An integrative review of current research on the role of the female urinary microbiota in overactive bladder symptoms.
The medical world has long upheld the notion that the female bladder is sterile. Recent studies provide evidence that this might not be the case. Bacterial DNA has been detected in the urine of women who have lower urinary tract symptoms (LUTS) and those who do not, suggesting an intrinsic microbiome of the female urinary tract (Brubaker & Wolfe, 2015; Hilt et al., 2014; Wolfe et al., 2012). The National Institutes of Health (NIH) Human Microbiome Project (2015) defines microbiome as the collection of microorganisms living in the human body, including eukaryotes, archaea, bacteria, and viruses. These discoveries could lead to new insights into little-understood women's health issues, including recurrent urinary tract infections (UTIs), and LUTS, including overactive bladder (OAB) (Brubaker & Wolfe, 2015). Traditional urine cultures do not detect all bacteria present in the urine, resulting in many negative culture UTIs going undiagnosed and untreated. New findings of bacteria present on traditionally negative urine cultures challenge the current practice of urine culturing and diagnosis, and present a need for new definitions, expanded culturing, and treatment options. This new information presents a paradigm shift in the scientific understanding of the female bladder.Background and Significance
Within the category of LUTS, OAB and incontinence diagnoses are evaluated the most frequently and are reportedly the most problematic. In a worldwide population study, prevalence of LUTS was expected to increase from 45.2% in 2008 to 45.8% by the year 2018 (Irwin, Kopp, Agatep, Milsom, & Abrams, 2011). Worldwide population prevalence of OAB was 10.7% and UI at 8.2% in 2008, and rates were projected to increase to 20.1% and 21.6%, respectively, by 2018 (Irwin et al., 2011). More than half of the female population in the United States report symptoms of urinary incontinence (Markland, Richter, Fwu, Eggers, & Kusek., 2011). OAB is currently defined by the International Continence Society (ICS) as urinary urgency, frequency, and nocturia, with or without urinary incontinence (UI) (Abrams et al., 2009). The National Association for Continence (NAFC) (2015) reports that more than 17% of women over the age of 18 years report signs of OAB. These numbers, although varying throughout the literature, are thought to be dramatically underreported (Irwin et al., 2011; Milsom et al., 2001). Women with OAB report a negative impact on their quality of life, including decreased sleep, work productivity, and physical/sexual activity, as well as increased incidences of depression and anxiety symptoms (Coyne et al., 2011). Researchers report that OAB symptoms range across age, race, and ethnicity, with prevalence increasing with age (Coyne et al., 2011).
Causes of OAB are multi-factorial, and in many cases, unknown. In light of new findings, researchers (Hilt et al., 2014) suggest the possibility that OAB symptoms are influenced by the urinary tract microbiota. This may suggest a need to reconsider symptom management and diagnosis. If symptoms were identified and diagnosed early, and behavior modification implemented at an early age, there may be a delay in progression of symptoms, as well as a decrease in negative health outcomes (Coyne et al., 2011). This integrative review explores current evidence on the microbiota of the female urinary tract as it relates to OAB, and provides direction for researchers and urologic healthcare providers to understand how and what other scientists are doing to measure these emerging concepts.
Search Methods
A comprehensive literature search was conducted using a multistep process to identify articles by first searching the records of six online databases (CINAHL, EMBASE, PubMed, BIOSIS, Web of Science, and Scopus) from 2008 to 2016. In 2008, the NIH launched the Human Microbiome Project; therefore, only literature after this point focuses on the relationship of microbiome on health. The search was carried out with the combination of keywords: "(microbiome OR microbiota) AND (urinary urgency OR overactive bladder) AND (female OR woman)." Second, manual searches of references in identified articles, as well as articles having cited identified articles, were also considered. Only articles published in English were included in this review, and inorganic causes of urgency, including cystitis, infection, and neurological causes, were excluded. A total of 177 articles were identified (see Figure 1). After duplicates were removed, and exclusion criteria were met, six quantitative articles remained. Of the six remaining articles, data were abstracted on study year, sample size, design, instruments, results/ conclusions, and level of evidence (see Table 1). The Johns Hopkins Nursing Evidence-Based Practice Appendix E: Research Evidence Appraisal Tool (Frank, 2014) was used to analytically evaluate the articles for level and quality of the evidence. Each article was assigned a level of evidence (I to III) and quality of evidence (A-C) score. Level I indicates a randomized control trial (RCT), Level II indicates a quasi-experimental study, and Level III indicates a non-experimental study, such as qualitative, descriptive, or case study. Quality ranges from A, indicating high quality, to C, indicating low quality or major flaws (Johns Hopkins Hospital/Johns Hopkins University, 2016).
