Diagnosing acute Lyme disease is often straightforward. If someone develops flu-like symptoms following a tick bite or spending time in nature, the diagnosis of Lyme disease is often considered. However, when someone is sick with multiple symptoms for an extended period of time, it can take years to get a correct diagnosis. There are many nuances associated with Lyme disease testing. Read below to learn about accurate testing for chronic or late-stage Lyme disease.
How was Lyme Disease Testing Criteria Developed?
There may not be a more complex infection to diagnose than chronic Lyme disease. When Lyme disease was first discovered in the 1970s, the Center for Disease Control (CDC) wanted to track the number of cases in the US, so they developed diagnostic criteria for surveillance reporting to local public health departments. The criteria needed to be narrow to increase the sensitivity of cases reported. Unfortunately, the surveillance criterion made its way into doctor’s offices, and physicians began using the narrow criteria as diagnostic parameters for Lyme disease.
If someone had symptoms following a tick bite – or even years after a tick bite – but did not have a large bullseye rash, meningitis, facial paralysis, or encephalomyelitis, they were told they did not have Lyme disease.
Another limitation of the Lyme disease surveillance criteria is it only includes symptoms often seen in acute cases of Lyme disease and excludes many symptoms consistent with late-stage Lyme disease. Throw in the misconception that people can only contract Lyme disease in the northeastern U.S., and Lyme disease is not typically considered as a possible cause of symptoms in the rest of the country.
Poor Sensitivity of Traditional Lyme Disease Testing
If a physician is familiar with the multiple presentations of Lyme disease and considers it as a possible diagnosis, standard laboratory testing has poor sensitivity so many cases are missed. The traditional laboratory test used to diagnose Lyme disease is a “two-tiered” test. This means an ELISA test is run first, and if it is positive, a second test called a western blot is performed to confirm the accuracy. If the ELISA test is negative, the western blot is not performed. The sensitivity of the ELISA test is so poor that it reports a false negative about half of the time. This means the more sensitive western blot never gets tested.
Physicians that specialize in treating tick-borne infections have historically considered the diagnosis of late-stage Lyme disease a clinical diagnosis. A clinical diagnosis is made if the patient has signs and symptoms consistent with a tick-borne infection and other diagnoses that could explain the signs and symptoms have been ruled out. However, in recent years specialized laboratory testing has advanced and should be used to confirm a suspected diagnosis.
In many scenarios other possible diagnoses have been ruled out, there has been a possible exposure to ticks (including the distant past with chronic Lyme disease), and the pattern of symptoms is consistent with Lyme disease. Specialized laboratory testing that is more sensitive than general national laboratory testing should be used to confirm the diagnosis.
Additional Challenges with Lyme Disease Testing
Another obstacle with many Lyme disease tests are they rely on detecting antibodies produced by the immune system against the Borrelia bacteria. In some circumstances, the level of antibodies may be low due to immune suppression which compromises the accuracy of the test. In addition, if a test is performed too soon after a tick bite, antibodies may have not yet formed. Also, if antibiotics are taken early in an infection, the medication can prevent antibody formation resulting in future negative tests.
In late-stage Lyme disease, the Lyme spirochete has burrowed into tissues like muscles, joint spaces, and organs. The bacteria can also form a protective structure around itself called a biofilm. These immune-privileged locations prevent the immune system from detecting the bacteria so antibodies are not produced for the test to detect.
ELISA (Enzyme-Linked Immunosorbent Assay)
ELISA methodology of testing works by attaching Lyme antigens to a surface in a laboratory. If a blood sample has Lyme antibodies, the antibodies will bind to the antigen. This creates an antigen/antibody complex that is linked to an enzyme (which is another antibody). In the last step, a substrate is added that allows the result to be measured.
The limitation of the ELISA test is the cut-off for a positive result is set extremely high to make the test highly specific. However, the high specificity comes at the cost of the sensitivity of the test. A review of research studies looking at the sensitivity of ELISA testing for Lyme disease revealed it is accurate less than half the time. Because of this, the standard two-tiered test for Lyme disease should not be relied upon to identify Lyme disease.
Immunofluorescence Assay (IFA)
Like the ELISA, the IFA methodology for Lyme disease testing is an indirect test that looks for antibodies formed against the bacteria that causes Lyme disease – Borrelia burgdorferi. In the laboratory, blood is added to a slide that contains the Borrelia antigens. If the blood contains antibodies to Borrelia, they will bind to the antigens on the slide. The final step is to view the slide under a fluorescent microscope (hence the name). Antibodies bound to the antigens will light up if they are present.
