Diagnostics

Patients who present with erythema migrans are not required to undergo serological testing as long as they live in a Lyme endemic region. Normal testing involves the use of an enzyme immunoassay (EIA) or indirect immunofluorescence assay (IFA) followed by a Western immunoblot (IgM or IgG) of samples that tested positive. One major issue with this method is that it can take 4-6 weeks after infection for the body to produce measurable amounts of antibodies (IgM being produced first, followed by conversion to IgG). Therefore, patients who were recently infected may test negative even though they are infected (false negative). On the other hand, patients who have been infected longer than 6-8 weeks and have arthritis will test positive. This is because IgG and even IgM antibodies against B. burgdorferi can remain for months or years after near or complete spirochetal elimination with antibiotics. Thus, if patients with past or asymptomatic Borrelia infection develop another illness, particularly one with neurological or joint symptoms, the symptoms might be attributed incorrectly to Lyme disease (false positive). In fact, false positive IgM results for B. burgdorferi can occur in over 50% of parvovirus B19 infections, EBV, anaplasmosis, and certain autoimmune diseases. If a patient has had symptoms for many months, and the only immunoreactivity is IgM with no IgG, this is almost certainly a false positive cross-reaction. Therefore, IgM testing should only be done if symptoms are acute (present for less than 6 weeks). It is important to note that one study found positive serologic test results have little diagnostic value in areas with low disease incidence, as fewer than 20% of positive test results were obtained from patients with clinically likely Lyme disease (Lantos et al. 2015). This means clinicians must consider a patient’s risk factors (especially exposure to deer tick habitats) when deciding whether to obtain/how to interpret serologic testing.

Evolution of serodiagnostic testing for Lyme disease in the U.S. (Branda et al. 2017) Click to enlarge.

Testing protocols for B. burgdorferi have evolved greatly since their establishment in 1994. EIAs and IFAs were developed for sensitivity and Western blots were developed for specificity. Assays were originally prepared from whole-cell cultured B. burgdorferi, lacking key in vivo expressed antigens and expressing antigens that can bind non-Borrelia antibodies. However, a new generation of EIAs has emerged, in which the antigen preparation consists of recombinant proteins, synthetic peptides, or synthetically engineered chimeric proteins, allowing for minimal cross-reactivity with nonspecific antibodies. The use of a “2-EIA” protocol in two-tiered testing has also been shown to be more sensitive in early Lyme disease than conventional two-tiered testing that uses a Western immunoblot. Western immunoblots present a challenge due to low sensitivity in early infection, technical complexity, and subjective interpretation when scored by visual examination, making them difficult to reproduce. However, removing the Western immunoblot removes valuable information about the extent and maturity of the antibody response. And while Western blots cannot differentiate between active infection and past exposure, improvements in serologic testing methods will not be able to address this issue. Rather, it will be addressed through improved detection methods. Direct detection of the microbe is strong evidence of an active infection, as opposed to indirect detection of antibodies (Branda et al. 2017).

Treatment & Public health Cost

Lyme disease can also be misdiagnosed based on symptoms. For instance, fever, muscle aches, and fatigue can be mistaken for viral infections (such as influenza and mononucleosis), joint pain can be mistaken for rheumatoid arthritis, and neurological symptoms can be mistaken for multiple sclerosis. Appropriate diagnosis and treatment are key factors in improving disease outcomes. Antibiotic therapy is nearly always effective at clearing infection. However, long-term antibiotic therapy is not recommended because this can deplete the normal microbiota, allowing pathogens to colonize the body. Other treatments that are not recommended include combinations of antibiotics, hyperbaric oxygen or ozone therapy, radiation-based therapies, intravenous immunoglobulin, and stem cell transplantation (Steere et al. 2016). These treatments can be very expensive (no insurance coverage), have no therapeutic benefit, and can lead to very serious adverse effects, including antibiotic-induced colitis, MRSA infections, GI dysbiosis, light sensitivity, sepsis, etc. These inappropriate treatments, in combination with misdiagnosis, have serious implications on the social and medical cost of Lyme disease.

