Effect of Bladder Injections of Botulinum Neurotoxin A on Biomarkers Associated with Inflammation and Urinary Infections in Patients with Neurogenic Detrusor Overactivity-Associated Incontinence: A Pilot, Prospective, Human Study.

Conflicting data exist regarding the effect of intradetrusor BoNT/A on the incidence of urinary tract infections (UTIs) in patients with neurogenic detrusor overactivity (NDO), contrary to the increase in UTIs noted in patients with idiopathic OAB. Associations between UTIs, chronic inflammation, and bladder overactivity are acknowledged, albeit not fully understood. Chronic bladder inflammation is common in both NDO and OAB patients, and both animal and human studies suggest a beneficial effect of BoNT/A on both urinary and systemic levels of inflammatory markers. To explore whether intradetrusor BoNT/A injections affect the background for the incidence of UTIs in humans, we investigated in parallel the effect of intradetrusor BoNT/A on the incidence of UTIs and on the urine mRNA levels of urinary pathogen-detecting Toll-like receptors TLR2, TLR4, and TLR5 and of factors acting as intermediates of immune response and promoters of inflammatory reactions (IL1β, IL6, TNFα, and PGE). For this purpose, we recruited 22 patients with NDO-associated incontinence who received at least one bladder BoNT/A injection. Urine specimens for the study of UTIs were obtained before the procedure and at routine urodynamic follow-ups at 4-6 weeks, 6 and 12 months post-BoNT/A, and at clinical relapse, while urine specimens for the study of biomarkers were collected at the time of BoNT/A injection and at the abovementioned follow-ups thereafter. Urine specimens from 10 adult healthy volunteers with no OAB symptoms served as the control group in the biomarker study. The genes of interest in the urine were studied by RNA isolation, reverse transcription, and real-time PCR. The urine mRNAs of all biomarkers tested appeared to be upregulated in the patients' samples compared with the controls, albeit only TLR2 and TLR5 mRNA increases were statistically significant. A progressive downregulation of TLR2, TLR5, IL1β, and IL6 urine mRNAs was noted at one and six months post-BoNT/A. TNFα and PGE mRNAs showed a transient increase at one month post-BoNT/A followed by a dramatic drop at the six months' follow-up. A similar trend for progressive decline was also noticed in the prevalence of both positive urine cultures and symptomatic UTIs in the same timepoints and additionally at 12 months post-treatment in patients who still benefited from the BoNT/A treatment. Upon clinical relapse, the mRNA levels of PGE, IL1β, and IL6 increased in parallel with an increase in the prevalence of UTIs, while the levels of TLRs and TNF-α did not follow the same trend. In summary, intradetrusor BoNT/A injections achieved significant decreases in the urine mRNA levels of pathogen-detecting TLRs, immune response, and inflammation mediator cytokines and PGE in our cohort of patients with NDO-associated incontinence. In parallel, decreases were noted in both the incidence of symptomatic UTIs and rates of positive urine cultures. At the time of clinical relapse, the markers of inflammation and immune response, but not TLRs, were upregulated in parallel with the increased incidence of UTIs, suggesting that the studied genes PGE, IL1β, and IL6 could be further explored as potential biomarkers for inflammation/immune response and UTIs in the neurogenic population.