Urogenital Infections and Inflammations

T.E. Bjerklund Johansen, F. M.E. Wagenlehner, Y.-H. Cho, T. Matsumoto, J. N. Krieger, D. Shoskes, K. Naber

Treatment of chronic prostatitis/chronic pelvic pain syndrome – UPOINT

Aaron C. Shoskes 1
Dominic Tran-Nguyen 2
 Daniel Shoskes 3


1 Des Moines University Medical College of Ostheopathic Medicine, Des Moines, United States
2 Des Moines University, Des Moines, United States
3 Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, United States

Abstract

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition, however many common therapies used in practice fail to show benefit when subjected to large randomized controlled trials. This discrepancy may be because CP/CPPS is a heterogeneous syndrome rather than one specific disease, which can explain the prior failure of any one therapy for all patients. In order to direct appropriate therapy, a six-point clinical phenotyping system was developed to evaluate patients with CP/CPPS. The clinical domains included are urinary symptoms, psychosocial dysfunction, organ-specific findings, infection, neurological/systemic complaints, and tenderness of muscles, producing the acronym UPOINT. Patients are diagnosed clinically for each domain and are given appropriate multimodal therapy for each positive domain. This approach is simple in theory and practice, and has proven effective in our hands for patients even after many years of failed therapies.


Summary of recommendations

  • UPOINT is an approach to CP/CPPS that uses multimodal therapy based on the patient’s clinical phenotype. While untested in controlled randomized trials, published outcomes using individual therapies of varying evidence (see below) consistently show high levels of patient improvement (Level of Evidence 2b: Grade of Recommendation B).
  • Anti-inflammatories should not be used as a monotherapy for the treatment of CP/CPPS, but should be considered as a component in multimodal therapy (Level of Evidence 1b: Grade of Recommendation A).
  • Antibiotics: the clinical evidence suggests that antibacterial therapy should not be used as a monotherapy, particularly in patients who have failed antibacterial therapy previously (Level of Evidence 1a: Grade of Recommendation A). Antimicrobial therapy may, however, be considered for antimicrobial naïve patients (Level of Evidence 1b: Grade of Recommendation C).
  • Alpha blocker therapy:  We recommend alpha blocker therapy for the newly diagnosed, alpha blocker naïve patients with significant voiding symptoms (Level of Evidence 1a: Grade of Recommendation C). In patients previously treated with alpha blocker therapy, alpha blocker monotherapy is not recommended (Level of Evidence 1b: Grade of Recommendation A).
  • Phytotherapy: Because of the few side effects of phytotherapy and the clinical efficacy of Quercetin and Cernilton suggested by these studies, these phytotherapies are recommended as a treatment modality of CP/CPPS (Cernilton Level of Evidence 1: Grade of Recommendation B) (Quercetin, Level of Evidence 1b: Grade of Recommendation A).
  • Neuromodulatory therapy: Though there is some benefit in select patients using oral neuromodulatory therapy, the evidence does not support neuromodulatories as a monotherapy (Level of Evidence 1b: Grade of Recommendation B).
  • 5 alpha reductase inhibitor therapies are not recommended for empiric monotherapy in male CP/CPPS patients (Level of Evidence 2: Grade of recommendation B). They should, however, be considered in patients with benign prostatic hyperplasia (BPH) (Level of Evidence 1a: Grade of recommendation A).
  • Physical therapy: From clinical experience and uncontrolled clinical trials, it is believed that physical therapy may be beneficial in patients with pelvic floor muscle spasm and pain (Level of evidence 3: Grade of recommendation B).

Introduction

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition that can cause a significant reduction in quality of life and substantial financial burden [1]. Symptoms include pelvic/genital pain, urinary frequency, and often erectile dysfunction which is not attributed to an other identifiable organ cause. Multiple factors may play a role in the pathophysiology of CPPS including initial urinary tract infection [2], intra-prostatic urinary reflux [3], inflammation, pelvic floor muscle spasm [4], or psychological traits like depression or stress [5].  However, none of these factors has been determined as the sole cause in majority of cases. Instead, a combination of these factors is likely contributing to CPPS and therefore therapy must likely be directed towards individual patient’s clinical phenotype. This is likely the reason why large studies of monotherapies for CPPS typically fail to show efficacy over placebo.

Because CP/CPPS is a syndrome with many presentations and not a specific disease, there is a need for an algorithm for phenotyping patients in order to direct appropriate treatment. This chapter will discuss monotherapies traditionally used for CP/CPPS, why these frequently tend to fail in a significant proportion of patients, the practical application of the UPOINT phenotyping system, and results of CP/CPPS treatment using UPOINT.

