Lyme disease is a difficult disease to accurately diagnose and for many patients this, unfortunately, means months, if not years, of frustration. Lyme disease diagnosis is rarely made through a blood test alone as these are often imprecise and inaccurate and may simply demonstrate previous infection with Borrelia bacteria which was successfully fought off by the patient, rather than a current symptomatic infection. Diagnosis of Lyme disease usually occurs after assessing a patient’s medical history, including exposure to high-risk tick areas and any recollection of tick bites, the characteristic bull’s eye Lyme disease rash, and other symptoms indicating the condition. The erythema migrans rash is often considered sufficient for a diagnosis of Lyme disease even in the absence of positive blood tests as it is so specific to infection with Borrelia bacteria.
Lyme Disease Mimics other Diseases
Lyme disease has been called the ‘great mimic’ as it can cause symptoms suggestive of a number of other conditions with the potential to lead to a misdiagnosis. Conditions that Lyme disease may be mistaken for include rheumatoid arthritis, Rocky Mountain Spotted Fever, mononucleosis, fibromyalgia, chronic fatigue syndrome, multiple sclerosis, Parkinson’s Disease, lupus, Crohn’s disease, and even mental health issues such as schizophrenia, psychosis, and bipolar disorder. Delaying appropriate treatment for any of these conditions, and for Lyme disease itself can have significant long-term consequences making early diagnosis essential for a positive outcome.
In general, a diagnosis of the condition involves a suspicion of symptoms of Lyme disease followed by a positive or indeterminate result with a standardized, sensitive ELISA test followed by verification with the more specific Western Blot assay. This should allow the diagnosing doctor to make a fairly good assessment of the presence of antibodies to Borrelia burgdorferi. The brief introduction of the Lyme disease vaccine can complicate diagnosis however, as can widespread infection without disease in many tick endemic populations. Seropositivity may not indicate current or active infection but simply the residual antibodies to an attack previously fought off. New variants of Borrelia bacteria also make things difficult for those testing antibodies to specific laboratory Borrelia strains meaning that infection may go undetected when due to hybrid bacterial types.
Testing for Lyme Disease
Historically, the standard tests for Lyme disease have relied on the cultivation of Borrelia burgdorferia bacteria from a sample of a patient’s blood or skin in order to demonstrate active infection. Such tests can take considerable time and resources and are not always available. They are also not particularly sensitive and have, therefore, been largely replaced by PCR testing to detect the presence of spirochaetal DNA in blood samples. Rapid hybridization of Borrelia bacteria has hampered efforts at standardizing such a test however, and several new species of Borrelia have been discovered which are not detected by these tests (Bunikis and Barbour, 2002).
Antibody testing for Lyme disease uses a combination of an enzyme-linked immunosorbent assay (ELISA) and Western Blot testing to improve sensitivity and specificity over the use of either test alone. These remain, even in combination, less than 100% accurate but can form part of a diagnosis of Lyme disease in the presence of symptoms of the condition and a history of exposure to ticks. Many patients have had false positives on such tests however, making it inappropriate to consider this the only criteria for Lyme disease diagnosis. Recombinant protein tests are being developed for more widespread use and have been shown to be more accurate and precise in a laboratory setting. Such test are also likely to be quicker and more cost-effective than the ELISA and Western Blot tests which remain the standard in most areas currently.
Using skin samples to test for Lyme disease can be highly effective in cases where a case is suspected due to the presence of erythema migrans. However, extracutaneous sample testing using a polymerase chain reaction (PCR) method is generally of low sensitivity, with the exception of those patients with Lyme arthritis having synovial fluid tested; this was found to be more than 90% sensitive in those untreated or partially treated for Lyme arthritis (Aguero-Rosenfeld, et al, 2005). PCR testing should not be relied upon as the sole support for a diagnosis of Lyme disease using extracutaneous samples. Instead, PCR is useful for confirming a diagnosis for patients with suspected Lyme arthritis who have a positive IgG test. Where a positive PCR result is obtained in patients with suspected late-stage Lyme disease symptoms but seronegativity this is largely thought to constitute a false-positive (Aguero-Rosenfeld, et al, 2005).
Problems with Lyme Disease Diagnosis
Despite there being a number of tests for Lyme disease touted by various manufacturers, there are none that are 100% accurate or precise and many that could give a dangerous false positive or false negative resulting in either treatment delays or inappropriate and dangerous treatment using antibiotics. Many tests, such as ELISA, Western Blot, IFA, T-cell activation, and the Gunderson test rely on the detection of serum antibodies to Borrelia bacteria. However, bacteria such as Borrelia have a knack for hiding in plain sight, essentially tricking the body into thinking they are part of its normal make-up and thereby producing no antibodies to the bacteria. Similarly, hybrid species of Borrelia bacteria may not be detected by a serum antibody test as the assay is only looking for antibodies to those Borrelia strains found in the laboratory.