The IFA lacks specificity and sensitivity, so it is not a preferred method for diagnosing Lyme disease. Antibodies from other infections can bind to the antigens on the test strip (called cross-reactivity) leading to a false-positive result.
The Western Blot for Lyme Disease
The western blot is also an antibody-based test but is more sensitive and specific than the ELISA and IFA tests. Specific surface proteins from the Lyme bacteria are produced on strips for a western blot test. If there are Lyme antibodies in a blood sample they will bind to the surface protein antigens. The pattern of binding indicates whether or not the result is positive. In Lyme disease, there are specific outer surface proteins (called bands) and the specific pattern formed on the blot increases the specificity of the test.
The outer surface proteins are numbered by weight in kilodaltons. Specific bands for Lyme disease include 23-25 kDa, 31 kDa, 34 kDa, 39 kDa, 41 kDa, and 83-93 kDa. The CDC criteria require at least two of three positive IgM bands and five out of ten positive IgG bands for a western blot result to be positive. The CDC criterion is stringent so some Lyme specialty laboratories have established their more inclusive criteria based on thousands of tests performed.
If someone was possibly exposed to ticks, had many clinical signs and symptoms of Lyme disease, but did not have the exact pattern considered to be positive by the CDC, they were told by their doctor they do not have Lyme disease.
A limitation of the CDC criteria for a Lyme disease western blot is bands 31 and 34 are not taken into consideration. The CDC excludes these two bands because a person might be positive for these bands if they received a Lyme vaccine. Ironically, very few people received the Lyme vaccine when it was available for a couple of years before it was removed from the market due to adverse reactions (and lawsuits). Based on over 25 years of experience and validation studies, the Lyme specialty laboratory Igenex requires two out of six bands to be positive for an IgM positive result.
Western blot tests offered by national commercial laboratories such as Quest and LabCorp develop their testing strip using a synthetic laboratory strain of Borrelia called B31. Igenex uses the synthetic B31 strain as well as the wild (occurs in nature) 297 strains to increase the sensitivity of their western blot
Because Igenex uses more inclusive criteria than the CDC and two strains of Borrelia for testing, their western blot may diagnose Lyme disease that is missed by commercial laboratories.
ImmunoBlot fro Lyme Disease
The Lyme immunoblot uses recombinant proteins on the blot so it is more sensitive than western blots that use native proteins. This test can detect Lyme disease as early as one week after exposure to the Borrelia bacteria and detect late-stage Lyme when antibodies are typically low. Like the western blot, an immunoblot result has to meet certain criteria for a positive result.
Additional species of Borrelia bacteria fall into the Tick-Borne Relapsing Fever Group (TBRF). The TBRF group causes symptoms similar to Lyme disease, and some species may be more common in other parts of the United States, like California. This may be why some Californians test negative on a traditional Lyme test.
T-Cell (Lymphocyte) Test
In recent years, the sensitivity of T-cell testing for Lyme disease has improved. This methodology detects an immune system cell (called a T-lymphocyte) that has formed in response to the Borrelia bacteria. T-cells are part of the cellular immune response, unlike antibodies that are created as part of a humoral immune response.
Early in infection, T-cells develop before antibodies are formed, so a T-cell test may help detect early Lyme disease. As the disease progresses, some people’s immune system does not convert from a cellular to a humoral response. This would prevent antibodies from forming, so a T-cell test would be informative in this scenario.
Positive Lyme antibody (including western blot and immunoblot) tests make it difficult to determine if someone has an active infection, or if memory antibodies persisted after the infection has resolved.
One of the great debates about chronic symptoms associated with Lyme disease is whether the infection is active or the immune system response has persisted contributing to symptoms. A T-cell test will produce cytokines directed at the Lyme bacteria when an infection is active. This is the reason T-cell testing has become my preferred test for all tickborne infections.
Putting Lyme Disease Testing Together
Late-stage Lyme disease can be difficult to diagnose. The CDC criterion was established for surveillance purposes only, so should not be used for diagnostic purposes. Lyme disease tests at national reference laboratories have poor sensitivity and specificity and laboratories that specialize in Lyme disease testing provide a more accurate result. No one testing methodology is perfect, so results need to be taken into consideration with symptoms.
T-cell testing for all tickborne infections will inform the doctor and the patient whether an infection or infections are active or not. I have also found T-cell testing informative for viral infections such as Epstein-Barr virus. Any good treatment plan should be based on accurate test results.
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