Vector-borne illness of stealth: The current state of Lyme disease diagnostics, treatment and research
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Lyme disease was first described in the United States in 1975, after two concerned mothers in Old Lyme, Connecticut, reached out to rheumatologists at Yale University regarding an influx of pediatric arthritis in their community. A surveillance study in 1976 led to the realization of a connection between the deer tick population, east of the Connecticut River, and the development of the telltale erythema migrans rash. In 1978, the vector tick carrier was confirmed, and thus, the mystery of the development of Lyme disease was uncovered. However, Lyme disease continues to pose a conundrum to providers, patients and researchers. As the most widely reported vector-borne illness in the U.S., Lyme disease presents an opportunity for education and improvement in prompt diagnosis and treatment.
Lyme disease is well-known to concentrate in the Northeast and upper Midwest, with only 14 states capturing 96% of all cases.
Microbiology and clinical presentation
Lyme disease is caused by Borrelia burgdorferi, a gram-negative bacteria containing flagella. It is a spirochete, with the genus Borrelia falling under the family Spirochaetaceae. The implicated vector of this pathogen is Ixodes scapularis, otherwise known as the deer tick, or blacklegged tick. The tick can be infected at any point in its life cycle, but the nymph is the usual culprit of human infection because it is small (< 2 mm) and easily hidden in inconspicuous areas of the body, such as the armpit, groin or scalp. Nymphs usually feed in the spring and summer months, and thus, the incidence of Lyme disease is highest during this time frame. Interestingly, the tick must be attached for at least 36 to 48 hours before the infection can be transmitted. Adult ticks are usually found and removed before then.
Lyme disease has not been shown to be transmitted through human-to-human or animal-to-human contact at this time.
Early symptoms
Early symptoms usually occur within the first few days — but can occur up to 30 days — after the tick bite. Many of the initial symptoms are nonspecific, such as fever, muscle pain, headache, fatigue or swollen lymph nodes. Although these symptoms may occur without a rash, an erythema migrans rash does occur in almost 80% of cases, with an average onset of 7 days. The rash usually begins at the site of the bite but can appear on any area of the body. It typically appears as a “bulls-eye,” usually with no accompanied itching.
Late symptoms
Sometimes months after being bitten, more severe symptoms may present in the absence of treatment. Severe headache or neck stiffness, heart palpitations, arthritic pain, facial palsy, or nerve pain with or without spinal cord swelling are possible.
Diagnostics
Lab diagnosis is the primary method for diagnosing Lyme disease in a patient. Previously, in 1994, the Second National Conference on Serologic Diagnosis of Lyme Disease convened with several public health agencies, including the CDC, FDA and NIH. Results of this conference spearheaded the widely accepted methods for diagnosis, using a two-test method. The first step includes a sensitive enzyme immunoassay (EIA), followed by a Western immunoblot assay. The second test is necessary only if the EIA yielded positive (or indeterminate) results; otherwise, the test is considered negative.
In July of this year, the FDA approved several new EIA tests for the diagnosis of Lyme disease. The probable benefit of this new testing approach is that two EIAs can be run concomitantly or sequentially, instead of the previous two-tiered approach. This new “modified two-test methodology” could decrease the time to diagnosis and improve clinicians’ confidence in the diagnosis.
Treatment
The following dosing is recommended for patients with normal renal function. Renal dose adjustments may be necessary in some circumstances.
First-line treatment
Per the 2006 Infectious Diseases Society of America guidelines, first-line treatment of early Lyme disease in adults without neurologic manifestation is doxycycline 100 mg twice daily, amoxicillin 500 mg three times daily or cefuroxime axetil 500 mg twice daily for a total of 14 days. For pregnant patients or children aged younger than 8 years, doxycycline should be avoided, and the treatments of choice would be either amoxicillin (50 mg/kg/day) or cefuroxime axetil (30 mg/kg/day).
Alternative treatment
Macrolides have been shown to be less effective than other recommended antimicrobial treatments; however, they may be considered in children or adults who otherwise cannot tolerate first-line treatment. If needed, azithromycin 500 mg for 7 to 10 days, clarithromycin 500 mg twice daily for 14 to 21 days or erythromycin 500 mg four times daily for 14 to 21 days can be considered. In patients in whom macrolides are used, close monitoring is recommended for prudent follow-up to ensure resolution of clinical manifestations.