Results
Sample characteristics, symptoms presentation and measurement, urine collection method, urine culturing method, and culture results were summarized across the studies. Urine collection method, culture method, and bacteria identified are presented in Table 2.
Sample Characteristics
The largest sample sizes were 247 women (Sorrentino et al., 2015) and 182 women (Pearce et al., 2015). Siddiqui and colleagues (2014) presented a case study with one woman. The remaining studies ranged from 65 to 118 women (Hilt et al., 2014; Lee et al., 2010; Pearce et al., 2014). The majority of studies evaluated participants aged 50 to 60 years, except for Hilt et al. (2014), where age was not specified, and Sorrentino et al. (2015), where the mean age was 47.7 years.
Symptom Presentation And Urinary Symptom Measurements
Many studies included in this review evaluated women who presented with OAB symptoms. However, Sorrentino et al. (2015) used a test group of women presenting to a uro-gynecology practice who were not specifically presenting with OAB symptoms alone and a control group of women presenting to a gynecology practice. Pearce et al. (2014, 2015) evaluated women with urge urinary incontinence (UUI), a common symptom of OAB but not necessarily representative of all OAB.
Urinary symptoms were analyzed using several validated tools across the studies. Lee et al. (2010) and Sorrentino et al. (2015) used the International Consultation on Incontinence Questionnaire for Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) (Abrams, Avery, Gardener, Donovan, & Board, 2006; Jackson et al., 1996). Lee et al. (2010) also used the Perception of Bladder Condition questionnaire (PPBC), as cited by Coyne, Matza, Kopp, and Abrams (2006), and a three-day bladder diary to assess symptoms. Hilt et al. (2014) and Pearce et al. (2014) used the Pelvic Floor Distress Inventory (PFDI) (Barber, Kuchibhatla, Pieper, & Bump, 2001) to assess symptoms, and Pearce et al. (2014) used the Overactive Bladder questionnaire (OAB-q) (Coyne et al., 2002). Siddiqui et al. (2014) did not assess symptoms and tools to measure urinary symptoms were not mentioned in Pearce et al. (2015).
The ICIQ-FLUTS is a 12-item scale used to evaluate a broad range of LUTS, including filling, voiding, and incontinence symptoms. The PPBC is a single-item tool to assess perception of bladder condition in patients with OAB. The PFDI measures the effect of pelvic floor disorders on quality of life. OAB-q specifically looks at OAB symptoms and the effect of OAB on quality of life. All of the tools used have been previously validated on similar populations with pelvic floor disorders. The ICIQ-FLUTS (Jackson et al., 1996) has a Cronbach's alpha of 0.78, the PFDI (Barber et al., 2001) has a Cronbach's alpha of 0.82 to 0.89, and the OAB-q (Coyne et al., 2002) has Cronbach's alpha values ranging from 0.86 to 0.94. The Cronbach's alpha demonstrates that all of the tools have high internal consistency and reliability. As a single-item measure, the PPBC had significant correlations between bladder diaries (p < 0.001) and the OAB-q (p < 0.001 (Coyne et al., 2006).
Urine Sample Collection And Analysis
Most commonly, transurethral catheterization (TUC) was used to obtain urinary samples. However, Sorrentino et al. (2015) used midstream clean-catch methods, and Lee et al. (2010) used urethral and vaginal swabs. Siddiqui et al. (2014) did not specify the urine collection method. Standard culture techniques were used in four of the six studies (Hilt et al., 2014; Lee et al., 2010; Siddiqui et al., 2014; Sorrentino et al., 2015). In addition, Hilt et al. (2014) reported the expanded quantitative culture (EQUC) and 16SrRNA sequencing (DNA sequence found in all bacteria and is commonly used in bacterial taxonomy), and Siddiqui et al. (2014) reported the results of a urine dipstick, urinalysis, and 16SrRNA sequencing. Pearce et al. (2014) evaluated the EQUC and 16SrRNA results, and Pearce et al. (2015) described the results of 16SrRNA sequencing and DNA sequencing.