Methods

For this review, papers published in the English, peer-reviewed literature were evaluated. Papers published in non-peer-reviewed supplements were not included. The Medline database was used to identifying relevant studies published in the English literature over the last 20 years. Search terms included chronic prostatitis, chronic pelvic pain, as well as the multiple specific monotherapies (e.g., alpha blocker, antibiotic, anti-inflammatory, etc.). Only studies that defined a population of CP/CPPS men, were randomized placebo- or sham-controlled design, and employed a valid outcome measure were evaluated.

Monotherapies

Anti-inflammatories

Clinical trials regarding the use of anti-inflammatories as a monotherapy in patients with CP/CPPS have included rofecoxib [6], celecoxib [7], pentosan polysulfate [8], zafilukast [9], prednisone [10], and tanezumab [11]. These clinical trials yielded mixed results.

Rofecoxib and celecoxib have showed modest benefit, particularly when used at high dosages. Pentosan polysulfate, though showing symptom improvement, did not result in a significant change in CPSI score as compared to placebo. Tanezumab, a humanized monoclonal antibody that targets nerve growth factor, did not show any benefit in a non-selected population of CP/CPPS men. The use of zafirlukast and coriticosteroids had failed to improve CPSI scores as well. The clinical evidence suggests that anti-inflammatory as a monotherapy is not effective and should not be used in this manner.

Antibiotics

Antibiotics are widely prescribed and are, for many physicians, considered the first line therapy for patients with CP/CPPS. Despite its widespread use, there are only three small randomized controlled trials recorded in the literature [12], [ 13], [14]. These trials investigated the use of ciprofloxacin, levofloxacin, and tetracycline. One study investigating a four-week trial of tetracycline as compared to placebo showed significant benefit for CP/CPPS patients; however its authors judged quality of the study to be poor. Trials investigating the use of levofloxacin and ciprofloxacin showed significant benefit, but were underpowered when trying to establish an antibiotic effect as compared to placebo. The 12-week trial of tetracycline vs placebo yielded significant benefit, however, its results were marred by quality issues – including small numbers, selected patients, and anti-nanobacterial therapy which included tetracycline.

Clinical evidence does not support the empiric use of antibiotics in culture negative CPPS patients. However, there are reports that suggest symptomatic relief with antibiotic therapy, regardless of the presence of cultured uropathogenic bacteria [ 15], [16]. Meta-analysis of antimicrobial trials, including trials that did not use CPSI measurements as an outcome, did show small, but statistically significant benefit [17], [18]. However, whether or not these results translate into clinical significance has yet to be determined. A possible explanation of the benefit of antibiotics in culture negative CP/CPPS patients may be that in these cases, the patients may be infected with unculturable pathogens. Alternatively, some antibiotics have anti-inflammatory properties independent of their anti-bacterial characteristics [19], [20]. The clinical evidence suggests that antibacterial therapy should not be used as a monotherapy, particularly in patients who have failed antibacterial therapy previously. Antimicrobial therapy may, however, be considered for antimicrobial naïve patients.

Alpha blockers (Level of Evidence 1: Grade of Recommendation C)

Eight randomized placebo-controlled trials have evaluated the use of different alpha-adrenergic antagonists in CP/CPPS patients. Terazosin [21], tamsulosin [22], [23], alfuzosin [24], doxazosin [25], and silodosin [26] have shown benefit in CP/CPPS patients. Tamsulosin and alfuzosin [18] however have failed to show significant benefit in two large NIH-sponsored studies.

Many of the smaller alpha blocker studies do show benefit in selected CP/CPPS patients. A possible explanation for the failure of tamsulosin [14] and alfuzosin [27] in the two large NIH-sponsored studies would be the enlistment of patients who may have failed prior alpha-blocker therapy and those that did not have voiding symptoms. Meta-analyses [17], [18], [28] investigating alpha blocker therapy do reveal efficacy. At present, though not yet proven, it is still believed that patients with CP/CPPS and bothersome or measurable voiding symptoms may have the most benefit using alpha blockers as part of an overall therapeutic strategy. We therefore recommend alpha blocker therapy for the newly diagnosed, alpha blocker naïve patients with significant voiding symptoms. In patients previously treated with alpha blocker therapy and in those without urinary symptoms, alpha blocker monotherapy is not recommended.

