Epidemiology, diagnosis and emerging therapies for Lyme disease of the Northern Hemisphere

Lyme disease is the most widespread tick-borne infection in the Northern Hemisphere and is challenging to diagnose and treat due to its changing clinical presentation, antigenic variation, tissue tropism, and the expanding distribution of vectors. This review includes ecology, pathogenesis, diagnostics, treatment, post-treatment, prevention, and novel translational approaches. A literature review was conducted to include literature published between January 2000 and March 2026 in PubMed/MEDLINE, Scopus, and Web of Science, with landmark studies used where applicable. Original research, clinical trials, systematic reviews, and major public health reports were prioritised. Two-tier serology is the most common diagnostic technique, but it has limited sensitivity in early infection and does not distinguish between active and past infection. Culture and PCR are only useful in a few instances. The use of new technologies such as multiomics biomarkers, metagenomics, T-cell assays, and AI-enhanced diagnostics is promising but has not yet been tested in a prospective multicentre study. Most of the early and disseminated disease can be treated with standard antibiotics, whereas the long-term therapy of PTLD is not justified and can cause more adverse effects. These preventive and curative advancements involve VLA15 vaccination, anti-tick and reservoir-specific approaches, microbiome-engineered vectors, and anti-persister/ biofilm. Lyme disease requires combined prevention, improved diagnostics, enhanced biomarker research, and well-designed PTLD trials. The short-term benefits will be based on the optimisation of existing diagnostics and vector control, and the long-term benefits will be based on rigorous validation of vaccines, biomarkers, and specific therapies.