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    Lyme Disease

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    Submitted by: Connor Flynn

    Definition

    Lyme disease, or Lyme borreliosis, is an increasingly prevalent illness caused by several bacteria in the Borrelia genus. Lyme disease is an increasingly common bacterial illness that exists throughout the world. Current diagnostic methods for Lyme disease are ineffective at detecting the illness during its early stages - when it is easiest to treat; thus, the improvement of Lyme diagnostics is a popular area of research in many scientific fields.

    1. Introduction

    While several species can cause Lyme disease, Borrelia burgdorferi is the predominant pathogenic species in North America; B. garinii and B. afzelii are responsible for most infections in Europe and Asia. The transmission of Borrelia is facilitated by ticks within the Ixodes genus, which serve as the primary vector and reservoir host for the bacterium. Borrelia is transferred to a mammalian host when an infected tick attaches to and feeds on the blood of the host. During blood-feeding, Borrelia, located in the salivary glands of the tick, enter the mammalian host via the tick’s saliva, transmitting the Lyme bacteria and causing the disease. By exploiting the natural feeding relationship of ticks on mammals, Borrelia is easily transmitted to deer, livestock, and humans.

    Since Burgdorfer’s seminal paper realizing Borrelia as the causative agent of Lyme disease[1], the wide range and inconspicuous nature of the disease have become clear. According to the Centers for Disease Control and Prevention (CDC), there are approximately 30,000 reported cases of Lyme disease in the United States each year; however, more recent estimates place this number as high as 300,000, owing to frequent misdiagnosis and under-reporting[2][3][4]. Not only is Lyme disease the most common vector-borne illness in the US, but recent studies suggest that it is on the rise in other locations as well. With climate change leading to the northern expansion of temperate conditions, reservoir and vector hosts of Lyme disease stray further and further from their original habitats. Because of this, B. burgdorferi is expected to expand its territory northward by 250–500 km in the next 30 years[5]. Increases in Lyme disease incidence are already occurring in many parts of Canada and are expected to continue into the next decades[6][7]. As well, Lyme disease continues to rise steadily throughout Europe (e.g., Germany, Sweden, Austria) and is beginning to take hold in Asia, particularly in regions of China[8][9][10].

    The earliest manifestation of Lyme disease is the appearance of a typically bullseye-shaped rash, known as an erythema migrans, at the site of infection. While this rash is generally sufficient for Lyme diagnosis, it only occurs in 70–80% of cases, making it unreliable as a main indicator[11]. Other than the erythema migrans, the most common symptoms are headaches and arthralgia, but these are far too general to indicate Lyme disease[12]. As the disease progresses, Borrelia disseminate from the site of tick attachment and travel throughout the body, causing early disseminated symptoms that can include multiple erythema migrans, carditis, and meningitis[3]. If left untreated for a prolonged period, Lyme disease may progress to a more severe late stage that can include encephalitis and arthritis, among other serious symptoms. While Lyme disease is easily treated with antibiotics if caught early, delayed diagnosis and/or treatment can prove more difficult to treat and lead to more serious health effects[13].

    2. Current Methods of Diagnosis

    In cases where an erythema migrans is not present or proves inconclusive, a global consensus of guidelines recommends the use of a standard two-tiered (STT) serology approach for the diagnosis of Lyme disease[14]. This approach involves an initial enzyme immunoassay (EIA) or immunofluorescence assay (IFA) to measure antibody response to Borrelia antigens — often in the form of a whole-cell Borrelia sonicate[12]. If this EIA/IFA returns a positive or equivocal result, then a follow-up Western blot is used to verify the presence of antibodies for a panel of specific Borrelia proteins. A meta-analysis of thirteen two-tiered serology studies across North America estimated the sensitivity of the approach at 46.3% for those with early-stage Lyme disease (symptoms for less than 30 days), 89.7% for those with early disseminated Lyme disease (30+ days), and 99.4% for those with late-stage Lyme disease[15]. Specificity estimates for the two-tiered methodology were approximately 99% for all disease stages.

    Recently, a modified two-tiered (MTT) approach, in which the western blot of the STT is replaced with a second immunoassay, was approved for use in the United States[16]. Compared to the STT, the MTT demonstrates increased sensitivity for early Lyme disease, similar or slightly higher sensitivity for later stages of the disease, and similar specificity for all stages[17]. A comparison of the STT and MTT approaches on several collections of sera from patients with erythema migrans and early Lyme disease estimated the sensitivity of the MTT test to be approximately 50%, while the sensitivity of the STT test on the same samples was approximately 40%[18].

    While the sensitivity of the current two-tiered serology approaches is very high for disseminated Lyme disease, it remains quite difficult to detect the disease in its early stages. The development of anti-Borrelia antibodies can take upwards of three weeks to reach sufficient detection levels in the blood[19]. Since the current standard relies on these antibodies, it is evident that a more direct method of detection is necessary to diagnose Lyme disease prior to its dissemination. The necessity of improved diagnostics is underscored by the recent and expected increases in Lyme disease, the potential for serious health difficulties, and the current diagnosis difficulties (e.g., misdiagnosis, false positives)[3].

