A prospective observational study of urinary cytokines and inflammatory response in patients with Overactive Bladder Syndrome.

BACKGROUND: Contemporary studies have discredited the methods used to exclude urinary tract infection (UTI) when treating overactive bladder (OAB). Thus we must revisit the OAB phenotype to check that UTI has not been overlooked. AIMS: To examine the differences in urinary cytokines IL6 and lactoferrin in OAB patients compared to controls, with references to microscopy of urine and enhanced quantitative urine culture. METHODS: A blinded, prospective cohort study with normal controls using six repeated measures, achieved two-monthly, over 12 months. RESULTS: The differences between patients and controls in urine IL6 (F = 49.0, p < .001) and lactoferrin (F = 228.5, p < .001) were significant and of a magnitude to have clinical implications. These differences were for lactoferrin correlated to symptoms (9.3, p = .003); for both to pyuria (IL6 F = 66.2, p < .001, Lactoferrin F = 73.9, p < .001); and for IL6 microbial abundance (F = 5.1, p = .024). The pathological markers had been missed by urinary dipsticks and routine MSU culture. CONCLUSION: The OAB phenotype may encompass patients with UTI that is being overlooked because of the failure of standard screening methods.

How can we improve investigation, prevention and treatment for recurrent urinary tract infections - ICI-RS 2018.

BACKGROUND: Recurrent urinary tract infection (rUTI) is a chronic condition and has a significant impact on health-related quality of life. The commonly used definition for rUTI is greater than three episodes in a year or more than two in 6 months. Current diagnostic methods have been used worldwide for over five decades, despite well evidenced criticism. Enhanced culture techniques demonstrate that the microbiome of the bladder is far more complex than previously thought and begs a reappraisal of our current testing. Treatment of rUTI is based on a small number of antibiotic trials with some evidence showing a reduction in the number of positive cultures, but one must be cautious in interpreting the results and weigh against the risk of generation of antimicrobial resistance (AMR). AIM: The International Consultation on Incontinence-Research Society think tank reviewed the literature with a view to improving investigation, prevention and treatment of rUTI. METHODS: A multidisciplinary team of experts were invited to present evidence regarding the current diagnostic methods, recent advances related to bladder biome mapping and current treatment strategies, including antibiotic and nonantibiotic options. Current guidelines regarding antibiotic stewardship and concerns regarding AMR were discussed. DISCUSSION: Outcome of the think tank discussions are summarised with a set of recommendations to inform future research. Particular consideration is given to bacterial survival in the bladder after treatment as well as defects in urothelial barrier function which may play a significant part in the failure to eradicate UTI.

Reassessment of Routine Midstream Culture in Diagnosis of Urinary Tract Infection.

Midstream urine (MSU) culture remains the gold standard diagnostic test for confirming urinary tract infection (UTI). We previously showed that patients with chronic lower urinary tract symptoms (LUTS) below the diagnostic cutoff on MSU culture may still harbor bacterial infection and that their antibiotic treatment was associated with symptom resolution. Here, we evaluated the results of the United Kingdom's MSU culture in symptomatic patients and controls. Next, we compared the bacterial enrichment capabilities of the MSU culture with those of a 50-µl uncentrifuged culture, a 30-ml centrifuged sediment culture, and 16S rRNA gene sequencing. This study was conducted on urine specimens from 33 LUTS patients attending their first clinical appointment (mean age, 48.7 years; standard deviation [SD], 16.5 years), 30 LUTS patients on treatment (mean age, 47.8 years; SD, 16.5 years) whose symptoms had relapsed, and 29 asymptomatic controls (mean age, 40.7 years, SD, 15.7 years). We showed that the routine MSU culture, adopting the UK interpretation criteria tailored to acute UTI, failed to detect a variety of bacterial species, including recognized uropathogens. Moreover, the diagnostic MSU culture was unable to discriminate between patients and controls. In contrast, genomic analysis of urine enriched by centrifugation discriminated between the groups, generating a more accurate understanding of species richness. In conclusion, the United Kingdom's MSU protocol misses a significant proportion of bacteria, which include recognized uropathogens, and may be unsuitable for excluding UTI in patients with LUTS.

Cross-over data supporting long-term antibiotic treatment in patients with painful lower urinary tract symptoms, pyuria and negative urinalysis.

PURPOSE: To measure the effects of an unplanned, sudden cessation of treatment in an unselected group of patients with chronic painful LUTS managed with protracted antimicrobial treatment and to report these observational data collected from a cross-over process. MATERIALS AND METHODS: The imposition of a guideline resulted in the immediate cessation of antibiotic treatment in a cohort of patients with chronic painful LUTS and microscopic pyuria. Patients were assessed before treatment withdrawal, whilst off treatment, and following reinstatement. Outcome measures included a validated symptom score, microscopic enumeration of urinary white cells and uroepithelial cells, and routine urine culture. RESULTS: These patients had reported treatment-resistant, painful LUTS for a mean of 6.5 years before treatment at this centre. Treatment was stopped in 221 patients (female = 210; male = 11; mean age = 56 years; SD = 17.81). Sixty-six per cent of women were post-menopausal. After unplanned treatment cessation, 199 patients (90%; female = 188; male = 9) reported deterioration. Eleven patients required hospital care in association with disease recurrence, including acute urinary tract infection (UTI) and urosepsis. Symptom scores increased after cessation and recovered on reinitiating treatment (F = 33; df = 2; p < 0.001). Urinary leucocyte (F = 3.7; df = 2; p = 0.026) and urothelial cells counts mirrored symptomatic changes (F = 6.0; df = 2; p = 0.003). Routine urine culture results did not reflect changes in disease status. CONCLUSION: These data support the hypothesis that treating painful LUTS associated with pyuria with long-term antimicrobial courses, despite negative urine culture, is effective. The microscopy of fresh unspun, unstained urine to count white cells and epithelial cells offers a valid method of monitoring disease. An unplanned cessation of antibiotic therapy produced a resurgence of symptoms and lower urinary tract inflammation in patients with chronic LUTS, supporting an infective aetiology below the level of routine detection.

