Lyme disease is an infection caused by the bacterium Borrelia burgdorferi, transmitted through infected tick bites. Diagnosis relies on indirect laboratory tests that detect the body’s immune response, rather than the bacteria itself. A false positive occurs when a person who has never had Lyme disease receives a test result indicating infection. The complexity of the immune system and testing methods means Lyme disease serology is prone to inaccuracies, complicating diagnosis and potentially leading to unnecessary treatment. Understanding the specific mechanisms that cause a false positive is important for accurately interpreting results.
The Two-Tiered Testing Framework
The standard method for laboratory confirmation of Lyme disease is the two-tiered testing protocol, designed to improve diagnostic accuracy. This process begins with a highly sensitive initial screening test, typically an Enzyme-Linked Immunosorbent Assay (ELISA), which detects antibodies against B. burgdorferi. Since the initial ELISA can yield positive results unrelated to a true Lyme infection, it is not definitive alone.
If the screening ELISA is positive or equivocal, the second tier of testing confirms the result. This confirmatory step usually involves a Western Blot (WB) test, which is more specific. The WB separates Borrelia proteins and looks for antibodies against specific protein bands. A result is considered positive only if both the initial screening and the confirmatory Western Blot meet specific criteria. This two-step process filters out non-specific reactions that occur in the initial, more sensitive screening test.
False positive results often occur at the first tier because the highly sensitive ELISA is likely to detect non-specific reactions. Although the Western Blot adds necessary specificity to rule out these reactions, the potential for an incorrect positive result remains due to various biological and technical factors.
Biological Causes of False Positives
The most frequent biological reason for a false positive Lyme test is antibody cross-reactivity, where the immune system confuses one pathogen for another. This occurs because antibodies generated to fight a different infection mistakenly bind to the antigens used in the Lyme test. This confusion happens when Borrelia burgdorferi proteins share structurally similar components with proteins found on other microbes or human cells.
Other Bacterial Infections
Several bacterial infections can cause cross-reactions due to shared protein structures. Spirochetal diseases, such as syphilis (Treponema pallidum), frequently lead to false positive Lyme results. This is due to the close evolutionary relationship between the bacteria, which results in shared flagellar antigens that the antibodies recognize. Infections with other types of Borrelia, like those causing relapsing fever, can also trigger a non-specific reaction.
Viral Infections
A number of common viral infections can also stimulate the immune system, producing antibodies that cross-react with Borrelia antigens. These include infectious mononucleosis (Epstein-Barr Virus or EBV) and Cytomegalovirus (CMV) infections. The intense, generalized immune response generated during these viral illnesses can produce a wide array of antibodies that are picked up by the Lyme test. Parvovirus B19 and Human Immunodeficiency Virus (HIV) have also been noted as potential causes of these misleading results.
Autoimmune Conditions
Conditions involving the immune system itself are another significant source of false positives. Autoimmune diseases, where the body mistakenly attacks its own tissues, often lead to the production of various autoantibodies that can interfere with the test. Patients with Systemic Lupus Erythematosus (SLE) or Rheumatoid Arthritis (RA) frequently test positive on the initial ELISA due to circulating autoantibodies. The presence of rheumatoid factor (RF) in patients with RA, for example, has been shown to nonspecifically recognize B. burgdorferi proteins.
The dysregulation in these autoimmune conditions means high levels of circulating immune complexes can nonspecifically bind to assay components. Although the Western Blot is generally better at distinguishing these cross-reactions, it does not completely eliminate the issue. Laboratory results must always be interpreted in the context of a patient’s overall clinical presentation and history.
Procedural and Technical Factors
Technical aspects of the testing process and limitations in antibody detection can also result in a false positive. One common issue is the persistence of antibodies long after a past infection has been successfully treated and resolved. The immune system develops long-term memory, and antibodies against Borrelia can remain detectable for months or years. A positive test in this scenario indicates only past exposure, not necessarily an active disease requiring treatment.
Issues with Western Blot interpretation also contribute to false positives. The test is considered positive only if a certain number of specific protein bands are present, based on strictly defined criteria. Lack of standardization or experience in some laboratories can lead to the misreading of faint or non-specific bands. Furthermore, CDC guidelines discourage using IgM antibody results for diagnosis if symptoms have lasted over 30 days, as the IgM test is less specific and prone to false positives in long-standing cases.
Laboratory errors related to handling and execution can introduce inaccuracies. Improper sample handling, reagent contamination, or incorrect calibration of equipment can lead to an artificially positive result. While quality controls exist, these technical mistakes represent a procedural risk. Interpretation is further complicated by the use of older testing methods and lack of standardization across commercial laboratories.
Prior vaccination can also be a factor, though this is less common today. The original Lyme disease vaccine, Lymerix, stimulated the production of antibodies against an outer surface protein of Borrelia. Individuals who received this vaccine may still have circulating antibodies that trigger a positive result on some tests, indicating vaccination-related immunity rather than a current natural infection.