Urogenital Infections and Inflammations

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

Sex and other host factors influencing urinary tract infection pathogenesis

Patrick D. Olson 1
 David Hunstad 2


1 Medical Scientist Training Program, Washington University School of Medicine, St. Louis, USA
2 Pediatrics / Molecular Microbiology, Washington University School of Medicine, St. Louis, United States

Abstract

Biological sex represents the most important host factor that influences urinary tract infections (UTIs), which are most commonly caused by uropathogenic Escherichia coli (UPEC). UTI susceptibility varies by sex and age throughout the patient lifespan, although the disease disproportionally afflicts women throughout the middle ages. Substantial male patient populations are also affected, and morbidity in complicated UTI is higher in men. This review highlights sex-related discrepancies in the disease, and how sex may influence the pathogenesis, outcomes, and treatment of ascending UTI.


1 Introduction

“From womb to tomb” it matters, argues the 2001 Institute of Medicine report [1]; biological sex should be a fundamental consideration in human health and disease. Indeed, a number of human diseases manifest profound sex-based differences in prevalence, incidence, severity, and response to treatment. Yet, sex as a biological variable has long been ignored experimentally in the biomedical sciences and clinically in the application of evidence-based medicine [2], [3]. Research and medicine in the US and other countries are currently on the verge of a paradigm shift in which sex should and will increasingly be considered from bench to bedside [2], [3], [4].

Such a sex bias is well entrenched in our understanding of urinary tract infections (UTIs), a collection of diseases which have been both prejudiced and understudied because of their disproportionate affliction of women and long-standing experimental and clinical sex biases. UTIs are among the most common bacterial infections that plague humans. On an epidemiologic basis, community-onset UTI is widely viewed as a disease only of women; indeed, its occurrence between 2 and 60 years of age is almost exclusive to females, and it is estimated that at least half of American women will suffer a UTI during their lifetimes [5]. However, in certain populations the incidence of male UTI matches or exceeds that in females; epidemiologic data also suggest a sex difference in morbidity from upper-tract UTI [6], [7], [8], [9]. To better understand resistance and susceptibility mechanisms to UTI, it is important that we consider age- and sex-related discrepancies that are evident in the disease, and how sex and other host factors may influence the pathogenesis and outcomes of ascending UTI.

2 Host factors influencing UTI

Though contemporary and emerging technologies will enable further investigation of the presumed sterility of the urinary tract, microbiologic health of the urinary tract depends on multiple host factors, including a finely tuned innate inflammatory response, which act to eliminate potential uropathogens from the bladder and kidneys [10], [11], [12], [13]. Despite repetitive exposure of this potentially hospitable, nutrient-rich environment to bacterial pathogens (e.g., following sexual intercourse [14]), bacteriuria in the otherwise healthy human host usually is transient [15], [16], [17]. Host traits that compromise the defenses of the urinary tract augment disease susceptibility, severity, and progression. Forward flow of urine provides a formidable mechanical defense; dysfunctional voiding and other urodynamic abnormalities are clearly associated with increased susceptibility to UTI in children and adults [18]. Such conditions in the adult female likely include pregnancy, which also predisposes to UTI [19]. Factors which increase the hospitability of the bladder microenvironment to infection, such as glycosuria associated with diabetes mellitus, likewise increase susceptibility to UTI [20]; hyperglycemia may also additionally compromise the activity of phagocytes. Finally, impairment of the innate immune response either by immunosuppression or genetic defects in innate components lead to increased frequency of UTI [12]. Multiple efforts to define human genetic variation imparting susceptibility to UTI have been modestly successful. Attention in this realm has been focused largely on host innate immune genes. However, it has also become clear that susceptibility is both polygenic and environmental, and that genetic determinants of distinct clinical syndromes (asymptomatic bacteriuria, cystitis, and pyelonephritis) must be pursued independently.

3 Sex and UTI

However, the host trait that is most influential in the development of UTI is undeniably biological sex. The frequency of UTI changes drastically across the lifespan and varies by sex [21]. As mentioned previously, the occurrence of UTI in middle age is almost exclusive to females. However, certain populations show an increased risk of male UTI.

UTI in young children is common [22], [23]. The sex ratio in UTI incidence among infants is approximately 2:1 – still favoring females, but at a much lower ratio than in later childhood and beyond. In fact, many studies have shown that male UTI cases outnumber females within the first 3–6 months after birth [24], [25], [26], [27], [28], [29], [30], [31]. Thereafter, UTI susceptibility wanes in males throughout later infancy. Infants and young children thus may represent a unique patient population in which to investigate sex differences in UTI. Clinically, prompt diagnosis and treatment of UTI in infancy is necessary to prevent renal scarring and potential long-term complications [32]. Interestingly, a history of maternal UTI during pregnancy has been associated with up to a 5.9-fold higher risk of UTI in both sexes during infancy [33], [34]. It is unclear if this risk arises from inheritance of genetic predisposition to UTI, intrapartum or postpartum transmission of virulent uropathogens from the maternal genitourinary tract to the microbiota of the infant, or other environmental factors.