Post-Treatment Lyme Disease Syndrome (PTLDS)

Even after appropriate treatment has been given, symptoms of Lyme disease can persist. This occurs in about 2% of the population. Patients with PTLDS do not have an active infection, but they must have proof of previously appropriately treated Lyme disease, and they often present with subjective symptoms, such as pain, fatigue, or behavioral and cognitive changes. Subjective post-Lyme symptoms are not unique to Lyme disease, but rather, are common to the recovery from many systemic illnesses. In fact, one study found that, after 12 months, patients treated for erythema migrans were no more likely to have subjective symptoms than an uninfected control group (Lantos 2015). So why does PTLDS develop? Patients with a longer duration of symptoms before treatment are more likely to develop post-treatment symptoms. Additionally, a polymorphism that is thought to decrease the expression of TLR1 is associated with increased levels of pro-inflammatory cytokines and persistent arthritis after antibiotic therapy (Steere et al. 2016).

“Chronic Lyme Disease”

What is “chronic Lyme” and how does it differ from PTLDS? “Chronic Lyme” is an alternative diagnosis that is used for medically unexplained symptoms, even when patients have no evidence of past or present Lyme disease. The diagnosis of “chronic Lyme” often lacks objectivity and instead is based on general, subjective symptoms, including myalgias, arthralgias, headache, fatigue, irritability, and cognitive dysfunction (Lantos 2015). Additionally, diagnosis does not require laboratory evidence. However, physicians who diagnose “chronic Lyme” often turn to laboratories that perform unvalidated tests that are not regulated by the FDA or perform standard serologic tests that lack evidence-based criteria (Feder et al. 2007).

Diagnoses of “chronic Lyme” fall into one of four categories. Patients with category 1 disease do not have objective clinical manifestations or laboratory evidence of B. burgdorferi infection, and they receive a diagnosis based on the nonspecific symptoms mentioned above. These nonspecific symptoms are common in more than 10% of the general population, regardless of whether Lyme disease is endemic in the area (Feder et al. 2007). Patients with category 2 disease have identifiable illnesses other than Lyme disease. They may or may not have a history of Lyme disease. They have received a misdiagnosis or a diagnosis that they are reluctant to accept and have sought an alternative diagnosis from a physician willing to treat them for “chronic Lyme.” Patients with category 3 disease do not have a clinical history of Lyme disease, but their serum samples contain antibodies against B. burgdorferi. Patients with category 4 disease have symptoms associated with PTLDS (Feder et al. 2007).

Some scientists and clinicians have argued that “chronic Lyme” is caused by persistent infection with B. burgdorferi. However, antibodies against B. burgdorferi in many of these patients are undetectable. On the contrary, patients in whom treatment for most infectious diseases has failed typically have persistent or rising concentrations of antibodies because of ongoing B cell stimulation by microbial antigens. Additionally, failure of treatment for bacterial infections typically occurs as a result of pathogens that have acquired resistance to antibiotics, difficulty in achieving sufficient concentrations of antibiotic at sites of infection, or impaired host-defense mechanisms. None of these factors are generally applicable to infection with B. burgdorferi (Feder et al. 2007).

Neuroborreliosis (Halperin 2017)

Neuroborreliosis refers to the neurological manifestations of Lyme disease, which can affect both the central nervous system (CNS) and the peripheral nervous system (PNS). As previously mentioned, neurological symptoms of Lyme disease can often be mistaken for neurological illnesses such as MS or ALS. Neuroborreliosis occurs in 10-15% of patients infected with B. burgdorferi. Clinical manifestations include meningitis, cranial neuropathy (most commonly facial nerve palsy), and painful radiculopathy. Encephalopathy (altered cognition or memory) can occur as part of the systemic infection but is not evidence of neuroborreliosis. Additionally, post-treatment Lyme disease symptoms (PTLDS) are unrelated to neuroborreliosis. Diagnostic tests for neuroborreliosis that affects the central nervous system often detect intrathecal antibodies to B. burgdorferi.


Sources

Lantos et al. 2015 (“Poor Positive Predictive Value of Lyme Disease Serologic Testing in an Area of Low Disease Incidence”): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599394/

Branda et al. 2017 (“Advances in Serodiagnostic Testing for Lyme Disease Are at Hand”): https://academic.oup.com/cid/article/66/7/1133/4706288

Steere et al. 2016 (“Lyme Borreliosis”): https://www.nature.com/articles/nrdp201690

Lantos 2015 (“Chronic Lyme Disease”): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477530/

Feder et al. 2007 (“A Critical Appraisal of ‘Chronic Lyme Disease’”): https://www.nejm.org/doi/full/10.1056/NEJMra072023

Halperin 2017 (“Neuroborreliosis”): https://link.springer.com/article/10.1007%2Fs00415-016-8346-2