocyte transformation test (1 out of 16 guidelines).

Clinical Implications: What This Means for Patients

This comprehensive review of international guidelines carries several important messages for patients and healthcare providers. First and foremost, there is a remarkable global consensus on how to diagnose Lyme disease. Despite the intense debate on the Internet and in the media, 15 out of 16 high-quality guidelines agree on the diagnostic approach for each stage of the infection.

The two-tier serology approach—ELISA followed by immunoblot—remains the cornerstone of laboratory diagnosis for all stages of Lyme disease except for the early localized skin manifestation (erythema migrans). For EM, the diagnosis is clinical, and serology is not recommended because it is not sensitive enough in the first weeks of infection (only 40% to 60% sensitivity).

This consensus is particularly important for patients who may be considering traveling abroad for testing. The review found no evidence that German guidelines (from recognized academic societies) recommend fundamentally different diagnostic approaches than French, American, or other European guidelines. The only discordant guideline came from the German Borreliosis Society, which is not officially recognized by German authorities as an academic society and scored the lowest on methodological quality.

For patients, this means that a diagnosis of Lyme disease made in France or other countries following established guidelines is based on the same scientific evidence and diagnostic principles as those used elsewhere. The perception that testing abroad provides more reliable results is not supported by this analysis of the scientific literature.

The review also highlights the importance of clinical diagnosis for early localized disease. If a patient develops the characteristic EM rash after a tick bite, treatment should not be delayed while waiting for blood test results, which may be falsely negative in the early stages.

Limitations of the Study

While this review provides a comprehensive overview of international guidelines, it has several limitations that should be acknowledged. First, the search was limited to guidelines published in French, English, and German, which may have excluded relevant guidelines published in other languages.

Second, the review only included guidelines published after 2004, and some of the included guidelines are now quite old. For example, the SPILF (French) guidelines date from 2006, and the IDSA (American) guidelines also date from 2006. These may not reflect the most recent evidence or diagnostic technologies.

Third, the quality scoring system, while adapted from a validated tool, was applied by the authors and may involve some subjectivity. However, the clear differences in scores between the highest and lowest quality guidelines suggest the tool was able to discriminate effectively.

Fourth, the review focused exclusively on diagnostic guidelines and did not evaluate treatment recommendations. Patients should consult their healthcare providers for guidance on treatment options.

Finally, the review did not address the controversial topic of "chronic Lyme disease" or post-treatment Lyme disease syndrome, which remains an area of active research and debate. The guidelines reviewed here focus on the diagnosis of active infection with B. burgdorferi sensu lato.

Recommendations for Patients

Based on this comprehensive review of international guidelines, patients can take the following steps to ensure appropriate diagnosis and management of suspected Lyme disease:

1. Recognize the early signs: If you develop a red, expanding rash (erythema migrans) at the site of a tick bite, seek medical attention promptly. The rash typically appears 3–30 days after the bite and expands outward, sometimes reaching up to 30 cm in diameter.
2. Do not wait for blood tests if you have EM: The characteristic rash is sufficient for a clinical diagnosis. Blood tests in the first weeks of infection are often negative (40–60% sensitivity) and should not delay treatment.
3. Understand the two-tier testing approach: For all stages of Lyme disease beyond early localized EM, the standard diagnostic approach is a two-tier serology: first an ELISA screening test, followed by an immunoblot for confirmation. This approach maximizes accuracy.
4. Be aware that testing abroad is not necessary: The review found that guidelines from recognized medical societies in Germany, France, the United States, and other countries all recommend the same diagnostic approaches. The only discordant guideline came from an organization not officially recognized by German authorities.
5. Seek specialist care for complicated presentations: If you have neurological symptoms, joint swelling, or other systemic manifestations, you may need evaluation by a specialist. Neuroborreliosis requires CSF analysis (lumbar puncture) in addition to blood tests.
6. Ask about PCR testing when appropriate: In some situations, such as atypical skin lesions or joint fluid analysis, PCR testing may be helpful as an adjunct to serology. However, PCR has limited sensitivity in blood and CSF and is not a replacement for serological testing.
7. Be cautious about unvalidated tests: The lymphocyte transformation test, recommended only by the German Borreliosis Society, is not endorsed by any other guideline due to lack of standardization and reproducibility. Be wary of laboratories offering tests that are not recommended by mainstream medical guidelines.
8. Follow up appropriately: If your initial serology is negative but symptoms persist, repeat testing after 4 weeks may be recommended to detect seroconversion.

