Cytokine and Immunoglobulin Dynamics in Phage Therapy: Insights from Clinical Cases

Abstract

BackgroundBacteriophage therapy is increasingly used for antibiotic-refractory infections, yet its immunologic effects in humans remain poorly defined. We evaluated cytokine and immunoglobulin responses in nine compassionate-use cases of intravenous phage therapy, including solid organ transplant recipients and patients with device-associated or refractory bacterial infections. MethodsSerial serum samples were analyzed by multiplex Luminex immunology and isotyping assays, with results correlated to host immune status, infecting organism, and clinical outcome. ResultsCytokine patterns were heterogeneous and appeared to reflect the infecting pathogen more than phage exposure. Pseudomonas aeruginosa infections elicited broad pro-inflammatory cytokine increases (notably MCP-3 and TNF-{beta}), while Staphylococcus aureus infection was associated with overall cytokine reduction except for IL-6. Most immunocompetent patients exhibited an early IgM response within 1-2 weeks of phage initiation, whereas immunocompromised hosts demonstrated attenuated antibody levels. Neither cytokine nor humoral responses correlated with clinical outcome. In one case, serum neutralization developed against a specific phage but not against a subsequent, distinct phage cocktail targeting the same organism, suggesting variability in phage immunogenicity. ConclusionOverall, intravenous phage therapy frequently induces IgM responses, which are more pronounced in immunocompetent patients, while cytokine dynamics depend more on pathogen and immune status than on phage administration itself. These findings underscore the need for standardized immune profiling in clinical phage trials to delineate beneficial versus detrimental immune responses and to inform the design of phage formulations with optimized immunogenic profiles.