Hypothesis / aims of study
Recent studies in mice suggest targeting COX-2 for treatment of recurrent urinary tract infections (RUTI) [1,2]. However, the role of COX-2 in human RUTI remains undefined. Our goal was to measure levels of PGE2, a product of the COX-2 enzymatic pathway, in patients with and without RUTI to determine if PGE2 has the potential to serve as urine biomarker for RUTI.
Study design, materials and methods
Following IRB approval and patient consent, urine was collected from post-menopausal women seen at a tertiary care urology clinic and cultured on CHROMagar. Patients had varying urine analysis (UA), history of urinary tract infections (UTI), and treatment regimens. Urinary PGE2 levels were measured in triplicate for each sample by an accurate and commercially available PGE2 ELISA (Enzo) that was normalized to urinary creatinine (Cr) by a quantitative creatinine assay (Sigma). PGE2/Cr levels were compared between groups of patients classified by several different criteria: clinical history of UTIs, clinical positive vs. negative UA, bacteriuria count (>10^4 CFU/ml), and urinary pH.
Interpretation of results
Recurrent UTIs may be explained by an interactive cycle of infection and inflammation. Host inflammation in response to initial bacterial pathogens include severe cystitis, exfoliation of urothelium, and COX-2 overexpression. This sets the stage for formation of quiescent intracellular bacterial communities, which is thought to cause recurrent infection . Additionally, studies in mice have found urothelial remodeling after infection, in which the urothelial cells are smaller, have weakened junctions, and lack terminal differentiation [1,2]. This sensitized urothelium may make certain RUTI patients’ bladders more susceptible to infection and thus perpetuate the cycle of infection and inflammation.
The rationale for inhibiting COX-2 is to target the host inflammatory stage of the cycle. Decreasing inflammation may decrease the likelihood of urothelial sensitization and recurrent infections. This was the idea in Hannan et al’s study in which mice were given an oral COX-2 specific inhibitor . These mice had reduced severity of pyuria, reduced incidence of chronic cystitis, and decreased bacterial titers when compared to control or COX-1 specific inhibitor . Gross bladder inflammation was reduced, shown by less edema and urothelial erosion .
The translational work to human RUTI is scarce. There have been randomized controlled trials of NSAID use in premenopausal women with uncomplicated UTIs showing resolution of infection with NSAIDs alone compared to antibiotics. In our cohort of post-menopausal RUTI women, we would potentially explore adjunct COX-2 inhibitor therapy in addition to antibiotic therapy. This may slow the progression of recurrence and decreases severity of each infection.
Because of potential side effects of COX-2 specific inhibitors, much work is to be done to correlate COX-2, PGE2, and a patient’s degree of bladder urothelial sensitization before implementing COX-2 inhibitor therapy. Urinary PGE2 levels could help as a guide or biomarker for women who are sensitized and thus potentially would benefit from COX-2 inhibition.