Revisiting the Lyme Disease Serodiagnostic Algorithm: the Momentum Gathers

Abstract

Lyme disease is a tick-borne illness caused by () , and it is the most common vector-borne disease in the United States, with an estimated incidence of 300,000 cases per year. The currently recommended approach for laboratory support of the diagnosis of Lyme disease is a standard two-tiered (STT) algorithm comprised of an enzyme-linked immunoassay (EIA) or immunofluorescence assay (IFA), followed by Western blotting (WB). The STT algorithm has low sensitivity in early infection, and there are drawbacks associated with the WB use in practice. Modified two-tiered (MTT) algorithms have been shown to improve the sensitivity of the testing in early disease while maintaining high specificity. In this issue of the, A. Pegalajar-Jurado et al. (J Clin Microbiol 56:e01943-17, 2018, https://doi.org/10.1128/JCM.01943-17) report the results of their evaluation of the Liaison VlsE CLIA, the Captia IgG/IgM EIA, and the C6 (Lyme) EIA as MTT algorithms compared with results with the STT algorithm using the same tests as the first-tier test and the ViraStripe IgM and IgG WBs as the second-tier test. The results showed that all MTT algorithms had higher sensitivities than STT algorithms and were highly specific. These results showed that MTT approaches are a valid alternative to the currently recommended STT algorithm for serodiagnosis of Lyme disease, opening the door for the development of rapid diagnostics and point-of-care testing that can provide diagnostic information during the initial patient visit.

Point-of-care serodiagnostic test for early-stage Lyme disease using a multiplexed paper-based immunoassay and machine learning

“…not certified by peer review) (which was The copyright holder for this preprint this version posted October 22, 2019. . https://doi.org/10.1101/19009423 doi: medRxiv preprint of our xVFA also outperforms a number of previous clinical studies investigating diagnostic performance of standard two-tier as well as modified two-tier testing with respect to the ultimate clinical diagnosis 9,17,38 .…”

“…If the first-tier is positive or equivocal, a Western Blot (WB) is then recommended for confirming the presence of 2 of 3 Immunoglobulin M (IgM) antibodies and/or 5 of 10 Immunoglobulin G (IgG) antibodies targeting Bb associated antigens 12 . A number of reports have also showed the efficacy of a modified two-tier test (MTTT) format, where the WB is replaced by a second complimentary EIA, and as a result, the FDA has recently approved the use of some EIAs as viable tests for the second tier [13][14][15][16][17] .…”

“…Therefore, to overcome this limitation, large-scale screening efforts alongside new epitope mapping and peptide synthesis are focused on developing a universal multi-antigen detection panel, with e.g. 5 to 10 LD-specific antigen targets being suggested for improving diagnostic performance for early LD 17,32,33 . Consequently, we have a unique opportunity to leverage advances in computation and machine learning, to train novel serodiagnostic algorithms with these rich, multi-antigen measurements derived from wellcharacterized clinical samples, to ultimately create new decision algorithms that outperform the traditional two-tier test [32][33][34] .…”

Lyme Disease Biosensors: A Potential Solution to a Diagnostic Dilemma

“…The reported 46.3% sensitivity is considerably low, with a potentially large number of false-negative results within the first month of infection [ 15 ]. Likewise, the MTT approach demonstrates only slightly improved sensitivity, at approximately 50%, for patients with early Lyme disease [ 18 ]. Some of the biosensors presented here ( Table 1 ) report sensitivities for early Lyme that exceed the STT/MTT approaches and have the potential to develop into a much-needed alternative [ 32 , 33 , 42 ].…”

“…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 ].…”