Improving Diagnosis of Lyme Disease: Laboratory and Clinical Approaches

Diagnostic testing for Lyme disease is challenging because of the low sensitivity of currently approved laboratory tests, the broad spectrum of clinical presentations, and differences in how clinicians interpret findings. Therefore, diagnosis may be optimized with a careful assessment of risk factors for exposure and the patient’s pattern of symptoms, according to experts who participated in a Contagion^® Peer Exchange panel.

The panelists also discussed novel technologies that could improve the sensitivity and specificity of laboratory-based diagnostic testing for Lyme disease, particularly in early-stage infections, but stated that mainstream adoption of these tests may be slow due to the reluctance of the Centers for Disease Control and Prevention (CDC) and other governing organizations to adopt new methods.

Laboratory-Based Diagnostic Testing: The 2-Tiered Approach

The current guidelines for diagnostic testing of Lyme disease from the CDC and the Infectious Diseases Society of America recommend 2-tiered serologic testing with an enzyme-linked immunosorbent assay (ELISA) followed by a confirmatory Western blot test if the ELISA is positive.

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However, the sensitivity for this 2-tiered approach is only about 50%, according to Samuel Shor, MD, FACP, and has been shown to be less sensitive in the early stages of the disease because of the lag time between infection and development of detectable levels of antibodies.

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Dr. Shor also pointed out that similar to results from tests for other infectious diseases, an antibody immune response is likely to be demonstrated in patients with greater immune suppression. “The sicker you are, paradoxically, the more likely you’ll be overlooked,” he said.

Cultures of the Borrelia burgdorferi (B. burgdorferi) pathogen are considered by most experts to be the gold standard for confirming Lyme disease. However, culturing the pathogen is not routinely available in clinical practice because of the relatively low sensitivity, long incubation time (cultures are kept for 8 to 12 weeks before being considered negative

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), and need for complex growth media. Furthermore, a single dose of antibiotics may interfere with the ability to culture the B. burgdorferi pathogen.

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However, Leonard Sigal, MD, noted that the sensitivity and specificity of the 2-tiered testing approach depends on what the clinician perceives as the gold standard and how he or she defines Lyme disease. Furthermore, Robert C. Bransfield, MD, DLFAPA, stated that using solely an antibody-based test for detection of the B. burgdorferi organism is problematic given that the microbe suppresses and evades the immune system.

However, he and the panelists agreed that the immunosuppressive nature of B. burgdorferi is not the sole contributor to the inaccuracy of testing, as ELISAs and Western blotting are highly sensitive for HIV. Nevertheless, the panelists stated that the 2-tiered serologic testing has insufficient sensitivity to diagnose Lyme disease.

Clinical Diagnosis: Geographic Considerations and Multisystemic Manifestations

In the absence of a highly sensitive laboratory test, the panelists discussed the importance of considering a patient’s risk factors for exposure and clinical presentation when assessing the likelihood of Lyme disease. According to data from the CDC, 95% of confirmed cases of Lyme disease were reported from 14 states in the northern and northeastern parts of the United States.

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However, Patricia V. Smith, president of the Lyme Disease Association, also noted that many investigators believe that Lyme disease is more widespread than traditionally thought, and Shor emphasized the importance of using clinical judgment when obtaining a patient history. He cited risk factors for exposure, including travel or location within a high-risk environment, but also stated that patients can still contract the disease in low-risk areas of the country, particularly in grassy areas and low brush, which are habitats for ticks and the mice that transfer them.

When assessing the patient’s clinical presentation, Drs. Bransfield and Shor emphasized the importance of recognizing characteristic symptom patterns. According to Dr. Shor, arthralgia and arthritis often migrate from one joint to another with or without inflammation, and the autonomic nervous system is often affected, with symptoms such as postural orthostatic tachycardia syndrome and fractioned and nonrestorative sleep. “I ask over 300 questions whenever I see a patient with Lyme disease,” said Dr. Bransfield. “You see a certain pattern that evolves; it’s a multisystemic illness that can evolve over time.”