Phytotherapy

Only two studies regarding phytotherapy met the criteria for this review. The phytotherapies investigated were quercetin [29] (an antioxidant anti-inflammatory product) and cernilton [30] (a standardized pollen extract). Quercetin improved symptoms in CP/CPPS patients when compared to placebo. Pollen extract showed efficacy in the reduction of pain and improvement of quality of life after 1 month of use. The mechanism of pain reduction is not established but quercetin is an antioxidant, anti-inflammatory and beta endorphin levels increase in prostate fluid during therapy. Because of the few side effects of phytotherapy and the clinical efficacy of quercetin and cernilton suggested by these studies, these phytotherapies are recommended as a treatment modality of CP/CPPS.

Neuromodulator therapy

Pregabalin was the only oral neuromodulatory randomized placebo-controlled study investigated in the treatment of CP/CPPS. One NIH sponsored study [31] comparing placebo to pregabalin showed a 6-point decrease in NIH-CPSI score, though these results were not statistically significant for the primary endpoint chosen. Pain scores and total CPSI, however, were significantly improved as compared to control. Though there is some benefit in select patients using oral neuromodulatory therapy, the evidence does not support neuromodulatories as a monotherapy (Level of Evidence 2: Grade of Recommendation B).

5 alpha reductase inhibitors and other hormone therapy

There is one randomized placebo-controlled trial comparing finasteride to placebo using CPSI score as a measurable outcome [32]. Another smaller study investigated mepartricin, an estrogen reducing agent [33].

Finasteride showed improvement in CPSI scores in CP/CPPS patients, though the results were not statistically significant. In the small study involving mepartricin, statistically significant improvement in CPSI scores were obtained when compared to placebo. Dutasteride was investigated as part of a long term, pre-planned analysis of older patients with CP/CPPS symptoms in a prostate cancer reduction trial and showed clinical benefit and a reduction in CPSI score over the long term [34]. Hormonal therapies, however, are not recommended for empiric monotherapy in male CP/CPPS patients. They should, however, be considered in patients with benign prostatic hyperplasia (BPH).

Physical therapies

Pain from CP/CPPS is often related to spasm of the pelvic floor muscles. Traditional western massage was compared with myofascial release physical therapy in men and women with chronic pelvic pain in a multicenter randomized NIH-sponsored study [35]. Other studies included extracorporeal shock wave treatment versus sham [36], percutaneous tibial nerve stimulation versus sham [37], electromagnetic therapy versus sham [38] and standard acupuncture [39] or electro acupuncture [40] versus sham treatment.

For the directed pelvic therapy versus traditional western massage, there was an improvement in CPSI scores in men, though not statistically significant. Randomized sham-controlled trials showed benefit with ESWT, acupuncture, percutaneous tibial nerve stimulation, and electro acupuncture.

From clinical experience and uncontrolled clinical trials, it is believed that physical therapy may be beneficial in patients with pelvic floor muscle spasm and pain.

Clinical phenotyping with UPOINT

The monotherapies discussed above have had limited success and one hypothesis would be that monotherapy fails due to the heterogeneous nature of CP/CPPS which is a syndrome rather than a single defined disorder. It would be ideal to clinically phenotype patients and target therapy to that phenotype. One such phenotyping system is UPOINT, named after the individual domains. The clinical domains are Urinary symptoms, Psychosocial dysfunction, Organ specific findings, Infection, Neurologic/Systemic, and Tenderness of muscles, which produces the acronym UPOINT. Each patient is evaluated clinically for involvement of each domain and symptom severity is assessed using the NIH-CPSI. This is followed by a multimodal therapeutic approach towards positive domains [41] (Figure 1). In studies on the validity of UPOINT, an increase in the number of positive UPOINT domains was found to correlate with increased total NIH-CPSI score, and the number of positive domains correlated with a longer duration of CP/CPPS symptoms [42], [43]. The greatest contribution to symptom severity was seen with the urinary, psychosocial, and tenderness domains [44]. These findings suggest that the UPOINT phenotyping system could prove useful as a clinical framework for directing multimodal therapy for treating CPPS.

Figure 1: UPOINT domains and associated therapies

One prospective study evaluated the use of the multimodal therapy based on UPOINT phenotyping in 100 patients and compared response after at least 6 months [45]. 84% of patients had at least a 6-point decrease in CPSI, with an average drop of 12 points. All patients experienced significantly improved CPSI sub-scores from baseline. These results are significantly better than any prior large trials treating CPPS using monotherapy, suggesting the additional benefit of the UPOINT phenotyping system for directing therapy.

