Serologic Response to Borrelia Antigens Varies with Clinical Phenotype in Children and Young Adults with Lyme Disease

Lyme disease is commonly diagnosed by serologic response to Borrelia burgdorferi and related species, but the relationship between serologic targets and clinical features is unknown. We developed a multiantigen Luminex-based panel and evaluated IgG responses in 527 children 1 to 21 years of age assessed for Lyme disease across 4 Pedi Lyme Net emergency departments, including 127 Lyme cases defined by either an erythema migrans (EM) lesion or positive C6 enzyme immunoassay followed by immunoblotting and 400 patients considered clinical mimics. Of 42 antigens tested, 26 elicited specific reactivity in Lyme patients without marked age-dependent variation. Children with single EM lesions typically lacked Borrelia-specific IgG. By principal-component analysis, children with early disseminated and late Lyme disease clustered separately from clinical mimics and also from each other. Neurological disease and arthritis exhibited distinct serologic responses, with OspC variants overrepresented in neurological disease and p100, BmpA, p58, and p45 overrepresented in arthritis. Machine learning identified a 3-antigen panel (VlsE_Bb, p41_Bb, and OspC_Bafz) that distinguished Lyme disease from clinical mimics with a sensitivity of 86.6% (95% confidence interval [CI], 80.3 to 92.1) and a specificity of 95.5% (95% CI, 93.4 to 97.4). Sensitivity was much lower in early Lyme disease (38.5%; 95% CI, 15.4 to 69.2). Interestingly, 17 children classified as Lyme mimics had a positive 3-antigen panel, suggesting that more comprehensive serologic analysis could help refine Lyme diagnosis. In conclusion, multiplex antigen panels provide a novel approach to understanding the immune response in Lyme disease, potentially helping to facilitate accurate diagnosis and to understand differences between clinical stages.