How do I know if I have Lyme disease?
That's a very good question.
Some conditions, such as high blood pressure, diabetes and heart disease, can be measured and diagnosed through direct examinations and tests.
Other infectious diseases are often characterized by unique symptoms and by laboratory tests of blood, and other factors.
Some diseases are manifested by lesions (measles, for example) or by lab tests.
For example, babesiosis can be revealed by the presence of the protozoa in red blood cells magnified through a microscope.
The Lyme disease spirochete, however, is elusive and difficult to capture or grow. It cannot easily be seen or otherwise detected.
To increase confusion, in its early stages the bacteria produces a range of vague, subjective symptoms that can match many other diseases.
In suspected cases that have no bull's-eye rash, no retrieved tick, and no inflamed joints, physicians must investigate the patient's immune system for signs of infection.
Research is underway to produce faster, simpler and more precise diagnostic tests. One avenue is "xenodiagnosis," and would involve luring spirochetes to the surface with tick saliva. That means isolating the chemicals in the saliva that the tick responds to, or allowing an uninfected tick to feed on the patient.
Meanwhile, doctors typically use two serologic tests to look for antibodies to the spirochete. However, antibodies are not the first immune defenders on the scene.
The body fights foreign bacteria, viruses and other microorganisms, using a two-layered immune defense.
The first line of defense consists of cells that envelope and destroy interlopers. The body also releases enzymes and other proteins to combat invading germs.
A by-product of this immune response is inflammation. This accounts for the erythema migrans rash and other Lyme symptoms, researchers said.
As the fight continues, the immune system calls on its adaptive or acquired system, which produces antibodies that search out and destroy specific pathogens. Immunoglobulin G, or IgG, a "sticky" antibody intercepts disease-causing agents.
Meanwhile, other antibodies, such as IgM, also target specific microbes, or parts of these germs. IgM is produced first and usually fades with time. IgG lingers.
This and other adaptive antibodies tend to stick around so that they can be called upon to counter another infection by the same pathogen.
The adaptive system helps keep us protected in the future, but it takes about two weeks or more to respond.
This means that antibody tests administered during this two-week or longer period would not show evidence of the spirochete, despite infection. This is true of many other diseases, as well.
Moreover, the tests themselves are considered less than ideal for all diseases, because antibodies from a previous, cured infection remain, meaning that once a patient tests positive for Lyme disease, he will test positive whether he is currently infected or not, doctors said.
The tests also require a degree of interpretation.
Frequently tests intended to diagnose are misused to screen for the disease, yielding a high number of false positive results, unnecessary antibiotics, and neglect of a possible non-Lyme disease problem that the patient may have.
"It's hard for people to understand the current tests. There is no perfect test," said Dr. Linda K. Bockenstedt, professor of rheumatology at the Yale medical school.
Bockenstedt is conducting research into more precise and accurate tests for Lyme disease.
If Lyme disease is suspected, a physician will typically first carry out an ELISA test.
ELISA is short for enzyme-linked immunosorbent assay.
Commercially available ELISA tests for Lyme disease use either chopped-up Lyme disease bacteria, genetically engineered B. burgdorferi proteins, or a mixture of both.
During the test, which is usually done in a private commercial lab, the mixture of Lyme bacteria pieces is placed in tiny wells on a plate.
Blood serum (blood minus red and white cells) from the patient is then added to the plate and wells, and allowed to incubate, Bockenstedt, said.
If the patient's blood contains antibodies to the Lyme bacteria, then the antibodies will lock onto some of the proteins in the wells. The plate is washed to remove unbound Lyme disease bacterium parts. Then another enzyme is added that is designed to lock onto human antibodies.
Yet another enzyme is placed on the plate. This enzyme turns a specific color when it binds to antigen-antibody complexes.
The plate can then be examined to see whether the patient's serum contains antibodies to Lyme disease bacteria.
If no antibodies are detected, no further tests are to be given, according to CDC guidelines. The patient is presumed not to have Lyme disease.
