As mentioned in the previous post, Lyme disease is an infection caused by Borrelia burgdorferi, a tiny bacterial spirochete (not a parasite!) that is transmitted through the bites of the Ixodes scapularis and Ixodes pacificus tick, found in the Northeast/Central and Western United States, respectively. The CDC estimates that approximately 300,000 cases of Lyme disease are diagnosed in the U.S each year, however despite appropriate therapy, many patients go on to receive extended courses of treatment based on repeat diagnostic tests that suggest they have not ‘cleared’ their infection. This arises from imperfect testing and imperfect interpretation of these tests, and creates significant confusion among both patients and primary care providers.

Although the CDC estimates that approximately 300,000 cases of Lyme are diagnosed in the U.S each year, an estimated 3.4 million tests are performed yearly for the diagnosis of Lyme disease. The current recommended testing algorithm for Lyme involves a 2-tiered system, starting with an enzyme immunoassay (EIA) screen, followed by confirmation with Western Blot IgM/IgG testing if (and only if) the EIA suggests exposure to Lyme. It is important for clinicians to understand these 2 tests and their significance in the diagnosis of Lyme disease.

First and foremost, both the EIA and Western blot tests are indirect testing methods to diagnose Lyme disease. What this means is that these tests do not detect the presence of living spirochetes in the body, but instead measure the immune response of a patient that has been exposed to the bacteria. The EIA test is considered the more sensitive test of the two, meaning that its purpose is to detect Lyme in those patients who truly have the disease. However, as with all tests that are sensitive, false positives can occur as well (from other tick borne infections, other infections caused by spirochetes, endocarditis and even some autoimmune disorders). Clinicians need to be aware that false positive EIA testing can occur, hence the need for confirmatory testing with Western Blot. It is also important for clinicians to realize that the sensitivity of the EIA varies widely based on the stage of the disease: With early stage Lyme (involving the classic erythema migrans rash or the more commonly seen round, red expanding macule at the site of the tick bite),

Image Source- CDC website

the sensitivity of EIA may only be 50-60%, while with later stages of Lyme, the sensitivity goes up to approximately 90%. Given this, clinicians have been advised that if the a patient is found to have a rash classic for Lyme (bull’s-eye rash), in an area endemic for Lyme disease, diagnostic testing is not needed, and treatment can be initiated empirically.

Once an EIA test is found to be positive or equivocal, Western Blot (WB) testing should always be performed to confirm exposure to Borrelia burgdorferi before any form of treatment is initiated. Western blot testing looks specifically for proteins that antibodies have binded to-on the WB, each protein-antibody binding complex is represented as a ‘band’. The more of these bands that are seen, the more specific the result. In the diagnosis of Lyme disease, at least 2 bands must be present on the IgM WB, and at least 5 bands of the IgG Western Blot. Anything less is considered a negative result (there are no border-line results regarding the Western Blot)! Again, clinicians need to be aware of a few things. First, the WB IgM test is ONLY useful when it returns positive during the first 4-6 weeks of illness. Beyond this time frame, the IgM is not a reliable marker of the disease (many false positives are seen), and the IgG WB is considered more reliable. If the patient has been ill for more than 4-6 weeks and the IgG test is negative, it is unlikely they have Lyme disease, despite the results of the IgM.

Once Lyme disease is diagnosed and treated, the patient is considered cured unless they are again re-infected by another Ixodes tick. There is no proven state of chronic spirochetemia (finding this in patient might could make you famous!), however patients often do experience symptoms of fatigue, arthralgias (without joint swelling), ‘brain fog’, and depression after being treated for Lyme. This is what is described as the ‘Post-Lyme’ syndrome, and is secondary to the body’s attempt to gradually recover from the infection rather than from ongoing infection. Post- Lyme syndrome does NOT require repeat testing for Lyme, and does NOT require re-treatment; in fact, a recent NEJM paper involving a randomized, double-blinded clinical trial reinforced the lack of any real benefit in prolonged therapy in patients with Post-Lyme symptoms (NEJM Article).

So why not re-test patients if they have the above symptoms? Both the EIA and WB results can remain positive for years after treatment of the illness. A study done by Robert Kalish and colleagues found that of 40 patients that were previously treated for early Lyme disease 10-20 years prior, 10% remained positive for IgM and 25% remained positive for IgG, despite the lack of any clinical symptoms concerning for Lyme. Of the 39 patients who had late stage Lyme previously, 15% had persistently positive IgM testing on WB, and an amazing 62% were still IgG positive! This again underscores the fact that both the EIA and WB tests are indirect tests for Lyme, and should NOT be used to determine if someone is re-infected with Lyme in the absence of any clinically significant symptoms.

So are there any direct tests that can be used to diagnose Lyme better? PCR testing and culturing methods are available, however these have generally low sensitivity and are not reliable in the setting of low burden infections. A positive PCR does not necessarily reflect active infection, as this test is used to detect DNA, which can be extracted from either living or dead spirochetes. More research is needed to find better ways to detect active infection and reinfection.

In short, clinicians should only test for Lyme in patients who have signs or symptoms consistent with the disease, in the setting of living in or being in an area endemic to the disease. Patients with rashes that are classic for Lyme in an endemic area do not require any further testing, and empiric treatment is acceptable. False positive and negative results exist for both the EIA and WB (no test is perfect), and clinicians should not re-test or re-treat patients with Post-Lyme symptoms. Knowing these basic facts can avoid unnecessary confusion with the diagnosis, and treatment of Lyme disease.

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Pubmed References:

Kalish, RA et al. Persistence of immunoglobulin M or immunoglobulin G antibody responses to Borrelia burgdorferi 10-20 years after active Lyme disease. Clin Infect Dis, 2001 Sept 15; 33(6):780-5.

Marques, AR. Laboratory Diagnosis of Lyme Disease-Advances and Challenges. Infect Dis Clin North Am. 2015 Jun; 29(2):295-307

Berende, A. et al. Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease. N Engl J Med, 2016; 374:1209-20

Wormser, GP et al. The Clinical Assessment, Treatment and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis and Babesiosis: Clinical Practice Guidelines from the Infectious Disease Society of America. CID, 2006; 43:1089-134.