Background: Any interpretation of laboratory diagnostic assays for Lyme borreliosis requires an understanding of the indications and the limitations of the currently available tests. Since the accuracy of serological tests for Lyme borreliosis varies, a critical appraisal of the current available laboratory tests for Lyme borreliosis in the EU was performed. Aim: To make inferences about the role that serological tests may play in the diagnosis of Lyme borreliosis based on their diagnostic accuracy. A secondary aim was to investigate sources of heterogeneity in test accuracy. Methods: The available literature on sensitivity and specificity of serological tests and lymphocyte transformation/stimulation tests used in Europe was systematically reviewed. Inclusion criteria were the evaluation of enzyme immunoassay, immunoblot or lymphocyte transformation/stimulation tests against a reference standard, and the usage of established clinical case definitions. All studies were assessed for quality, using QUADAS-2 (a tool for the systematic review of diagnostic accuracy studies). For meta-analyses, a hierarchical meta-regression method was used that incorporated both sensitivity and specificity, while taking into account the possible correlation between the two. For investigation of sources of heterogeneity, test type (commercial or in-house), immunoglobulin type, antigen type and study quality were added as covariates to the model in order to assess their effect on test accuracy. Results: Seventy-eight of the 8026 unique titles found in the initial search were included in the study. The summary estimates of sensitivity for any Enzyme immunoassay (EIA) or Immunoblot (IB) in case-control studies were as follows: erythema migrans 0.50 (95% CI 0.40–0.61); neuroborreliosis 0.77 (95% CI 0.67–0.85); Lyme arthritis 0.96 (95% CI 0.89–0.98); acrodermatitis chronica atrophicans 0.97 (95% CI 0.94–0.99) and Lyme borreliosis-unspecified 0.73 (95% CI 0.53–0.87). The estimates for specificity were around 95%. A large heterogeneity was found in sensitivity and specificity. The heterogeneity could only be partially explained by the covariates. In the cross-sectional studies, sensitivity was similar compared to the case-control studies, whereas specificity was remarkably lower, at around 80% for both neuroborreliosis and Lyme borreliosis-unspecified. None of the other tests – two-tiered algorithms, specific antibody index, LTT or LST – outperformed either EIA or IB. Conclusions: This review provides a systematic overview of test accuracy of serological tests used for Lyme borreliosis. The overall estimates of sensitivity and specificity should be interpreted with caution, as the results showed much variation and the included studies were at high risk of bias. The data in this review do not provide sufficient evidence to make inferences about the value of the tests for clinical practice. More information is needed on prevalence of Lyme borreliosis among those tested and the clinical consequences of a negative or positive test result. The sensitivity and specificity estimates from this review might be used to provide a first idea of the possible ranges in predictive values when the test is being used in different patient groups. Interpretation of serological tests for the diagnosis of Lyme borreliosis needs to be done with caution and is only supportive of the diagnosis in combination with a clinical presentation compatible with the established case definitions. Future research should primarily focus on more targeted clinical validation of these tests and research into appropriate use of these tests.
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