The ELISA test is considered very sensitive. In fact, the test is so sensitive that it can detect antibodies to bacteria that are similar, but not identical to, the Lyme disease bacterium. This unwanted response is called cross-reaction, Bockenstedt said.
To make sure the test is responding to the right antibodies, serum from uninfected people is placed in one well, and serum from other patients who are confirmed to be carrying the Lyme disease bacteria is placed in another control well, Bockenstedt said.
Since people have different immune responses, some tests reveal many antibodies, while others may be faint. The person evaluating the test must be able to distinguish a low immune response from both a cross-reaction, or the absence of a response.
If the ELISA is positive, physicians following the guidelines then order a western blot, or immunoblot test.
In this test, B. burgdorferi is again broken into pieces, generally by using chemicals. Known bacterial proteins are placed in lanes on a membrane.
An electrical charge is passed through the membrane, pulling proteins in the wells to the opposite end of the membrane. Smaller proteins move more rapidly than larger proteins. This separates the test proteins into bands. The membrane is then exposed to components of the patient's blood, she said.
Antibodies, including IgG and IgM latch onto the selected proteins, which are known by the tester. An involved process stains the antibodies and transfers the membrane onto photographic film.
As In ELISA, control lanes are used to calibrate the test, which appears as parallel lines of proteins sorted by molecular weight and captured antibodies.
While ELISA is considered sensitive, but not specific, the western blot shows the specific proteins that the immune system is responding to, Bockenstedt said.
The inevitable problem with both of these tests is that they are not 100 percent accurate in determining who is, or is not, infected with Lyme disease.
"There's an art to it," said Dr. Henry M. Feder Jr., professor of pediatrics and family medicine at the University of Connecticut Health Center.
"ELISA gives more false positive by cross-reacting, and is not good for early Lyme disease. The western blot looks at sections of the spirochete where antibodies attach," he said.
The spirochete itself can generally only be found by taking fluid from an infected joint and then creating millions of copies of whatever DNA is in the joint fluid, using polymerase chain reaction, or PCR. The DNA of the spirochete is then isolated.
This test is invasive, however, as well as expensive and difficult to perform, Feder said. PCR would not constitute a good screening test.
"We would all love to have a better test," he said.
Bockenstedt has begun preliminary research on a diagnostic test for Lyme disease, based on whether Borrelia proteins can induce a "signature" of initial immune cells. This is different from current tests because it does not rely on antibodies.
Serologic tests, such as ELISA and western blot, are bedeviled by false positives, meaning they find disease where there is none.
"More than half of the people (tested for Lyme disease) shouldn't be," Feder said, because they either do not meet the CDC and IDSA testing criteria, have already been tested negative several times, or have disorders unrelated to Lyme disease.
Or as one doctor put it, "Lyme disease is under-reported and over-treated."
The CDC has the clearest explanation of the mathematical thicket surrounding the reliability of diagnostic test results.
Consider a population of 100 people, 40 of whom are infected with a pathogen. Further, assume the test is 98 percent sensitive and specific.
With this common disease, mathematics predicts 1 percent false negatives, and 3 percent false positives.
That means one of the 40 people who tests positive does not have the disease, and three people mistakenly are diagnosed with the disease, while one person who actually has the disease is not diagnosed, the CDC calculated.
In a rare disease affecting one person in 100, epidemiologists expect 67 percent false positives, and zero false negatives. Sixty-seven percent means a physician could achieve more accurate results by flipping a coin.
The infection rate in Connecticut is slightly less than one-tenth of one percent, suggesting that no matter how well the ELISA and western blot tests are performed, a large percentage of the results will be false positives, Dr. Eugene Shapiro, professor of pediatrics, epidemiology, and investigative medicine at Yale University School of Medicine, and others said.
To think of it another way, if the rate of infection is close to the test's ability to distinguish between infected and not infected, there is likely to be a high rate of false positives, a diagnostics researcher said.
Moreover, an uninfected patient convinced he has Lyme disease will be proven "right" if he goes from doctor to doctor and is given a dozen tests.