Urine Culture Results
False negatives for routine cultures were noted in Hilt et al. (2014) and Pearce et al. (2014), with about 6% showing positive growth on routine culture, and 60% to 80% growth on EQUC. Similar routine culture findings were found in Sorrentino et al. (2015), with 6% showing significant bacteriuria supporting prior results. Pearce et al. (2015) found 51.1% were 16SrRNA sequence positive similar to EQUC results, suggesting accuracy across these methods. Lee et al. (2010) had high routine culture results of 42%, which may be due to collection methods. Hilt et al. (2014) found a significant correlation between results of EQUC and 16SrRNA sequencing.
Table 2 lists the bacteria and dominant urotypes isolated across the studies. However, differences in frequency and dominance of bacteria might be due to differences in collection and culturing methods, symptoms of sample, and purpose of the study. Two studies (Pearce et al., 2014, 2015) identified one dominant bacteria --a "urotype." Lactobacillus were identified in Hilt et al. (2014) and Pearce et al. (2014, 2015). Pearce et al. (2014) found different strands of Lactobacillus in the UUI group (Gasseri) and control group (Crispatus). Ureaplasma were identified in Lee et al. (2010) and Siddiqui et al. (2014) as linked to OAB symptoms. Hilt et al. (2014) and Pearce et al. (2014) identified Aerococcus in OAB/ UUI groups and not in the control groups. Findings ranged from symptom relief with treatment (Lee et al., 2010) to a suggestive protective role of the microbiome in post-procedure UTIs (Pearce et al., 2015).
Limitations
The level of evidence across these studies was low. The primary study design of the articles reviewed was descriptive (Hilt et al., 2014; Lee et al., 2010; Pearce et al., 2014; Sorrentino et al., 2015), utilizing varying culture mechanisms and symptom scales. Sample sizes varied; however, the majority of studies reported small sample sizes. There was also a high level of homogeneity across studies, resulting in a lack of analysis based on race, geographic, and other demographic data. The purpose of four of the six articles was to evaluate the female urinary microbiome either by culture method (Hilt et al., 2014; Pearce et al., 2014) or in relation to OAB and other urinary symptoms (Pearce et al., 2015; Sorrentino et al., 2015). Lee et al. (2010) focused on mycoplasma infections in particular and the efficacy of azithromycin antibiotic therapy on overactive bladder symptoms. Siddiqui et al. (2014) did not specify a study purpose. This is an emerging area; thus, these findings across this cadre of studies were not unexpected.
The age range (50 to 60 years) of women may also present some limitations in transferability. The majority of women were postmenopausal, which may represent a different urinary microbiome due to hormonal changes than younger premenopausal women. Additionally, the variances in collection and analysis methods also limit this review. The different symptom measurement tools do not all measure the same OAB symptoms or quality of life. Some looked at overarching LUTS and pelvic floor disorders and not specifically OAB symptoms. Variances in symptom construct and bacteria identified by various culture methods make results difficult to compare across studies.
Implications for Nursing And Patient Care
The integrative review supports the role of the female urinary microbiome on OAB symptom presentation and potential protection. The studies reviewed represent emerging literature on the presence of bacteria in the urinary tract and impact on OAB symptoms. Findings from this integrative review suggest that bacteria in the female urinary tract could contribute to OAB symptomology and challenge the traditional understanding of OAB management. These findings support the need to better understand the urinary microbiome and to disregard the old notion of urine as sterile. Based on this information, practice changes are needed to identify bacterial causes of OAB symptoms, individualize treatment, and suggest prevention strategies. Standard culturing practice needs to be re-evaluated in light of the research findings discussed. Results from these studies also provide direction for further research in terms of how previous researchers have collected and measured bacteria in urine.
The findings of Hilt et al. (2014) and Pearce et al. (2014) support a significant false negative rate using standard urine culturing practices. This challenges current culturing practice and our understanding of "culture negative" because many bacterial infections go undetected, leading to chronic UTI symptoms similar to OAB. Lee et al. (2010) found women with OAB reported symptom relief after treatment with azithromycin for positive cultures; however, there was a potential placebo effect as the five women that remained culture positive after antibiotic therapy also reported relief of symptoms.