Treatment of early Lyme with neurologic involvement
IV ceftriaxone 2 g daily should be used for 14 days, but cefotaxime 2 g every 8 hours would be a reasonable alternative, if available. Clinicians may also consider 18 to 24 million units of penicillin G per day for early Lyme disease with meningitis or neurologic manifestations.
Late Lyme, or ‘Lyme arthritis,’ treatment
Usually, Lyme arthritis can be successfully treated with the same doses of oral agents that are used for early Lyme disease but with an extended duration of 28 days. Typically, a lumbar puncture in these patients should be performed to determine neurologic involvement. With Lyme arthritis and objective evidence of neurologic manifestation, IV ceftriaxone therapy should be administered for 2 to 4 weeks. For patients with recurrent episodes, extended antibiotic therapy is recommended. If the arthritic manifestations have improved but not resolved, oral therapy is reasonable, whereas no improvement would warrant further IV therapy. Some patients may require symptomatic therapy with anti-inflammatory agents, corticosteroids or antirheumatic medications. In patients with limited movement or persistent illness, synovectomy may be considered.
Post-treatment Lyme disease syndrome (PTLDS)
After treatment with the recommended antibiotics for Lyme disease, some patients may experience prolonged fatigue, trouble thinking or pain for up to 6 months. It is believed by some experts that PTLDS is triggered as an autoimmune response to the original bacterial infection. There is currently no proven cause of PTLDS. Unfortunately, there are also no current effective treatments for PTLDS. A retrospective cohort analysis from 2018 analyzed long-term antibiotics in those patients with extensive symptoms 6 months after early Lyme treatment. There was an increased incidence of adverse events (such as electrolyte disturbances) and all-cause morbidity (including increased ED visits) for patients who received treatment compared with those who did not. The article did not address any changes or potential improvements in actual PTLDS symptoms for these patients.
Source: CDC.
Lyme disease prevention
There is currently no licensed vaccine to protect against Lyme disease in humans. Valneva, a French biotech company, recently initiated a phase 2 study of its Lyme disease vaccine candidate, VLA15. Data from that trial are expected in the middle of next year. The CDC currently recommends that people use Environmental Protection Agency-registered insect repellents like DEET and wear permethrin-treated clothing and gear to prevent tick bites where disease-carrying ticks are found.
Current research: What is the future of Lyme disease treatment?
As a result of the increasing incidence and unanswered questions surrounding Lyme disease, there is significant room for improvement in research and understanding of potential treatments. The National Institute of Allergy and Infectious Diseases has several current studies ongoing to evaluate clinical, microbiological and immunological characteristics of PTLDS. The results of this research should add to the current understanding of Lyme disease and its long-term manifestations. Further research will certainly enhance our understanding and appropriate treatment of these patients.
- References:
- CDC. Lyme disease. Diagnosis and testing. https://www.cdc.gov/lyme/diagnosistesting/index.html. Accessed October 27, 2019.
- CDC. Lyme disease. Post-treatment Lyme disease syndrome. https://www.cdc.gov/lyme/postlds/index.html. Accessed October 27, 2019.
- CDC. Preventing tick bites on people. https://www.cdc.gov/lyme/prev/on_people.html. Accessed November 21, 2019.
- Elbaum-Garfinkle S. Yale J Biol Med. 2011;84:103-108.
- FDA. FDA clears new indications for existing Lyme disease tests that may help streamline diagnoses. https://www.fda.gov/news-events/press-announcements/fda-clears-new-indications-existing-lyme-disease-tests-may-help-streamline-diagnoses. Accessed October 27, 2019.
- Goodlet KJ, Fairman KA. Clin Infect Dis. 2018;doi:10.1093/cid/ciy329.
- Mead P, et al. MMWR Morb Mortal Wkly Rep. 2019;doi:10.15585/mmwr.mm6832a4.
- Wormser GP, et al. Clin Infect Dis. 2006;doi:10.1086/508667.
- Valneva. Valneva initiates second phase 2 study for its Lyme disease vaccine candidate VLA15. https://valneva.com/press-release/valneva-initiates-second-phase-2-study-for-its-lyme-disease-vaccine-candidate-vla15. Accessed November 21, 2019.
- For more information:
- Bailey N. Kernan, PharmD, is a PGY-1 pharmacy resident at Denver Health Medical Center. Kernan can be reached at bailey.kernan@dhha.org.
- Kati Shihadeh, PharmD, BCIDP, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.
Disclosures: Kernan and Shihadeh report no relevant financial disclosures.