Tick-Borne Co-Infection in Lyme Disease: Clinical Impact, Diagnostic Challenges, and Therapeutic Perspectives

Tick-borne co-infections are an increasingly recognized and clinically important aspect of Lyme borreliosis, particularly in regions where <i>Ixodes</i> ticks transmit a wide range of bacterial, protozoan, and viral pathogens. In addition to <i>Borrelia burgdorferi sensu lato</i>, these ticks frequently harbor microorganisms such as <i>Babesia</i> spp., <i>Anaplasma phagocytophilum</i>, <i>Ehrlichia</i> spp., <i>Borrelia miyamotoi</i>, <i>Bartonella</i> spp., and several tick-borne viruses. Co-infections may increase disease severity, prolong symptom duration, and contribute to atypical or overlapping clinical presentations, thereby complicating diagnosis and management. Growing evidence from epidemiological studies, clinical case series, and experimental in vivo and in vitro models indicates that pathogen-pathogen and pathogen-host interactions can modulate immune responses and influence disease progression. Diagnostic challenges arise from non-specific clinical features and limitations of current laboratory methods. From a therapeutic perspective, although standard antibiotic regimens for Lyme disease are effective against some bacterial co-infections, they do not provide coverage for protozoan or viral agents, necessitating pathogen-specific and, in some cases, combination treatment strategies. This review synthesizes current knowledge on the epidemiology, clinical impact, diagnostic limitations, and treatment approaches for tick-borne co-infections associated with Lyme disease, and highlights critical evidence gaps and future research directions to improve patient outcomes.