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Urinary Symptoms and Their Associations With Urinary Tract Infections in Urogynecologic Patients

Dune, Tanaka, J., MD; Price, Travis, K., MS; Hilt, Evann, E., MS; Thomas-White, Krystal, J., MS; Kliethermes, Stephanie, PhD; Brincat, Cynthia, MD, PhD; Brubaker, Linda, MD, MS; Schreckenberger, Paul, PhD; Wolfe, Alan, J., PhD; Mueller, Elizabeth, R., MD

doi: 10.1097/AOG.0000000000002239
Contents: Infectious Disease: Original Research
ABOG MOC II

OBJECTIVE: To assess urinary symptoms associated with urinary tract infection (UTI) in a urogynecologic population of women.

METHODS: In this cohort study, we enrolled 150 urogynecologic patients who completed the validated UTI Symptom Assessment questionnaire and contributed transurethral catheterized urine samples. The primary measure (UTI diagnosis) was defined in three ways. Self-report (a nonculture-based UTI diagnosis) was defined by a yes or no response to the query “Do you think you have a UTI?” Two culture-based UTI diagnoses also were analyzed: standard urine culture (104 colony-forming units [CFU]/mL or greater) and enhanced quantitative urine culture (10 CFU/mL or greater) of any uropathogen. Statistical analyses were performed on patient demographics and urinary symptom prevalence among patient groups.

RESULTS: Although the presence of the urinary symptoms of frequency and urgency (respectively) differ somewhat between UTI-positive and UTI-negative women (self-report [P=.005 and P<.001], standard urine culture [P=.038 and P=.044], or enhanced quantitative urine culture [P=.059 and P=.098]), the presence of dysuria (pain or burning) during urination was significantly more prevalent in UTI-positive women for all UTI definitions (self-report P<.001, standard urine culture P<.001, and enhanced quantitative urine culture P=.010). Furthermore, women reporting dysuria had higher severity and bother scores for all other urinary symptoms assessed by the UTI Symptom Assessment questionnaire compared with women not reporting dysuria (frequency P=.001, urgency P=.006, dysuria P<.001).

CONCLUSION: Our findings show that, in women seeking urogynecologic care, the presence of frequency and urgency of urination does not confirm a culture-based UTI diagnosis. Instead, clinicians can more readily detect UTI using the presence of dysuria, which more effectively discriminates UTI-positive and UTI-negative individuals, regardless of the culture-based method used to diagnose UTI.

In a urogynecologic population, dysuria is associated with culture-based urinary tract infection diagnosis, whereas frequency and urgency have no association with urinary tract infection.

Department of Urology, Center for Female Pelvic Health, Weill Cornell Medicine, New York, New York; the Departments of Microbiology and Immunology and Pathology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; the American Medical Society for Sports Medicine, University of Wisconsin–Madison, Madison, Wisconsin; the Departments of Obstetrics & Gynecology and Urology, Loyola University Medical Center, Maywood, Illinois; and the Departments of Obstetrics & Gynecology and Reproductive Medicine, University of California–San Diego, San Diego, California.

Corresponding author: Tanaka J. Dune, MD, Department of Urology, Center for Female Pelvic Health, Weill Cornell Medicine, 525 E 68th Street, New York, NY 10065; email: tanakadune@gmail.com.

Supported by a grant from the Falk Foundation (LU#202567) and National Institutes of Health grants R21DK097435-01A1 and 1P20DK108268.

Financial Disclosure Dr. Brubaker has received grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Diabetes and Digestive and Kidney Diseases during conduct of a different study. She has received editorial fees from Up-To-Date. Dr. Wolfe has received Investigator Initiated Grants from Astellas Scientific and Medical Affairs (ASMA) and Kimberly Clark Corporation for different studies. Dr. Mueller has received grants and personal fees from ASMA, personal fees from Peri-Coach, and personal fees from Allergan during the conduct of the study but outside the submitted work. The other authors did not report any potential conflicts of interest.

Presented at the International Continence Society's 45th annual meeting, October 6–9, 2015, Montreal, Canada; and at the American Urogynecologic Society's 36th annual meeting, October 13–17, 2015, Seattle, Washington.

The authors thank Mary Tulke, RN, Bozena Zemaitaitis, Arianna Griffin (medical student), and Kathleen McKinley, MT (ASCP), for their assistance with participant recruitment, sample collection, and clinical microbiology contributions. The authors sadly acknowledge the death of their coauthor, Paul Schreckenberger.