In summary, this review of 16 international guidelines demonstrates that the diagnosis of Lyme disease is well-standardized across Europe and North America. Patients can have confidence in the diagnostic approach recommended by their healthcare providers, which is based on a strong international scientific consensus.

Frequently Asked Questions

What is the most reliable way to diagnose Lyme disease?

For most stages of Lyme disease, the standard diagnostic approach is two-tier serology: first an ELISA screening test, followed by an immunoblot for confirmation. This method is recommended by 15 out of 16 international guidelines. However, for the early skin rash (erythema migrans), diagnosis is clinical, and blood tests are not recommended because they are often negative.

Why is a blood test not recommended for the early Lyme disease rash?

In the early localized stage, when the characteristic erythema migrans rash appears, blood tests for antibodies are only 40% to 60% sensitive. This means up to 60% of patients with early infection would test negative. Therefore, guidelines recommend clinical diagnosis based on the rash, and treatment should not be delayed while waiting for blood test results.

Is it necessary to go abroad for Lyme disease testing?

No. A review of 16 international guidelines found that recognized medical societies in Germany, France, the United States, and other countries all recommend the same diagnostic approaches for Lyme disease. The only discordant guideline came from an organization not officially recognized by German authorities. Testing abroad is not supported by scientific evidence.

What tests are used for neurological symptoms of Lyme disease?

For neuroborreliosis, the standard diagnostic approach includes a cerebrospinal fluid (CSF) cell count and protein measurement, along with two-tier serology in both CSF and blood to detect intrathecal antibody synthesis. This is recommended by 15 out of 16 guidelines. PCR may be useful but is noted as not very sensitive in CSF samples.

What is the lymphocyte transformation test for Lyme disease?

The lymphocyte transformation test is recommended only by the German Borreliosis Society, which is not officially recognized by German authorities. It is not endorsed by any other guideline due to lack of standardization and reproducibility. Patients should be cautious about laboratories offering tests that are not recommended by mainstream medical guidelines.

How is Lyme arthritis diagnosed?

Lyme arthritis, a late manifestation, is diagnosed using two-tier serology, which is highly sensitive at this stage. Most patients have strongly positive antibody responses. Some guidelines also recommend examining synovial fluid for cell count and performing PCR on the fluid, but a negative PCR does not rule out Lyme arthritis.

What should I do if I have a tick bite and a rash?

If you develop a red, expanding rash (erythema migrans) at the site of a tick bite, seek medical attention promptly. The rash typically appears 3–30 days after the bite and expands outward. Do not wait for blood tests, as they are often negative in early infection. The rash is sufficient for a clinical diagnosis, and treatment should not be delayed.

Source Information

Original Article Title: European and American guidelines for the diagnosis of Lyme borreliosis

Authors: C. Eldin, A. Raffetin, K. Bouiller, Y. Hansmann, F. Roblot, D. Raoult, P. Parola

Journal: Médecine et maladies infectieuses, Volume 49, 2019, Pages 121–132

Publication Date: Available online December 6, 2018

DOI: https://doi.org/10.1016/j.medmal.2018.11.011

Affiliations: Aix Marseille Université, IRD, SSA, VITROME, IHU-Méditerranée Infection, AP–HM, Marseille, France; Service de maladies infectieuses et tropicales, centre hospitalier de Villeneuve, Villeneuve-Saint-Georges, France; Service de maladies infectieuses, CHU Besançon, UMR CNRS 6249 Chrono-Environnement, université de Bourgogne Franche-Comté, Besançon, France; Service des maladies infectieuses et tropicales, hôpitaux universitaires de Strasbourg, ESGBOR (ESCMID Study Group for Lyme Borreliosis), Strasbourg, France; Service de médecine interne, maladies infectieuses et tropicales, U1070 Pharmacologie des anti-infectieux, université de Poitiers, CHU Poitiers, Poitiers, France; Aix Marseille Université, IRD, MEPHI, IHU-Méditerranée Infection, AP–HM, Marseille, France

Note: This patient-friendly article is based on peer-reviewed research published in an open-access journal under the CC BY-NC-ND license. The original article can be accessed through ScienceDirect.