Practical guide to phenotyping with UPOINT

After evaluating a patient using UPOINT, a physician can use the positive phenotypes in order to guide the most suitable therapy. Patients are positive for the urinary domain if they bothersome urinary symptoms (e.g. increased/decreased frequency, weak stream, irritation, or obstruction), a CPSI urinary score greater than 4, or a high postvoid residual (PVR>100cc’s). Pain is the most frequent presenting symptom in patients, but many of these other urinary symptoms can be commonly found. Patients are positive for the psychosocial dysfunction domain of UPOINT with a demonstration of clinical depression, catastrophizing (feelings of helplessness and hopelessness about their condition), anxiety, stress and/or a history of sexual or other physical abuse on specific history or questionnaires. Patients positive for this domain are those with specific bladder or prostate symptoms. Organ specific findings include pain localized to the prostate on physical examination, hematospermia, or WBCs/markers of inflammation found in prostatic secretions,  while bladder symptoms include pain relieved by bladder recycling (filling and voiding), ongoing inflammation, or a positive analgesic bladder challenge (relief of pain after infusion of the bladder with a topical anesthetic, i.e. lidocaine). Patients are positive for infection if there is a history or current presence of identifiable bacteria in prostatic fluid or evidence of chronic bacterial prostatitis. Neurologic or systemic symptoms can include pain outside of the lower abdomen/pelvis, fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, or diagnosis of another systemic or neurological disease. Finally, symptoms for muscle tenderness include muscle spasm and muscle or fascial ‘trigger points’ (palpable nodules in muscle that are tender to palpation).

Treatment guided by UPOINT

Urinary symptoms can be treated with alpha-blockers or anticholinergic medications. Psychosocial symptoms, or “catastrophizing”, are treated with psychological counseling and stress reduction. Organ specific symptoms related to the prostate are treated with bioflavonoids such as quercetin. Bladder symptoms indicative of interstitial cystitis can include Infections are treated with adequate courses of culture-directed therapies. Neurologic or systemic symptoms are treated with tricyclic antidepressants or gabapentin/neuroleptics. Lastly, muscle tenderness is treated with a pelvic floor physical therapy and/or trigger point injections. For example, a patient with urinary and organ specific domains could be treated with an alpha-blocker and quercetin, while another with neurologic and tenderness would be treated with pregabalin and pelvic floor physical therapy.

An online resource has been made available for use by urologists, where one enters patient data and is given the UPOINT clinical phenotype with suggested therapies. A web-based algorithm is available at http://www.upointmd.com

Subsequent studies on UPOINT

While UPOINT was developed in order to comprise the significant symptoms of CPPS, there is potential for the addition of other domains if these domains added to the diagnostic value of the system. One European study investigated whether the addition of another domain (sexual dysfunction) could improve the correlation between UPOINT positive domains and CPSI scores in two separate populations. The traditional UPOINT system correlated with symptom severity in the Italian, but not in the German group . The investigated modified phenotyping system (UPOINTS), using an additional sexual dysfunction domain, correlated significantly with NIH-CPSI scores in the German cohort [46]. Another Canadian study found the addition of this sexual dysfunction domain improved the system’s correlation with quality of life [47]. This finding was further studied in a population of one hundred patients in the US [48]. While 28% of men with CP/CPPS reported bothersome erectile dysfunction, addition of the sexual dysfunction domain decreased the correlation between the UPOINT system and symptom severity. Additionally, NIH-CPSI scores, pain sub-scores, and quality of life measures were unaffected by erectile dysfunction. Therefore, inclusion of a sexual domain did not appear to add value in this patient population.

Conclusions

While there have been advances in the research for the treatment of men with CP/CPPS over the last 15 years, a solely evidence-based approach to treatment yields insufficient results for most patients. No one individual treatment that shows significant clinical efficacy to be recommended as a monotherapy for CP/CPPS. A multi-modal therapeutic approach to treatment specifically directed to each individual patients’ clinical phenotypic profile is likely the best management strategy. Use of the UPOINT phenotyping system allows for this individualization and potentially better outcomes, despite the current lack of randomized controlled trials evidencing this.