Hilt et al. (2014) reports a significant correlation between results of EQUC and 16SrRNA sequencing were supported by rates of detection in other studies (Lee et al., 2010; Pearce et al., 2014, 2015). Therefore either method would be an appropriate substitute for the traditional culture when results of traditional culture are "negative" and yet symptoms remain.
The identification of a dominant bacteria, or urotype, is a new concept and could represent overgrowth indicative of urinary symptom presentation or protection (Pearce et al., 2014, 2015). Some dominant bacteria were associated with OAB symptom presentation, including Aerococcus and Streptococcus (Hilt et al., 2014; Pearce et al., 2014), and Ureaplasma (Lee et al., 2010; Siddiqui et al., 2014). This supports a potential microbial cause of OAB symptomatology. The presence of Lactobacillus in women without OAB symptoms (Hilt et al., 2014; Pearce et al., 2014, 2015) suggests a protective role in preventing OAB and UUI symptoms. Based on these findings, there may be a role for probiotics in supporting healthy urinary microbiome and preventing symptoms. Results of Pearce et al. (2014) with Lactobacillus gasseri associated with the UUI group and Lactobacillus crispatus with the control group require further research as to the effects of certain bacteria at the species level. More research is needed to determine causation to make recommendations for screening, diagnosing, and managing women who present with OAB symptoms.
Recommendations for Future Research
This is an emerging field, and research is limited regarding the effects of bacteriuria on OAB symptoms; thus, more research is needed to support knowledge development. Research with larger sample sizes, younger populations, and more diverse women is needed to truly understand the impact of the bladder microbiome on symptom presentation. Identifying which bacteria are markers for symptoms and whether a protective function of the microbiome exists is needed. Changes with age and hormones in women and how this affects the microbiome of the bladder would also need to be addressed. It is also important to assess the effect of dietary consumption of known bladder irritants (e.g., caffeine, tobacco, carbonation, alcohol) on the urinary microbiome; findings from such studies could lead to clinical interventions.
Conclusion
As the population continues to age and OAB symptoms become more prevalent, management and treatment interventions starting at a young age will be increasingly important. Understanding pathophysiology of this condition will aid in diagnosis and treatment. Findings from this review support a urinary microbiome, and suggest protective and pathologic roles of certain bacteria in symptom presentation. Further research into the management of specific bacteria on symptom relief will need to be conducted.
doi:10.7257/1053-816X.2017.37.2.94
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Kimberly J. Angelini, WHNP-BC, is a PhD Student, Boston College, Boston, MA, and a Board Certified Women's Health Nurse Practitioner, Dowd Medical Gynecology, Reading, MA.
Caption: Figure 1. PRISMA Chart of Literature Search
Table 1. Literature Table Article Level of Sample/ Symptoms Evidence * Lee et III-C n = 84 Mean age al., 2010 = 51 years OAB Hilt et III-C n = 65 Mean age al., 2014 = Not specified OAB control (routine GYN surgery) Pearce et III-B n = 118 Mean age al., 2014 = 63 years for UUI and 49 years for control UUI control (no UUI) Siddiqui et III-C n = 1 Mean age al., 2014 = 61 years OAB Pearce et III-B n = 182 Mean age al., 2015 = 55.8 years for sequence positive and 61.3 years for sequence negative UUI Sorrentino III-B n = 247 Mean age et al., = 47.2 years 2015 Uro-Gyn and GYN practice Article Design/ Purpose Tool Lee et Multicenter longitudinal PPBC ICIQ al., 2010 descriptive study. -FLUTS Identify incidence of 3-day mycoplasma infections diary and evaluate antibiotic efficacy in women with OAB. Hilt et Cross-sectional PFDI al., 2014 descriptive study. Determine whether the urinary microbiome comprises of live bacteria missed on routine culture. Pearce et Cross-sectional PFDI OAB-q al., 2014 descriptive study. Characterize female urinary microbiome with EQUC and 16SrRNA sequencing. Siddiqui et Case study. Not specified. NA al., 2014 Pearce et Secondary Analysis of Not specified al., 2015 ABC trial. Characterize female urinary microbiota by 16SrRNA sequence. Assess relationship of bacteriuria to treatment response and post treatment UTI risk. Sorrentino Cross-sectional ICIQ-FLUTS et al., descriptive study. 