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. 2025 Feb 25;12:1519163. doi: 10.3389/fmed.2025.1519163

Table 2.

Proposed research classification criteria for Lyme disease.

Group 1. Well-defined Lyme disease
Early Lyme disease
Erythema migrans rash (EM)
EM 1: diagnosed by health care provider (HCP) (either in person or telemedicine) and occurring after exposure to a suspected Lyme endemic area or high incidence state

  • EM 1A: Method of ascertainment (MOA): self-report and medical record documentation of an EM rash

  • EM 1B: MOA: self-report of HCP diagnosed EM and either: photo of EM or Class 1 lab test confirmation

OR
Disseminated “Objective” manifestations

  1. Clinical history includes at least one of the following symptoms/signs, which are not better accounted for by another cause (MOA: medical records and/or self-report).

  • Neurologic: lymphocytic meningitis; encephalitis; encephalomyelitis, cranial neuritis (especially facial palsy); radiculoneuropathy. Other neurologic signs (with objective measures): encephalopathy, polyneuropathy

  • Carditis: Acute onset 2nd or 3rd degree atrioventricular conduction defects; myocarditis; pericarditis

  • Arthritis: Recurrent joint swelling in one or more joints

  • Dermatologic: Multiple EM rashes or Acrodermatitis chronica atrophicans

AND

  • 2. Lab test Confirmation (requires at least one of the Class 1 lab tests) (MOA: self-report & documentation)
Group 2. Probable Lyme Disease.
2A. Chronic Multisystem Symptoms attributed to Lyme disease (insufficient to meet Group 1), not better explained by another diagnosis, and evidence of a positive Class 1 lab test or a highly suggestive IgG Western blot (WB) or Immunoblot (IB) (MOA: self-report with lab documentation)

  1. MOA: Class 1 lab test confirmation (excluding IgM WB)

  2. MOA: Highly suggestive IgG WB or IB (e.g., at least 4 of 10 IgG Bands)

OR
2B. EM rash after exposure to a suspected Lyme endemic area or a high incidence state but not previously diagnosed as EM by a health care provider and no photo or Class 1 lab test confirmation is available.

  1. MOA: self-report and medical record confirming a prior rash consistent with EM but not recognized as an EM at that time (e.g., misdiagnosis as cellulitis or spider bite)

  2. MOA: self-report only but clinical history consistent with EM (i.e., no medical record or photo or positive Class 1 test)

OR
2C. Viral like illness (not better explained by another cause) after exposure to a suspected Lyme endemic area or a high incidence state with subsequent lab tests showing either: (a) positive Class 1 lab test; or (b) Enzyme Immunoassay (EIA) (indeterminate or positive) & positive IgM WB within 6 months of the viral illness (specify if within 4 weeks or between 4 weeks and 6 months)

  1. MOA: medical records, lab test and self-report

  2. MOA: lab test and self-report
Group 3. Possible Lyme Disease.
Individuals not meeting criteria for Groups 1 or 2 but who have multi-system symptoms not better explained by another diagnosis with evidence of possible prior exposure to Bb based on a Lyme disease test. (MOA: self-report and lab documentation)
1. History of suspected exposure to a Lyme endemic area or a high incidence state
AND
2. History of signs or symptoms consistent with Lyme disease (with or without prior health care provider recognition)
AND
3. A positive or highly suggestive past Lyme assay not sufficient to meet Group 1 or 2 above
Group 4. Uncertain.
Those who do not meet any of the above criteria but for whom a provider has clinically diagnosed the individual with suspected Lyme disease (MOA: self-report).
Class 1 laboratory tests (performed in a CLIA-certified lab)

  • Standard two-tier tests (STTT): a positive or equivocal enzyme immunoassay (EIA) or immunofluorescence assay (IFA) as the first step and western blotting (WB) as the second step.

    • ○ Positive IgM Western blot (WB)/Immunoblot (IB) is sufficient when using the time frame guidelines indicated for Group 1 (within 4 weeks of illness onset) or Group 2 (within 6 months of illness onset). Requires at least 2 of 3 bands (Osp C, 39, 41 kDa).

    • ○ Positive IgG WB/IB is sufficient at any time. Requires at least 5 of 10 bands (18, Osp C, 28, 30, 39, 41, 45, 58, 66, 93 kDa).

  • Modified two-tier test (MTTT): positive or equivocal first-tier screen, followed by a different positive or equivocal confirmatory FDA-cleared EIA (13)

  • Any FDA-cleared test for Lyme disease: 510(k) Premarket Notification link: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm. Search link using Lyme, Borrelia, or name of manufacturer or device.

  • Positive single-tier IgG Western blot/Immunoblot (at least 5 IgG bands)

  • Positive Bb specific EIA (for example, C6 or another VlsE-based Peptide EIA)

  • Detection of Borrelia burgdorferi or B. mayonii by PCR

  • Isolation of Borrelia burgdorferi or B. mayonii in culture

These proposed criteria are meant to assist researchers as they design research studies on Lyme disease to allow for greater inclusiveness and generalizability. The selection of criteria and methods of ascertainment (MOA) depend on the study goals.