Detrusor Overactivity (DO) is a condition characterised by symptoms of urgency, frequency and nocturia with or without urge incontinence. Symptom severity waxes and wanes over time and the cause is unknown. In recent years many authors have hypothesised that infection and inflammation are important contributors to the aetiology of refractory DO (see for example [1]). 

The proposed mechanism is that inflammation promotes cytokine release which sensitises afferent nerve activity in the bladder leading to urgency [2]. In order to analyse any relationship between severity of urgency symptoms and cytokine concentration a symptom score for OAB and for UTI was compiled. We hypothesised that one or both of these symptom scores would correlate with the concentration of relevant urinary cytokines.

An OAB symptom score was designed, which comprised one point each for Frequency, Urgency, Nocturia, Urge Incontinence, and a First Desire to Void <150mL on urodynamics (total score out of 5). The presence of these symptoms was obtained from the most recent clinical assessment.

A UTI score, out of 7, comprised 2 points for current UTI status (2 points for isolation of a single bacterial species >106 CFU/mL single organism; 1 point for polymicrobial infections on MSU), in patients who were positive for UTI then an additional 3 points were allowed for pyuria and red blood cells on MSU (with 2 points for >100 WBC/ high powered field; 1 point for 10-100 WBC; 1 point was for Red blood cells), and two points for a history of proven recurrent UTI (defined as ≥3 infections in 12months). 

Midstream urine samples were collected with careful labial toilet from postmenopausal women (>50 years). Controls were women with prolapse or urodynamic stress incontinence. RDO patients, with normal voiding function, were urodynamically diagnosed. 
Urinary cytokines (n=22) were analysed using [Human Cytokine 27-plex Assay (Bio-Rad)]. Cytokines were grouped into pro-inflammatory, chemokines and regulatory cytokines based. Symptom scores were correlated with cytokine concentrations.

MSU were collected from 140 postmenopausal women. Women were divided into two aged matched groups with 45 controls (age range) and 95 RDO (age range). The OAB symptom score (out of 5) was significantly higher in patients with refractory DO as expected (median 4, IQR 4-5) compared to controls (median 0; IQR 0-0; P<0.0001). The UTI scores (out of 7) were also significantly higher in women with refractory DO (median 1 (IQR 0-3)) than controls (median 0 (IQR 0-0); P<0.001). 

In women with refractory DO, the UTI score did not significantly correlate with the OAB symptom score (P 0.9841). Similarly, in DO patients the OAB symptom score didn’t correlate with concentrations of any of the cytokines measured.

The UTI score did correlate with cytokine concentrations measured in women with refractory DO (Table 1). Five of the 10 pro-inflammatory cytokines measured significantly correlated with the UTI score. Six of the seven chemokines correlated while tow of the 5 regulatory cytokines correlated with the UTI score. 

A co-morbidity scores was designed and analysed but gave no contribution to the results.

The major finding of this analysis is that the concentration of pro-inflammatory cytokines and chemokines significantly correlated with the UTI score in women with refractory DO. Chemokines are small immune mediators that are responsible for inducing chemotaxis or recruitment of immune cells to a site of infection. For example IL-8/ MIP-1 induces chemotaxis of neutrophils causing them to migrate toward the site of infection. IP-10/ MIP-1β both stimulate chemotaxis of macrophages while RANTES and exotxin are chemotactic for numerous immune cells. These findings highlight the importance of immune cell recruitment in the immune response to UTI in women with refractory DO. 

One surprising finding from the current results was that OAB symptom score didn’t correlate with the urinary cytokine levels even though the UTI score did. This finding was unexpected given the number of studies that have reported a role for infection in the aetiology of the refractory state [ref]. Five of the 7 points in the UTI score are derived from the MSU result, which is conducted on the same urine sample as the cytokine analysis. In contrast the OAB symptom score was determined from the most recent clinical history, which was not collected on the same day as the urine sample. We would expect that the OAB symptom score would be more discriminating if it was revised to include factors that can feasibly be collected on the same day as the urine sample. It is well known that DO symptoms wax and wane over time and detailed history relating to urgency symptoms on the day that the urine samples were collected would need to be obtained if we were to correlate OAB symptoms with urinary cytokine levels.

These studies support a role of immune cell recruitment in the response to infection in women with refractory DO. Recruitment of immune cells may be associated with tissue damage and further enhancement of increased cytokine signalling which may lead to enhanced sensitivity of afferent nerves which would promote urgency symptoms. This study also highlights the importance of collecting clinical history and samples together if the concentration of cytokines is to be correlated with clinical symptoms.

Moore K, Malykhina AP (2014) What is the role of covert infection in detrusor overactivity, and other LUTD? Neurourol Urodyn 33: 606¬610.
Yoshimura N, de Groat WC (1999) Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation. J Neurosci. 1999;19(11):4644-4653.