2015 Evaluate presence of bacteriuria in women without acute UTI symptoms. Association of bacteriuria with urinary symptoms. Article Culture Results Lee et 42.5% positive cultures. al., 2010 Hilt et 6.2% positive standard al., 2014 culture. 80% showed growth on EQUC. Correlation between bacteria found on EQUC and 16SrRNA sequencing. Pearce et 5.9% positive standard al., 2014 culture. 60% showed growth on EQUC. Majority of samples dominated by one genus (urotype). Siddiqui et Baseline routine culture al., 2014 positive for Streptococcus. After treatment, routine culture negative but 16SrRNA had Streptococcus in 2 times higher sequence. Pearce et 51.1% sequence positive. al., 2015 Sequence negative were at greater risk for post treatment UTI; suggests protective role of microbiome. Sorrentino 6.5% had significant et al., bacertiuria (6 GYN and 2015 10 urogyn). After adjusting for age, parity, symptomatic prolapse, menopause, and surgical history --urinary urgency, bladder pain, nocturia, and nocturnal enuresis remained significantly associated with bacteriuria (p < 0.05). Notes: OAB = overactive bladder, GYN = gynecologic, UUI = urge urinary incontinence, Uro-Gyn = urogynecologic, EQUC = expanded quantitative urinary culture, PPBC = Patient Perception of Bladder Condition questionnaire, ICIQ-FLUTS = International Consultation on Incontinence Questionnaire for Female Lower Urinary Tract Symptoms, PFDI = Pelvic Floor Distress Inventory, OAB-q = Overactive Bladder Questionnaire. * The Johns Hopkins Nursing Evidence-Based Practice Appendix E: Research Evidence Appraisal Tool (Frank, 2014) ratings for Level of Evidence (I-III) and quality of evidence (A-C) score. Level I indicates a randomized control trial (RCT), Level II indicates a quasi-experimental study, and Level III indicates a non-experimental study, such as qualitative, descriptive, or case study. Quality ranges from A, indicating high quality, to C, indicating low quality or major flaws (Johns Hopkins Hospital/Johns Hopkins University, 2016). Table 2. Bacteria Identified and Collection Article Lactobacillus Gardnerella Ureaplasma Mycoplasma hominis Lee et al., X X 2010 Hilt et al., X x 2014 Pearce et X X x al., 2014 Siddiqui et x X al., 2014 Pearce et X X al., 2015 Sorrentino et al., 2015 Article Chlamydia Corynebacterium Streptococcus trachomatis Lee et al., X 2010 Hilt et al., X X 2014 Pearce et x x al., 2014 Siddiqui et X al., 2014 Pearce et x x al., 2015 Sorrentino et al., 2015 Article Actinomyces Staphylococcus Aerococcus Sneathia Lee et al., 2010 Hilt et al., X X X 2014 Pearce et x X x X al., 2014 Siddiqui et al., 2014 Pearce et x X x al., 2015 Sorrentino et al., 2015 Article Enterobacterace Atopobium Prevotella Bacteroides urealyticus Lee et al., 2010 Hilt et al., x x 2014 Pearce et X x x al., 2014 Siddiqui et X X al., 2014 Pearce et X x X X al., 2015 Sorrentino et al., 2015 Article GBS E. Coli Coliform Other Urine Sample Lee et al., Urethral and 2010 cervical swab TUC Hilt et al., x x TUC 2014 Pearce et X x Not specified al., 2014 Siddiqui et X x TUC al., 2014 Pearce et X Clean catch al., 2015 mid-stream Sorrentino X X et al., 2015 Article Test Lee et al., Mycoplasma IST2 2010 kit and PCR Hilt et al., Standard culture, 2014 EQUC, 16SrRNA sequencing Pearce et EQUC, 16SrRNA al., 2014 sequencing Siddiqui et Dipstick, al., 2014 routine culture, UA, 16SrRNA sequencing Pearce et 16SrRNA sequencing al., 2015 Sorrentino Routine culture et al., 2015 Notes: TUC = transurethral catheterization, PCR = polymerase chain reaction, EQUC = expanded quantitative urine culture, UA = urinalysis; X = dominant finding/"urotype," x = found in lesser amounts.
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Author: | Angelini, Kimberly J. |
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Publication: | Urologic Nursing |
Article Type: | Report |
Date: | Mar 1, 2017 |
Words: | 4237 |
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