Recalcitrant chronic bladder pain and recurrent cystitis but negative urinalysis: What should we do?

PURPOSE: Lower urinary tract symptoms (LUTS) may be associated with chronic urinary tract infection (UTI) undetected by routine diagnostic tests. Antimicrobial therapy might confer benefit for these patients. MATERIALS AND METHODS: Over 10 years, we treated patients with chronic LUTS. Pyuria was adopted as the principal biomarker of infection. Urinary leucocyte counts were recorded from microscopy of fresh midstream urine (MSU) samples. Antibiotics were prescribed and the prescription adjusted to achieve a measurable clinical response and a reduction in pyuria. RESULTS: We treated 624 women [mean age = 53.4 years; standard deviation (SD) = 18] with chronic LUTS and pyuria. Mean duration of symptoms prior to presentation was 6.5 years. Only 16% of MSU cultures submitted were positive (≥105 cfu ml-1). Mean treatment length was 383 days [SD = 347; 95% confidence interval (CI) = 337-428]. Treatment was associated with a reduction in total LUTS (F = 98; p = 0.0001), 24-h frequency (F = 75; p = 0.0001), urinary urgency (F = 90; p = 0.0001), lower urinary tract pain (F = 108; p = 0.0001), voiding symptoms (F = 10; p = 0.002), and pyuria (F = 15.4; p = 0.0001). Full-dose first-generation antibiotics for UTI, such as cefalexin, nitrofurantoin, or trimethoprim, were combined with methenamine hippurate. We recorded 475 adverse events (AEs) during 273,762 treatment days. There was only one serious adverse event (SAE). We observed no increase in the proportion of resistant bacterial isolates. CONCLUSION: This large case series demonstrates that patients with chronic LUTS and pyuria experience symptom regression and a reduction in urinary tract inflammation associated with antimicrobial therapy. Disease regression was achieved with a low frequency of AEs. These results provide preliminary data to inform a future randomized controlled trial (RCT).

Lower urinary tract symptoms that predict microscopic pyuria.

INTRODUCTION AND HYPOTHESIS: Urinary dipsticks and culture analyses of a mid-stream urine specimen (MSU) at 105 cfu ml-1 of a known urinary pathogen are considered the gold standard investigations for diagnosing urinary tract infection (UTI). However, the reliability of these tests has been much criticised and they may mislead. It is now widely accepted that pyuria (≥1 WBC µl-1) detected by microscopy of a fresh unspun, unstained specimen of urine is the best biological indicator of UTI available. We aimed to scrutinise the greater potential of symptoms analysis in detecting pyuria and UTI. METHODS: Lower urinary tract symptom (LUTS) descriptions were collected from patients with chronic lower urinary tract symptoms referred to a tertiary referral unit. The symptoms informed a 39-question inventory, grouped into storage, voiding, stress incontinence and pain symptoms. All questions sought a binary yes or no response. A bespoke software package was developed to collect the data. The study was powered to a sample of at least 1,990 patients, with sufficient power to analyse 39 symptoms in a linear model with an effect size of Cohen's f2 = 0.02, type 1 error probability = 0.05; and power (1-ß); 95% where ß is the probability of type 2 error). The inventory was administered to 2,050 female patients between August 2004 and November 2011. The data were collated and the following properties assessed: internal consistency, test-retest reliability, inter-observer reliability, internal responsiveness, external responsiveness, construct validity analysis and a comparison with the International Consultation on Incontinence Modular Questionnaire for female lower urinary tract symptoms (ICIQ-FLUTS). The dependent variable used as a surrogate marker of UTI was microscopic pyuria. An MSU sample was sent for routine culture. RESULTS: The symptoms proved reliable predictors of microscopic pyuria. In particular, voiding symptoms correlated well with microscopic pyuria (χ2 = 88, df = 1, p < 0.001). The symptom inventory has significant psychometric characteristics as below: test-retest reliability: Cronbach's alpha was 0.981; inter-observer reliability, Cronbach's alpha was 0.995, internal responsiveness F = 221, p < 0.001, external responsiveness F = 359, df = 5, p < 0.001. The correlation coefficients for the domains of the ICIQ-FLUTS were around R = 0.5, p < 0.001. CONCLUSION: This symptoms score performed well on the standard, psychometric validation. The score changed in response to treatment and in a direction appropriate to the changes in microscopic pyuria. It correlated with measures of quality of life. It would seem to make a good candidate for monitoring treatment progress in ordinary clinical practice.