Conflict of interest

Daniel Shoskes: Farr Laboratories, Triurol


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[41] Shoskes DA, Nickel JC, Rackley RR, Pontari MA. Clinical phenotyping in chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis: a management strategy for urologic chronic pelvic pain syndromes. Prostate Cancer Prostatic Dis. 2009;12(2):177-83. DOI: 10.1038/pcan.2008.42
[42] Shoskes DA, Nickel JC, Dolinga R, Prots D. Clinical phenotyping of patients with chronic prostatitis/chronic pelvic pain syndrome and correlation with symptom severity. Urology. 2009 Mar;73(3):538-42; discussion 542-3. DOI: 10.1016/j.urology.2008.09.074
[43] Hedelin HH. Evaluation of a modification of the UPOINT clinical phenotype system for the chronic pelvic pain syndrome. Scand J Urol Nephrol. 2009;43(5):373-6. DOI: 10.3109/00365590903164514
[44] Samplaski MK, Li J, Shoskes DA. Clustering of UPOINT domains and subdomains in men with chronic prostatitis/chronic pelvic pain syndrome and contribution to symptom severity. J Urol. 2012 Nov;188(5):1788-93. DOI: 10.1016/j.juro.2012.07.036
[45] Shoskes DA, Nickel JC, Kattan MW. Phenotypically directed multimodal therapy for chronic prostatitis/chronic pelvic pain syndrome: a prospective study using UPOINT. Urology. 2010 Jun;75(6):1249-53. DOI: 10.1016/j.urology.2010.01.021
[46] Magri V, Wagenlehner F, Perletti G, Schneider S, Marras E, Naber KG, Weidner W. Use of the UPOINT chronic prostatitis/chronic pelvic pain syndrome classification in European patient cohorts: sexual function domain improves correlations. J Urol. 2010 Dec;184(6):2339-45. DOI: 10.1016/j.juro.2010.08.025
[47] Davis SN, Binik YM, Amsel R, Carrier S. Is a sexual dysfunction domain important for quality of life in men with urological chronic pelvic pain syndrome? Signs "UPOINT" to yes. J Urol. 2013 Jan;189(1):146-51. DOI: 10.1016/j.juro.2012.08.083
[48] Samplaski MK, Li J, Shoskes DA. Inclusion of erectile domain to UPOINT phenotype does not improve correlation with symptom severity in men with chronic prostatitis/chronic pelvic pain syndrome. Urology. 2011 Sep;78(3):653-8. DOI: 10.1016/j.urology.2011.04.016

The ZB MED – Information Center for Life Sciences, Germany, together with the European Association of Urology (EAU) provided the opportunity to publish a “Living Textbook” on “Urogenital Infections and Inflammations” in an open access form. This “Living Textbook” represents also an update of the Textbook on Urogenital Infections published 2010 by the International Consultation on Urological Infections and the EAU: http://www.icud.info/urogenitalinfections.html.

The “Living Textbook” will cover infections and inflammations of the kidney, the urinary tract, as well as the male and female genital tract considering pathogenesis, diagnostics, treatment, prophylaxis and future aspects. The “Living Textbook” will be structured into about 26 Sections each with two section co-chairs responsible for peer review of the chapters of each section. Each chapter should reflect the background to the topic and highlight all of the critical evidence relating to the subject. The intention is to provide an up to date, concise synthesis of the literature on that topic, and for clinical topics also recommendations based on levels of evidence for contemporary clinical practice, as well as suggested research recommendations.

The editors hope that this “Living Textbook” may become a useful instrument for physicians of different specialties taking care about patients suffering from these diseases.

Truls E. Bjerklund Johansen (Norway),

Florian ME Wagenlehner (Germany),

Yong-Hyun Cho (South Korea),

Tetsuro Matsumoto (Japan),

John N Krieger (USA),

Daniel Shoskes (USA),

Kurt G. Naber (Germany).

Publishing at PUBLISSO

Your chapter will be published at the PUBLISSO platform (https://books.publisso.de).

Information for corresponding authors

It is necessary for all corresponding authors to register at PUBLISSO.
To register at PUBLISSO please click the following link: http://books.publisso.de/publisso_gold/register

After registration, please complete your user profile. Information from your user profile will appear in the published chapter and the authors board of the book (http://books.publisso.de/publisso_gold/book/52). If you are displayed in the authors board, you can be contacted by readers and other professionals. You can also contact other authors of the book for exchange and to build a network.
(If you do not want to be displayed in the authors board, but stay registered, you can disable this feature in your profile settings. In this case, your affiliation (publication data) will be displayed in the published chapter only.)

We kindly ask you to provide the co-authors email addresses in the manuscript so that we can contact them in case of queries.