    The entry is from 10.3390/bios10100137

    References

    1. W Burgdorfer; A G Barbour; S F Hayes; J L Benach; E Grunwaldt; J P Davis; Lyme disease-a tick-borne spirochetosis?. Science 1982, 216, 1317-1319, 10.1126/science.7043737.
    2. CDC Lyme Disease: Data and Surveillance. Available online: https://www.cdc.gov/lyme/datasurveillance/index.html (accessed on 28 September 2020).
    3. Shapiro, E.D. Borrelia burgdorferi (Lyme disease). Pediatr. Rev. 2014, 35, 500–509.
    4. Lloyd, V.K.; Hawkins, R.G. Under-detection of Lyme disease in Canada. Healthcare 2018, 6, 125.
    5. Julie A. Simon; Robby R. Marrotte; Nathalie Desrosiers; Jessica Fiset; Jorge Gaitan; Andrew Gonzalez; Jules K. Koffi; Francois‐Joseph Lapointe; Patrick A. Leighton; Lindsay R. Lindsay; et al. Climate change and habitat fragmentation drive the occurrence of B orrelia burgdorferi , the agent of Lyme disease, at the northeastern limit of its distribution. Evolutionary Applications 2014, 7, 750-764, 10.1111/eva.12165.
    6. Nelder, M.P.; Wijayasri, S.; Russell, C.B.; Johnson, K.O.; Marchand-Austin, A.; Cronin, K.; Johnson, S.; Badiani, T.; Patel, S.N.; Sider, D. The continued rise of Lyme disease in Ontario, Canada: 2017. Canada Commun. Dis. Rep. 2018, 44, 231–236.
    7. Ogden, N.H.; Lindsay, L.R.; Morshed, M.; Sockett, P.N.; Artsob, H. The emergence of Lyme disease in Canada. Can. Med. Assoc. J. 2009, 180, 1221–1224.
    8. Lindgren, E.; Jaenson, T.G.T. Lyme Borreliosis in Europe: Influences of Climate and Climate Change, Epidemiology, Ecology and Adaptation Measures; WHO: Copenhagen, Denmark, 2006.
    9. Stone, B.L.; Tourand, Y.; Brissette, C.A. Brave new worlds: The expanding universe of Lyme disease. Vector-Borne Zoonotic Dis. 2017, 17, 619–629.
    10. Fang, L.-Q.; Liu, K.; Li, X.-L.; Liang, S.; Yang, Y.; Yao, H.-W.; Sun, R.-X.; Sun, Y.; Chen, W.-J.; Zuo, S.-Q.; et al. Emerging tick-borne infections in mainland China: An increasing public health threat. Lancet Infect. Dis. 2015, 15, 1467–1479.
    11. Skar, G.L.; Simonsen, K.A. Lyme Disease. In StatPearls [Internet]; StatPearls Publishing: Treasure Island, FL, USA, 2020.
    12. Andrew Moore; Christina Nelson; Claudia Molins; Paul Mead; Martin Schriefer; Current Guidelines, Common Clinical Pitfalls, and Future Directions for Laboratory Diagnosis of Lyme Disease, United States. Emerging Infectious Diseases 2016, 22, 1169–1177, 10.3201/2207.151694.
    13. T.F. Hatchette; I Davis; B L Johnston; Lyme disease: clinical diagnosis and treatment. Canada Communicable Disease Report 2014, 40, 194-208, 10.14745/ccdr.v40i11a01.
    14. C. Eldin; A. Raffetin; K. Bouiller; Y. Hansmann; F. Roblot; D. Raoult; P. Parola; Review of European and American guidelines for the diagnosis of Lyme borreliosis. Médecine et Maladies Infectieuses 2019, 49, 121-132, 10.1016/j.medmal.2018.11.011.
    15. Lisa A. Waddell; Judy Greig; Mariola Mascarenhas; Shannon Harding; Robbin Lindsay; Nicholas Ogden; The Accuracy of Diagnostic Tests for Lyme Disease in Humans, A Systematic Review and Meta-Analysis of North American Research. PLOS ONE 2016, 11, e0168613, 10.1371/journal.pone.0168613.
    16. Paul Mead; Jeannine Petersen; Alison Hinckley; Updated CDC Recommendation for Serologic Diagnosis of Lyme Disease. MMWR. Morbidity and Mortality Weekly Report 2019, 68, 703, 10.15585/mmwr.mm6832a4.
    17. Adoracion Pegalajar-Jurado; Martin E. Schriefer; Ryan J. Welch; Marc R. Couturier; Tiffany MacKenzie; Rebecca J. Clark; Laura V. Ashton; Mark J. DeLorey; Claudia R. Molins; Evaluation of Modified Two-Tiered Testing Algorithms for Lyme Disease Laboratory Diagnosis Using Well-Characterized Serum Samples. Journal of Clinical Microbiology 2018, 56, e01943-17, 10.1128/jcm.01943-17.
    18. Adriana R. Marques; Revisiting the Lyme Disease Serodiagnostic Algorithm: the Momentum Gathers. Journal of Clinical Microbiology 2018, 56, 1–7, 10.1128/jcm.00749-18.
    19. Steven E Schutzer; Barbara A Body; Jeff Boyle; Bernard M Branson; Raymond J Dattwyler; Erol Fikrig; Noel J Gerald; Maria Gomes-Solecki; Martin Kintrup; Michel Ledizet; et al. Direct Diagnostic Tests for Lyme Disease. Clinical Infectious Diseases 2018, 68, 1052-1057, 10.1093/cid/ciy614.
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