Each author has indicated that he or she has met the journal’s requirements for authorship.

Clinicians typically rely on patient-reported symptoms to diagnose urinary tract infection (UTI) in ambulatory adult women. Seven classic UTI symptoms, including frequency and urgency of urination, are included in the only validated UTI symptom survey,1 yet many clinicians accept that frequency and urgency are nonspecific for a culture-based UTI diagnosis and frequency and urgency may add little or nothing to a UTI diagnosis in a urogynecologic population.

Clinicians face a dilemma when assessing UTI in urogynecologic patients with chronic frequency or urgency. In this population, Fitzgerald et al2 found that chronic frequency and incontinence of urine were unlikely to be symptoms reliably associated with UTI. Thus, despite scant evidence, patients and clinicians may rely on changes in baseline symptoms to detect UTI (eg, worsened urgency or frequency, dysuria). In the urogynecologic population, clinicians typically assume a nonbacteriologic etiology for urgency or frequency when standard UTI testing is negative. However, recent advances in understanding the female urinary microbiota3–11 demonstrate that most women have detectable bacteria present using an enhanced quantitative urine culture protocol despite a negative standard urine culture.10,11 This new knowledge complicates our understanding of bladder health and disease, including UTIs.

We determined the proportion of patients with symptoms using three different definitions of UTI (self-report, standard urine culture, and enhanced quantitative urine culture). Our goal was to determine whether urinary symptoms differ among the diagnosis methods as well as to identify symptoms that are the strongest indicators of UTI regardless of diagnosis method.

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MATERIALS AND METHODS

The a priori sample size for this cohort was 150 urogynecologic patients. Participants were enrolled after approval by Loyola University Chicago Health Sciences' institutional review board. Participants were volunteers from consecutively approached adult women seeking clinical urogynecologic care at Loyola University Medical Center's Female Pelvic Medicine and Reconstructive Surgery Unit between June 2014 and August 2015. Exclusion criteria included age younger than 18 years, pregnancy, catheterization (indwelling or intermittent), or insufficient English skills to complete study measures. Participants contributed demographic and questionnaire data as well as a single transurethral catheterized urine sample. Two cohorts, each with 75 women, were formed based on their self-report of UTI presence using the query: “Do you feel you have a UTI?” (yes or no). All participants completed the validated UTI Symptom Assessment questionnaire,1 in which the participant rates the severity and bother for seven common UTI symptoms (frequency and urgency of urination, dysuria [pain or burning], difficulty urinating, lower abdominal or pelvic pain or pressure, low back pain, blood in urine). Scores for each symptom range from 0 (no symptom) to 3 (highest severity or bother). The UTI Symptom Assessment questionnaire further groups the seven symptoms into four domains (Appendix 1, available online at http://links.lww.com/AOG/A987). Participants who reported UTI symptoms (yes cohort) were also asked to qualitatively document any UTI-related symptoms.

Participants were clinically characterized using standard urogynecologic history and physical assessments. Consistent with Loyola's urogynecologic clinical care protocol for all patients, each patient-participant’s urine was collected aseptically through transurethral catheterization and placed into BD Vacutainer Plus C&S preservative tubes. Each specimen was processed by two clinical laboratory methods: the standard urine culture method and the expanded spectrum version of the enhanced quantitative urine culture method.11 Table 1 displays the parameters of these two culture-based methods. The standard urine culture protocol used 1 microliter of urine spread quantitatively (ie, pinwheel streak) onto 5% sheep blood (blood agar plate) and MacConkey agars and incubated aerobically at 35°C for 24 hours. The limit of microbial detection for standard urine culture is 103 colony-forming units (CFU)/mL. The standard urine culture UTI diagnosis definition was 104 CFU/mL or greater of a uropathogen. The expanded spectrum enhanced quantitative urine culture protocol used 1, 10, and 100 microliters of urine spread quantitatively (ie, pinwheel streak) onto 5% sheep blood (blood agar plate), MacConkey, chocolate, Columbia nalidixic acid agar, and Centers for Disease Control and Prevention anaerobic blood agar plate and incubated aerobically, in 5% CO2, anaerobically, or in microaerophilic conditions at 35°C for 48 hours, although some plates were documented for growth earlier, at 24 hours. The limit of microbial detection for the enhanced quantitative urine culture is 10 CFU/mL. The UTI diagnosis definition for enhanced quantitative urine culture was 10 CFU/mL or greater of a uropathogen.