Information for co-authors

After publication of your chapter, your affiliation (publication data) will be displayed in the published chapter.

If you also want to be displayed in the authors board of the book (http://books.publisso.de/publisso_gold/book/52), we kindly ask you to register at PUBLISSO. If you are displayed in the authors board, you can be contacted by readers and other professionals. You can also contact other authors of the book for exchange and to build a network.

To register at PUBLISSO please click the following link: http://books.publisso.de/publisso_gold/register

If you do not want to be displayed in the authors board of the book, you do not have to register. Your affiliation (publication data) will be displayed in the published chapter only.

Support

If you have any further questions please don’t hesitate to contact the PUBLISSO editorial office:

E-Mail: livingbooks@zbmed.de
Phone: +49 221 478-7093

General

The textbook will be structured in sections with two co-chairs each. Each section will start with an introductory chapter written by the two respective co-chairs presented like an editorial commentary in regard to the following chapters (see proposed contents of the book). The two co-chairs of each section will also peer review all chapters in their section and stimulate a consensus discussion within their section together with the authors and the main editors if needed.

Chapters

Each chapter should reflect the background to the topic and highlight all of the critical evidence relating to the subject. The intention is to provide an up to date, concise synthesis of the literature on that topic, and for clinical topics also recommendations based on levels of evidence for contemporary clinical practice, as well as suggested research recommendations.

Manuscript

Each manuscript should have up to approximately 3,000 words (excluding abstract, tables/figures and references). The abstract should count about 300 words.

Structure

The outline of each chapter should be structured as follows (similar as in the edition 2010, which can be downloaded for free: http://www.icud.info/urogenitalinfections.html):

  1. Abstract
  2. Summary of recommendations*/key notes*
    (*which ever term is more appropriate)
  3. Introduction
  4. Methods
  5. Results
  6. Further research
  7. Conclusions
  8. Acknowledgement
  9. Conflict of interest of each author
  10. References

Citation style

As a citation style, the Vancouver style is preferred.

Please mark your references in the text with square brackets ([1], [2], ...).

Summary of recommendations

We would like to have the Summary of recommendations at the beginning after the abstract (as in the edition 2010). However, we do not expect as in the edition 2010, that each recommendation is also specified according to Level of Evidence and Grade of Recommendation, because such a claim would not only need a systematic literature search (see below), but also a structured discussion in a defined group of experts.

Systematic literature search

A systematic literature search should be performed, at least of PUBMED/MEDLINE but ideally of several relevant databases in addition (like Cochrane CENTRAL) to find recent, high quality systematic reviews and/or primary research studies. It is not expected to perform for all chapters a de novo systematic review, if such reviews are already published recently, but it still may be indicated for some items. For questions relating therapy, it should be focused on evidence from (systematic reviews of) randomized controlled trials if available.

The method of the systematic literature search needs to be fully described in the section “Methods”, e.g.:

“A systematic literature search was performed for the last ... (usually 10) years in MEDLINE, Cochrane etc. with the following key words ... and the following limitations: e.g. UTI, age (adult?), ... clinical studies ... English ... abstract available ... only peer reviewed ...

A total of ... publications were identified, which were screened by title and abstract ... After exclusion of duplicates ... a total of ... were included into the review (analysis), supplemented by citations or known to the authors ... ”.

Clinical topics

Clinical topics should be focused on the importance to clinical practice according to the up to date scientific knowledge as presented in the literature. It should relate to questions/complaints/symptoms of patient/population concerning definition, diagnosis, therapy/prevention, intervention, and outcome in comparison, if different approaches are feasible. Please choose patient-important outcomes and focus on those, which you deem critical for decision-making.

Level of evidence and grade of recommendations

Any recommendation should be based on the level of evidence and the grade of recommendation. For this purpose the following system, modified from the Oxford Centre for Evidence-based Medicine should be used (EAU guidelines 2015):

Level of evidence (LE)

Level Type of evidence
1a Evidence obtained from meta-analysis of randomised trials
1b Evidence obtained from at least one randomised trial
2a Evidence obtained from one well-designed controlled study without randomization
2b Evidence obtained from at least one other type of well-designed quasi-experimental study
3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports.
4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities.

Grade of Recommendations (GoR)

Grade Nature of recommendations
A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial
B Based on well-conducted clinical studies, but without randomised clinical trials
C Made despite the absence of directly applicable clinical studies of good quality

Comments (EAU guidelines 2015)

The aim of assigning a LE and grading recommendations is to provide transparency between the underlying evidence and the recommendation given.