Lyme disease diagnosis can be complicated further by the fact that it may take a number of weeks for the body to produce sufficient antibodies to bacteria to the level detectable by laboratory testing. Bacterial invaders of the body usually trigger an immunoglobulin M (IgM) response which builds over two to four weeks and then often dissipates after six months unless infection persists. Patients with chronic Lyme disease usually has detectable IgM levels, but an absence of this antibody, or low levels may not indicate that the patient is cured as other ill-effects may be occurring due to autoimmune reactions, permanent damage from a, now cleared, infection, or an entirely different condition initially misdiagnosed as Lyme disease. Testing a patient within two weeks of a tick bite and dismissing Lyme disease is also dangerous as they may not have built up detectable levels of Borrelia-specific-IgM by that time.
At around four to eight weeks after initial infection, the body produces a second antibody, namely IgG. This peaks at around six weeks and usually dissipates after twelve months or so. Whereas IgM is the largest type of antibody, IgG is the smallest. IgG antibodies are the most common type however, forming around 75-80% of all the antibodies in the body. These are also the only kind that can cross the placenta, making them extremely important in protecting an unborn baby from Lyme disease infection. Where a baby has a detectable level of IgG antibodies it does not mean that they have an active infection, merely that the antibodies entered their blood through the placenta. Monitoring is essential for signs of Lyme disease, but it is not thought that this type of infection transmission occurs in most cases. Where an infant is producing IgM antibodies to Borrelia bacteria however, this does constitute a sign of infection as such antibodies cannot be the result of placental transfer. In some cases where infection occurred early in pregnancy a foetus may not recognize the bacteria as foreign and may not produce antibodies to the infection.
When determining the most accurate test for Lyme disease for a particular patient a doctor must attempt to determine the timing of their exposure to the infectious spirochaetes. An early IgG Western Blot might find little evidence of infection, whereas an early IgM may prove positive. Similarly, a positive IgG ELISA test may indicate previous infection but no active disease.
Tissue-Typing and Lyme Disease Diagnosis
Tissue-typing is another method being used by some to help aid in diagnosing Lyme disease. It is now known that the limited numbers of specialized lymphocytes present in each individual’s circulation differ slightly, which is why it is so important to make an accurate human leukocyte antigen (HLA) match when carrying out tissue transplants for medical treatment. Where donor and recipient have vastly different HLA types an immune system reaction, and subsequent rejection of tissue, can occur. The possible ramifications for infectious diseases such as Lyme disease of individual HLA types is that some patients may be more vulnerable to symptoms in one particular tissue or body system than other patients with a different HLA profile. Indeed, some patients may not only create antibodies to the invading organism but also to their own cells thereby triggering an autoimmune reaction.
The doctor involved in diagnosing Lyme disease in the original cases in Old Lyme in Connecticut, later determined that those patients with tissue type HLA-DR2 and HLA-DR4 suffered more severely from arthritis and chronic disease than patients with different tissue types. Subsequently, patients with other specific tissue types have been found to have a higher incidence of neurological symptoms and diseases such as Multiple Sclerosis, perhaps also making them more vulnerable to neurological symptoms should they contract Lyme disease. Patients with Lyme carditis, a heart complication resulting from infection with Lyme disease, have been found in a number of cases to generate an auto-antibody to cardiolipin. This suggests that there may be some benefits to testing a patient’s tissue type and searching for auto-antibodies where symptoms are present in a specific body system following possible Lyme disease infection. Such tissue-type tests are expensive however and may not have significant overall benefit to justify their use in most patients.
Diagnosing physicians are also recommended to assess the likelihood of certain clinical manifestations of Lyme disease in particular patient populations. Lyme disease is most prevalent in the US in children between the ages of two and fifteen, and in adults between 30-59yrs old. However, the development of multiple sclerosis, for example, is much more common in those between 20-30yrs old. Understanding the epidemiology of the disease is vital for reducing the risk of misdiagnosis.
Bunikis J, Barbour AG., Laboratory testing for suspected Lyme disease. Med Clin North Am. 2002 Mar;86(2):311-40. Review.
Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP., Diagnosis of lyme borreliosis. Clin Microbiol Rev. 2005 Jul;18(3):484-509.
Depietraopaolo, D.L., Powers, J.H., Gill, J.M., Foy, A.J., Diagnosis of Lyme Disease, Am Fam Physician. 2005 Jul 15;72(2):297-304.