Table 1

Table 1

Continuous variables were reported as means with SDs or medians with ranges; categorical variables were reported as frequencies and percentages. Pearson χ2 tests (or Fisher exact tests, when necessary) and two-sample t tests (or Wilcoxon rank-sum tests, when appropriate) were used to compare demographics and culture results (eg, abundance and diversity) between cohorts. All statistical analyses were conducted using SAS 9.4 or SYSTAT 13.1.

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RESULTS

Table 2 shows the demographics of the 150 participants in this study population (150 participants); their average age was 62.3±14.9 years; most were white (81%) and overweight {mean body mass index [calculated as weight (kg)/[height (m)]2] 29.3±6.3}. Nearly all participants (92% [138/150]) endorsed symptoms on the UTI Symptom Assessment questionnaire. Additional patient and clinical demographics were previously published.11

Table 2

Table 2

Using the standard urine culture protocol, only 38% (57/150) of samples grew bacterial colonies (11 different species from 10 different genera, median number of one microbial species per urine sample). In contrast, using the expanded spectrum enhanced quantitative urine culture, nearly all samples (139/150 [93%]) grew microbial colonies (98 different species from 36 different genera, median number of two microbial species per urine sample). Table 3 is a list of uropathogens that is consistent with the current clinical uropathogen literature. All 11 species detected by standard urine culture and 23 of the species detected by the expanded spectrum enhanced quantitative urine culture are considered to be uropathogens.

Table 3

Table 3

Table 2 also displays the study population dichotomized by self-report. Of the 150 participants, by our a priori study design, 75 were in each self-reported cohort (yes or no); these two groups were similar demographically (Table 2). We did not detect significant differences in the proportions of urine samples with detected bacteria (mo self-reported UTI 89% [67/75] compared with self-reported UTI 96% [72/75]; P=.12) or total unique species per urine sample (75 compared with 66; P=.31). Although the no self-reported UTI cohort had a larger median number of detected species per urine sample when compared with the self-reported UTI group, the difference was not statistically significant (3 [interquartile range 1–5] compared with 2 [interquartile range 1–4]; P=.12).

Table 2 also displays the percentage of patients reporting each UTI symptom. Symptoms were endorsed by all women who self-reported UTI (100% [75/75]) and most women in the no self-reported UTI population (84% [63/75]). However, women who self-reported UTI had higher average scores (severity and bother scores combined) for the seven symptoms of the UTI Symptom Assessment questionnaire. In addition to the UTI Symptom Assessment questionnaire-measured symptoms, 64 of 75 women in the self-reported UTI population qualitatively reported their UTI symptoms and 19% (12/64) indicated the presence of malodorous urine. Although the presence of frequency and urgency of urination differed between the cohorts (P=.038 and P=.044, respectively), dysuria (pain or burning) was significantly more prevalent in the self-reported UTI population (P<.001).

Table 4 displays the study population dichotomized by culture-based UTI diagnoses. Fifty-seven individuals (38%) met the criterion for UTI using standard urine culture, most (91%) of whom also self-reported UTI. Except for age, the standard urine culture-defined UTI-positive population did not differ demographically from the UTI-negative population.

Table 4-a

Table 4-a

Table 4-b

Table 4-b

Nearly all (98%) of the standard urine culture population defined UTI-positive, and a majority (88% [82/93]) of the UTI-negative population endorsed symptoms on the UTI Symptom Assessment questionnaire. Similar to results by self-reported UTI (Table 2), the presence of frequency (P=.038) and urgency (P=.044) of urination differed between the standard urine culture-defined cohort’s UTI-positive population, but dysuria was even more prevalent (P<.001) in the UTI-positive cohort and did a better job of distinguishing the UTI-positive and -negative cohorts. Twenty percent (9/44) of women who were both standard urine culture-defined UTI-positive and self-reported UTI reported malodorous urine.

One hundred ten (73%) women met the criterion for UTI as defined by the enhanced quantitative urine culture; most also self-reported UTI (63% [69/110]). The enhanced quantitative urine culture-defined UTI-positive population did not differ demographically from the UTI-negative population. Most of the enhanced quantitative urine culture-defined UTI-positive and UTI-negative women endorsed symptoms on the UTI Symptom Assessment questionnaire (92% [101/110] and 93% [37/40], respectively). The presence of frequency (P=.059) and urgency (P=.098) of urination did not differ between the cohorts, whereas dysuria was significantly more prevalent in the enhanced quantitative urine culture-defined UTI-positive population (P=.01). Nineteen percent (11/57) of women who were both enhanced quantitative urine culture-defined UTI-positive and self-reported UTI reported malodorous urine.

