Unconventional diagnostic tests for Lyme borreliosis: a systematic review

Abstract

Background: Lyme borreliosis (LB) diagnosis currently relies mainly on serological tests and sometimes PCR or culture. However, other biological assays are being developed to try to improve Borrelia-infection diagnosis and/or monitoring. Objectives: To analyse available data on these unconventional LB diagnostic assays through a systematic literature review. Methods: We searched PubMed and Cochrane Library databases according to the PRISMA-DTA method and the Cochrane Handbook for Systematic Reviews of Interventions. We analysed controlled and uncontrolled studies (published 1983e2018) on biological tests for adults to diagnose LB according to the European Study Group for Lyme Borreliosis or the Infectious Diseases Society of America definitions, or identify strongly suspected LB. Two independent readers evaluated study eligibility and extracted data from relevant study reports; a third reader analysed full texts of papers to resolve disagreements. The quality of each included study was assessed with the QUADAS-2 evaluation scale. Results: Forty studies were included: two meta-analyses, 25 prospective controlled studies, five prospective uncontrolled studies, six retrospective controlled studies and two case reports. These biological tests assessed can be classified as: (i) proven to be effective at diagnosing LB and already in use (CXCL-13 for neuroborreliosis), but not enough to be standardized; (ii) not yet used routinely, requiring further clinical evaluation (CCL-19, OspA and interferon-a); (iii) uncertain LB diagnostic efficacy because of controversial results and/or poor methodological quality of studies evaluating them (lymphocyte transformation test, interferon-g, ELISPOT); (iv) unacceptably low sensitivity and/or specificity (CD57 þ natural killer cells and rapid diagnostic tests); and (v) possible only for research purposes (microscopy and xenodiagnoses). Discussion: QUADAS-2 quality assessment demonstrated high risk of bias in 25/40 studies and uncertainty regarding applicability for 32/40, showing that in addition to PCR and serology, several other LB diagnostic assays have been developed but their sensitivities and specificities are heterogeneous and/or under-evaluated or unassessed. More studies are warranted to evaluate their performance parameters.

Neuropsychiatric and Psychological Symptoms in Patients with Lyme Disease: A Study of 252 Patients

“…The test value remains positive as long as T memory lymphocytes are still activated by the borrelia in the body of the affected person, which means that the LTT also proves valuable in later stages of the disease [3]. Although the LTT is currently not recommended by any guideline due to its low specificity [17], we nevertheless asked about it, as it is frequently used in German clinical practice.…”

Immunoserological Diagnosis of Human Borrelioses: Current Knowledge and Perspectives

“…In addition to serological tests, other techniques have been suggested to improve the diagnosis of Lyme disease. A recent systematic review included 40 studies of unconventional tests (Raffetin et al, 2019). The QUADAS-2 quality assessment was used for each study, revealing a high risk of bias in 25/40 studies and uncertainty regarding applicability in 32/40.…”

“…Some tests could not be included in this analysis since the princeps study did not specify their performances, including CCL-19 (Aucott et al, 2016), Apolipoprotein B-100 (Crowley et al, 2015;Strle et al, 2017), IFN-alpha (Jacek et al, 2013), CD57+ NK-cells (Marques et al, 2009), OspA membrane protein (Cheung et al, 2015;Magni et al, 2015) and xenodiagnosis (Marques et al, 2014). Figure 1 presents the range of the sensitivities and specificities (such as mentioned in each of the studies included in this review of the literature) of unconventional diagnostic tests (CXCL-13, lymphocyte transformation test, IFN-gamma, Electron Microscopy, LM-method for microscopy, and rapid diagnostic tests) (Raffetin et al, 2019). As illustrated in Figure 1, CSF concentration of C-X-C motif chemokine Ligand-13 (CXCL-13), which is a molecule produced by antigen-presenting cells to attract B lymphocytes, is the only test that can bring significant improvement.…”

“…As illustrated in Figure 1, CSF concentration of C-X-C motif chemokine Ligand-13 (CXCL-13), which is a molecule produced by antigen-presenting cells to attract B lymphocytes, is the only test that can bring significant improvement. Unconventional LB-diagnostic tests could be classified as follows in this systematic review: accurate diagnostic tests, which need a better standardization and a better cut-off definition, such as CXCL-13 in cerebrospinal fluid; promising tests still under clinical evaluation and not used routinely, such as OspA membrane protein detection, CCL-19, and IFN-alpha; uncertain tests, because of a lack of proof of their performance in the studies (controversial results, poor methodological quality), including lymphocyte transformation tests and IFN-gamma ELISPOT; non-validated tests with too low sensitivity and/or specificity, such as CD57+ NK-cells and rapid diagnosis tests; tests for research purposes as they could be accurate but could not be practically developed in routine practice, including xenodiagnosis and microscopy (Raffetin et al, 2019). In this study, no test performed acceptably for late disseminated Lyme disease.…”

64Cu-DOTATATE Positron Emission Tomography (PET) of Borrelia Burgdorferi Infection: In Vivo Imaging of Macrophages in Experimental Model of Lyme Arthritis

“…by culture or molecular methods have a variable and suboptimal sensitivity. Likewise, Borrelia DNA can persist for months in the skin or in synovial fluid even after successful treatment, which renders the difficulty for direct detection of Borrelia DNA to unequivocally verify an active infection [ 5 , 6 , 7 ]. Therefore, new methods to monitor disease activity in patients with LB would be of paramount interest to practice precision medicine in these patients and to promote a shift from empirical treatment to personalized medicine with expected improvement in patient outcome.…”