It should be noted that when recommendations are graded, the link between the level of evidence and grade of recommendation is not directly linear. Availability of randomized controlled trials may not necessarily translate into a grade “A” recommendation where there are methodological limitations or disparity in published results.

Alternatively, absence of high level evidence does not necessarily preclude a grade A recommendation, if there is overwhelming clinical experience and consensus. In addition, there may be exceptional situations where corroborating studies cannot be performed, perhaps for ethical or other reasons and in this case unequivocal recommendations are considered helpful for the reader. The quality of the underlying scientific evidence - although a very important factor – has to be balanced against benefits and burdens, values and preferences and costs when a grade is assigned.

Since the same rating system should be used in all chapters, for the sake of brevity the same sentence could be used in “Methods” for all manuscripts, because the rating system will be described in details in the Preface of the book:

“The studies were rated according to the level of evidence and the strength of recommendations graded according to a system used in the EAU guidelines modified from the Oxford Centre for Evidence-based Medicine [1].”

References

[1] European Association of Urology. Guidelines. Methodology section. 2015 ed. Arnhem: European Association of Urology; 2015. p. 3. ISBN/EAN: 978-90-79754-80-9. Available from: http://uroweb.org/wp-content/uploads/EAU-Extended-Guidelines-2015-Edn..pdf

The Living Handbook of Urogenital Infections and Inflammations is issued by:

European Association of Urology
att. Maurice Schlief, EAU executive manager business affairs

P.O.Box 30016
NL-6803 AA Arnhem, The Netherlands

Phone: 0031-26-38.90.680
E-mail: m.schlief@uroweb.org

Editor in Chief

responsible for the contents according to § 5 TMG and § 55 Abs. 2 RStV (Germany):

Kurt G. Naber, MD, PhD
Assoc. Professor of Urology

Technical University of Munich
Karl-Bickleder-Str. 44c
94315 Straubing, Germany

E-mail: kurt.naber@nabers.de

John N. Krieger MD, PhD

University of Washington Section of Urology

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Daniel Shoskes MD, PhD

Cleveland Clinic Glickman Urological and Kidney Institute

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Yong-Hyun Cho MD, PhD

St. Mary's Hospital, The Catholic University of Korea Department of Urology

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Tetsuro Matsumoto MD, PhD

University of Occupational and Environmental Health Department of Urology

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Florian M. E. Wagenlehner MD, PhD

Justus-Liebig University of Giessen Clinic of Urology and Andrology

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Truls Erik Bjerklund Johansen MD, PhD

Oslo University Hospital Urology Department

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Kurt G. Naber MD, PhD

Technical University of Munich

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Punit Bansal MD, PhD

R G Stone and Super Specialty Hospital
Department of Urology

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Riccardo Bartoletti

University of Pisa
Department of Translational Research and New Technologies

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Truls Erik Bjerklund Johansen MD, PhD

Oslo University Hospital
Urology Department

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PD Dr. med. Gernot Bonkat

University Basel
alta uro AG, Merian Iselin Klinik, Center of Biomechanics & Calorimetry (COB)

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Prof. Tommaso Cai MD

Santa Chiara Regional Hospital
Dept. of Urology

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Dr Leyland Chuang

Ng Teng Fong Hospital, National University Health System
Department of Medicine

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Prof. Milan Cizman

University Medical Centre
Department of Infectious Diseases

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Alison Crawford MSc

Queen's University
Department of Psychology

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Pfofessor Svetlana Dubrovina MD, PhD

Rostov Medical State University
Obstetrics and Gynaecology

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Dr Valerie Huei Li Gan MBBS (S'pore), MRCS (Edin), MMed (Surg), FAMS (Urology)

Singapore General Hospital
Department of Urology

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Philip Hanno

University of Pennsylvania

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Ass prof MD Gundela Holmdahl

Queen Silvia Childrens Hospital, Sahlgrens Academy
Pediatric surgery and urology

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Udo B. Hoyme

HELIOS Hospital Erfurt Ltd.
Department of Gynecology and Obstetrics

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David Hunstad

Washington University School of Medicine
Pediatrics / Molecular Microbiology

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Gitte M. Hvistendahl

Aarhus University Hospital

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Prof. Michael KOGAN M.D., PhD