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DISCUSSION

Our findings suggest that, in urogynecologic patients, dysuria is a better clinical clue to UTI than urinary frequency or urgency or both. Although clinicians and validated UTI measures that include urinary urgency and frequency have utilized the standard urine culture as the current standard for UTI diagnosis, this approach has not been evaluated in urogynecologic patients. In our participants, urgency and frequency correlated poorly with culture-based UTI diagnostic tests and did not contribute to a correct UTI diagnosis. Dysuria, however, appeared relevant and more specific; therefore, the use of dysuria as a key UTI symptom warrants further assessment.

Abnormal urinary odor is not included in the currently validated UTI assessment tool, yet participants often reported this symptom as a sign of UTI; this correlates with our clinical experience. We suggest that odor be included in a modified tool, at least for urogynecologic populations. Conversely, hematuria was rarely reported and may have less importance as a UTI-related symptom in this population.

It is critical that we improve current UTI detection methods. In response to patient-reported symptoms, clinicians consider it proper to empirically treat acute uncomplicated UTIs in premenopausal women who experience infrequent episodes of UTI with typical symptoms, for example, urgency and frequency.12–14 In urogynecologic populations, however, the chronic presence of these symptoms complicates the UTI diagnosis. Clinicians often rely on standard urine culture, which requires growth of at least one uropathogen above a certain threshold.15 However, our group has found that this method misses most non–Escherichia coli uropathogens.11 This and other emerging knowledge about urinary microbiota may provide information about the absence of good bacteria as well as the presence (or overabundance) of bad bacteria. In a companion to this study,11 we reported that urine samples from women who did not self-report UTI were likely to be predominated by Lactobacillus, Streptococcus, and Gardnerella species, an observation that is consistent with previous reports.8,9,16 In contrast, the urine of women with UTI were more likely to contain traditional uropathogens at the expense of Gardnerella, Streptococcus, and Lactobacillus species,11 which may be a clue to the composition of healthy microbiota, consistent in part with previous observations.9,16 Given its beneficial role in the genitourinary tract,17–20 Lactobacillus species in the bladder may prevent UTI or facilitate microbial restoration after UTI treatment. Thus, clinicians must balance appropriate, selective UTI testing with the risk of antibiotic overuse. Given the beneficial protective role of certain bacteria in the bladder,6,8 improved UTI testing and treatment algorithms in urogynecologic patients may improve patient care.

The colony count threshold has been debated extensively. In this study, we tested a traditional threshold with the standard method as well as a lower threshold with an enhanced culture protocol. The former was chosen because it is the most widely used threshold and method for UTI diagnosis in this patient population. We chose the latter to detect as many potential pathogens as possible.

Strengths of our study include various definitions of UTI, including simple self-report, two different thresholds for culture methods, and the enhanced quantitative urine culture technique. Our study also benefits from an enhanced means of describing patient symptoms through the validated UTI Symptom Assessment questionnaire. Finally, we reduced vulvovaginal contamination through standardized urethral catheterization collection techniques.

Limitations of this study include a lack of ethnic diversity of the study population. We recommend caution in generalizing our findings beyond this subspecialty population. In addition, we did not complete an a priori power calculation as a result of a lack of effect size estimates in the literature. We hope our findings will inform these aspects of future studies.

Clinicians may wish to include microbial assessment using the streamlined version of the enhanced quantitative urine culture, which we recently recommended for patients with negative standard urine culture results and persistent or refractory urinary symptoms.11 Good antibiotic stewardship in this population may need to incorporate a more personalized approach to antibiotic use that aligns more closely with specific symptoms. Such techniques will help clinicians and patients move away from the simplistic approach of kill the uropathogen and better understand the role of good and bad bacteria that inhabit the female bladder. Also, certain women may benefit from an approach that ensures restoration of a healthy urinary microbiota after UTI treatment. Further research into these compelling areas of women's urinary health may reduce the morbidity and costs associated with poorly controlled bladder symptoms and improve diagnostic precision and treatment.

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REFERENCES

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