However, Dr. Sigal pointed out that the broad spectrum of clinical presentations can drastically influence the clinician’s index of suspicion. Although the characteristic erythema migrans, facial palsy, lymphocytic meningitis, rapidly progressive heart block from Lyme carditis, and arthritis with large effusions would raise the clinician’s index of suspicion (particularly in endemic areas), patients who have less well-defined symptoms with causes that are difficult to identify require a more careful assessment, stated Dr. Sigal. “The index of suspicion has to be high enough for you to actually say, ‘Well, I don’t know that this is Lyme disease, but if it is, I want to make sure that this person is treated.’ The question is, ‘What’s the reasonably high level of likelihood?’”

For patients in whom he has a moderate level of suspicion, Dr. Shor administers a therapeutic trial of minocycline, because of its high central nervous system penetration, for 1 month and assesses whether symptoms improve to determine if the symptoms were caused by Lyme disease. However, he warned that patients with Lyme disease may exhibit a Jarisch-Herxheimer response, an inflammatory response related to the introduction of or change in antibiotics in spirochetal infections, which may make their symptoms appear worse at first.

Improving Sensitivity of Laboratory-Based Diagnostic Testing

The low sensitivity of the current 2-tiered testing and the broad spectrum of clinical presentations make diagnosis of Lyme disease a complex clinical process, according to Dr. Bransfield. He and the panelists discussed novel technologies that could improve laboratory-based testing and diagnosis, particularly in the early stages of the disease.

Dr. Shor discussed a recent study

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that he and his colleagues published in which they used a novel analyte harvesting nanotechnology (Nanotrap particles) to super-concentrate urinary Borrelia outer surface protein A (OspA), a highly specific protein across multiple strains, and probed the urine samples with a highly specific anti-OspA monoclonal antibody. Prior to treatment, all 24 patients who received a new erythema migrans rash diagnosis tested positive for urinary OspA and 8 of 8 patients went from detectable to undetectable levels after symptom resolution post treatment.

Dr. Shor also noted that this test could be particularly useful for patients in the early stages of the disease, who often test negative on ELISA tests because they have not had an immunologic response. Dr. Sigal also added that Nanotrap particle—based testing may introduce a sensitive and specific option that is more convenient than polymerase chain reaction testing, which may be useful for diagnosing an active infection in patients but is difficult to perform regularly.

However, Smith noted that the biggest obstacle for this and other novel technologies may be persuading the CDC to adopt new testing methods. “The CDC is very reluctant to move on to new technology,” she said. “They want to stick with a 2-tier, antiquated test that, again, is probably missing at least 50% of our patients.”

The video clips of the Peer Exchange are available here: http://www.contagionlive.com/peer-exchange .

References

1. CDC. Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep. 1995;44(31):590-591.
2. Marques AR. Laboratory diagnosis of Lyme disease - advances and challenges. Infect Dis Clin North Am. 2015;29(2):295-307. doi: 10.1016/j.idc.2015.02.005.
3. Liveris D, Schwartz I, Bittker S, et al. Improving the yield of blood cultures from patients with early Lyme disease. J Clin Microbiol. 2011;49(6):2166-2168. doi: 10.1128/JCM.00350-11.
4. Nadelman RB, Nowakowski J, Forseter G, et al. Failure to isolate Borrelia burgdorferi after antimicrobial therapy in culture-documented Lyme borreliosis associated with erythema migrans: report of a prospective study. Am J Med. 1993;94(6):583-588.
5. Lyme disease data and statistics. CDC website. https://www.cdc.gov/lyme/stats/. Updated December 19, 2016. Accessed September 13, 2017.
6. Magni R, Espina BH, Shah K, et al. Application of Nanotrap technology for high sensitivity measurement of urinary outer surface protein A carboxyl-terminus domain in early stage Lyme borreliosis. J Transl Med. 2015;13:346. doi: 10.1186/s12967-015-0701-z.