Though women represent >90% of UTI patients between early childhood and late middle age [5], [35], [36], complicated UTI manifests in both sexes across this time frame in patients with indwelling urinary catheters, diabetes mellitus, spinal cord injuries, immunosuppression, and structural or urodynamic abnormalities. Notably, while female cases of complicated and upper-tract UTI (pyelonephritis) outnumber male cases overall, men carry an increased risk of mortality from these infections [6], [7], [8], [9]. Thousands of men, particularly those of advancing age, also suffer from acute and chronic bacterial prostatitis, a clinical diagnosis with signs, symptoms, and etiological pathogen profiles that overlap substantially with those of lower UTI in females [37], [38]. The incidence of UTI in males increases substantially after 60 years of age, largely because of abnormal voiding patterns due to acquired urodynamic abnormalities (e.g., benign prostatic hyperplasia) [5], [21], [39]. In total, UTIs comprise debilitating diseases with substantial morbidity and occasional mortality among males [37], [38].

Though a number of distinct bacterial pathogens may cause UTI and prostatitis, uropathogenic Escherichia coli (UPEC) predominate among etiological agents in both sexes, causing >80% of community-onset UTI, roughly one fourth of hospital-acquired UTI, and >70% of infectious prostatitis [5], [21], [40]. Our knowledge of the molecular details of UPEC pathogenesis has been developed largely in an exclusively female murine model. In this widely used model of bacterial cystitis, female mice are briefly catheterized and uropathogenic bacteria inoculated into the bladder lumen; however, the bladders of male mice are not reliably accessed by catheter, precluding studies of male cystitis and pyelonephritis using this method. Upon delivery to the female bladder, UPEC and other uropathogens first encounter the stratified transitional epithelium, lined by a single layer of large, multinucleated superficial facet cells apically coated with an array of integral membrane proteins known as uroplakins [41]. UPEC exploit mannose moieties decorating these uroplakins as the receptor for their major virulence determinant, adhesive type 1 pili [42], [43]. Following type 1 pilus-mediated attachment to the uroepithelium, UPEC are rapidly internalized into superficial facet cells [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61]. After a single bacterium has invaded a facet cell, it may then rapidly replicate in the host cell cytoplasm, initially forming loose collections that subsequently coalesce into densely packed intracellular bacterial communities (IBCs) [50]. Infected bladder epithelial cells may be exfoliated, eliminating some IBCs in the urine [62], [63]; meanwhile, a subset of UPEC may flux from the mature IBC, assume a filamentous morphology that resists neutrophil phagocytosis, and initiate further rounds of IBC formation by invading nearby naive epithelial cells [64], [65]. Murine and in vitro evidence for this IBC cascade has been corroborated by detection of shed IBCs in female human urines [66], [67], suggesting that the murine IBC pathway recapitulates acute cystitis in women.

This paradigm, in which cystitis pathogenesis depends on an intracellular cascade, has been recently expanded to male hosts. The technical barriers to modeling UTI in male mice have long been simply accepted in the field, with the rationalization that females comprise the important population of UTI patients anyway. To overcome the technical hurdles, we recently devised and optimized a strategy to induce UTI via mini-surgical inoculation of the bladder in both sexes of mice. Acute UPEC cystitis in male mice recapitulated the intracellular bacterial community pathway previously shown in females [68]. Intracellular bacteria have also been recently identified within exfoliated bladder epithelial cells from the urine of infected male infants [69]; these findings collectively suggest that the IBC cascade is important for the development of acute bacterial cystitis in both sexes.

The sex discrepancies seen in UTI epidemiology have been traditionally attributed to anatomic (and less conclusively, hygienic) factors, including the permissiveness of the surrounding vaginal and perineal environments to microbial colonization, a shorter distance from the anus to the urethral meatus, and shorter urethral length in females. Our data demonstrating similar bladder infectivity between male and female mice after direct inoculation [68] offers empirical data to support this long-standing hypothesis that UTI risk in females is potentiated by these anatomic features, and is not driven by intrinsic epithelial receptivity or comparatively diminished immune resistance within the urinary tract of women. Conversely, normal anatomy represents a key defense against ascending bacterial infection in boys (past infancy) and men [68].

4 Male UTI

Unfortunately, the epidemiology, diagnosis, and treatment of UTI in male populations have been poorly described compared to the robustly studied female populations, although substantial differences exist between them [70]. Infections of male accessory organs, including prostatitis, epididymitis, orchitis, and seminal vesiculitis, can also be classified as exclusively male forms of UTI. UTI in adult male patients is often viewed as “complicated,” if only because of the relative paucity of cases in men compared to women.