Rostov State Medical University
Department of Urology

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Dr Akihiro Kanematsu

Hyogo College of Medicine
Department of Urology

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Frieder Keller

University Hospital Ulm
Department Internal Medicine 1, Nephrology

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Professor Katarzyna Kilis-Pstrusinska PhD, MD

Wroclaw Medical University
Department of Pediatric Nephrology

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MD, PhD Tae-Hyoung Kim

Chung-Ang University
Urology

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John N. Krieger MD, PhD

University of Washington
Section of Urology

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Prof Ekaterina Kulchavenya

Novosibirsk Research TB Institute, Novosibirsk State Medical University

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Dr Christina Kåbjörn Gustafsson

Ryhov Hospital Jönköping
Pathology

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Dr. Bela Köves

South Pest Teaching Hospital
Department of Urology

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Dr. med. Giuseppe Magistro

Ludwig-Maximilians-University of Munich
Department of Urology

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Vittorio Magri

ASST-North
Urologic Clinic

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András Magyar

South-Pest Hospital
Department of Urology

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Professor Emeritus Brian Morris

University of Sydney
School of Medical Sciences

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Baerbel Muendner-Hensen

ICA-Deutschland e.V.

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Stephen F. Murphy

Feinberg School of Medicine, Northwestern University
Department of Urology

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Kurt G. Naber MD, PhD

Technical University of Munich

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Prof. Yulia Naboka

Rostov State Medical University
Department of Microbiology

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Dr. J. Curtis Nickel MD

Queen's University
Department of Urology

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Professor Ralph Peeker MD PhD

University of Gothenburg
Department of Urology

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Tamara Perepanova

N.A. Lopatkin Research Institute of Urology and Interventional Radiology

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Prof. Gianpaolo Perletti M. Clin. Pharmacol.

University of Insubria
Department of Biotechnology and Life Sciences

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Felice Petraglia

Department of Biomedical, Experimental and Clinical Sciences, University of Florence
Obstetrics and Gynecology

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Michel Pontari

Temple University School of Medicine
Department of Urology

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Dr. Jörgen Quaghebeur PhD. Med. Sci.

University Hospital Antwerp and University Antwerp
Department of Urology

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Yazan F. Rawashdeh

Aarhus University Hospital
Paediatric Urology Section, Department of Urology

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Professor Claus Riedl MD

-
Urology

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Matthew Roberts

The University of Queensland
Faculty of Medicine

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PD Dr. med Guido Schmiemann MPH

Institut für Public Health und Pflegeforschung, Universität Bremen
Abteilung Versorgungsforschung

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Caroline Schneeberger MD PhD

Academic Medical Center (AMC)

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Prof. Dr. med. Peter Schneede

Klinikum Memmingen
Department of Urology

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Aaron C. Shoskes

Des Moines University Medical College of Ostheopathic Medicine

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Daniel Shoskes MD, PhD

Cleveland Clinic
Glickman Urological and Kidney Institute

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Prof. Dr. Roswitha Siener

University of Bonn
University Stone Centre, Department of Urology

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Sofia Sjöström

Queen Silvia Childrens Hospital, Sahlgrens Academy
Pediatric surgery and urology

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Mathew Sorensen

University of Washington School of Medicine
Department of Urology

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Prof. Dr. Dr. Walter Ludwig Strohmaier FEBU

Regiomed-Klinikum Coburg. Medical School Regiomed
Urology and Paediatric Urology

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Satoshi Takahashi

Sapporo Medical University School of Medicine
Department of Infection Control and Laboratory Medicine

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Professor Paul Anantharajah Tambyah

Yong Loo Lin School of Medicine, National University Hospital
Department of Medicine

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Peter Tenke

Jahn Ferenc South Pest Teaching Hospital
Department of Urology

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Praveen Thumbikat


Department of Urology

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Dr. Jose Tiran Saucedo

IMIGO / Universidad de Monterrey
Obstetrics and Gynaecology

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Dominic Tran-Nguyen

Des Moines University

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Dean Tripp

Queen's University
Psychology, Anesthesia & Urology

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Prof. SEONGHEON WIE

The Catholic University of Korea, St. Vincent's Hospital
Division of Infectious Diseases, Department of Internal Medicine

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Florian M. E. Wagenlehner MD, PhD

Justus-Liebig University of Giessen
Clinic of Urology and Andrology

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Assoc. Prof. Christian Wejse

Aarhus University, Aarhus University Hospital
Department of Infectious Diseases/Center for Global Health, Dept of Public Health

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Prof. Dr. Mete Çek

Trakya University, School of Medicine
Urology

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