Males also exhibit an increase in some specific risk factors that potentiate UTI. A lack of circumcision increases risk for UTI in both infants [71], [72], [73] and adult men [74]. Men have a striking predilection for spinal cord injury, outnumbering female cases four to one; chronic, recurrent UTIs present a difficult and often lifelong challenge in patients with neurogenic bladder arising from such injuries and other causes [75]. Complicated UTI also manifests in hospitalized males with indwelling urinary catheters, those receiving immunosuppression, and those with structural abnormalities (particularly in infancy).

Optimal treatment regimens (antibiotic choice and duration) for uncomplicated UTI in females have been the subject of numerous clinical trials, and the contemporary clinician can rely on published guidelines for these patients [76], while evidence supporting proper choice of antimicrobial agents and duration of therapy for men is less clear. Many expert recommendations call for extended (14 days or longer) courses of antibiotic therapy to treat male UTI [39], [77], [78], [79]. However, a recent study found no differences in acute resolution or recurrence rate between male UTI patients treated for <7 days versus those treated for >7 days; moreover, longer-duration therapy was associated with the subsequent development of Clostridium difficile infection [80]. Ongoing studies and clinical trials are expected to inform the development of more evidence-based and specific recommendations for treating male UTI [81].

5 Hormones

Developing evidence suggests that hormonal milieu, specifically estrogen and testosterone influence, may impact UTI susceptibility and severity. Our increasing knowledge of this field is particularly interesting as it may ultimately inform approaches that represent alternatives to antibiotic treatment.

There are extensive but somewhat conflicting data on the influence of estrogen on susceptibility to UTI. Young adult women, who exhibit the highest estrogen levels, account for the majority of community-onset UTI cases, and high estrogen levels have been linked to increased UTI susceptibility [82]. However, post-menopausal females also experience an increased incidence of UTI, which in some cases has been treated with estrogen supplementation. Results from murine studies employing ovariectomized and/or estrogen-supplemented females to examine the influences of estradiol on UTI pathogenesis are likewise conflicting. Some studies have found modest increases in bladder bacterial burdens in estrogen-depleted hosts, particularly during the acute phase of cystitis [83], [84]. Conversely, we found no change in susceptibility to chronic cystitis or pyelonephritis in ovariectomized female mice [68], and Curran et al. noted an increased risk of upper-tract UTI in mice following estrogen treatment [85]. These experimental models notably bypass the vaginal and periurethral microenvironment, as mice are inoculated by transurethral catheterization of the bladder. Collectively, the available data suggest that the impact of estrogen on bacterial pathogenesis within the urinary tract proper is likely minor. However, many have posited that estrogens may influence periurethral colonization by uropathogens and alter UTI-relevant facets of the vaginal environment (e.g., composition of the vaginal microbiome, dryness, sexual intercourse frequency). In line with this hypothesis, a Cochrane review concluded that topical estrogens show possible benefit in reducing UTI risk, albeit with a number of side effects [86]. Of note, recent evidence suggests that high estradiol levels may cause opposing changes in both bladder fortification and receptivity to infection, providing a viable hypothesis for inconsistent estrogenic influences on UTI. High estradiol levels may induce expression of major adhesive receptors for uropathogens in bladder epithelial cells in vitro (thereby promoting increased bacterial adherence and invasion), while a protective effect may be attributable to its ability to induce antimicrobial peptides during acute UTI [84].

The influence of testosterone on UTI susceptibility has only recently been explored. As described above, our initial investigation of sex differences in murine UTI pathogenesis revealed that susceptibility to acute cystitis remained fairly similar between sexes [68]. However, male mice displayed strikingly higher susceptibility to chronic cystitis and severe pyelonephritis, as well as formation of renal abscess – an event that is very uncommon in immunocompetent female mice [68], [87], [88]. Castration substantially abrogated male susceptibility to UTI, while provision of exogenous testosterone restored severe UTI outcomes, demonstrating a previously unrecognized role of androgens in UTI susceptibility [68]. If testosterone administration also promotes these complicated UTI outcomes in female mice, then modulation of androgens might ultimately be a viable adjunct therapy in some UTI patients. Future investigation using our model of surgical infection for sex comparisons will continue to give insight into mechanistic differences in UTI initiation, progression, and persistence in both male and female hosts [68].

6 Conclusion

Men and women display fundamental differences in their susceptibility to infectious diseases. These dissimilarities stem from a multitude of differences: in pathogen exposure, cultural and behavioral issues, anatomy, hormonal expression, treatment efficacy, socio-economic influences, and many more. Most notably, sex differences in immunity have been clearly described, with females displaying enhanced resistance to many infections because of more robust immune responses controlling pathogens [89], [90], [91]. This enhanced defense in women has been hypothesized to have evolved from the need to protect their fetuses from infection [92], and is associated with the greater frequency and severity in women of many chronic inflammatory and autoimmune diseases [93], [94].

Ascending UTI represents a contradiction to this paradigm, being one of the few infectious diseases which disproportionately afflicts females over males. In considering how biological sex influences UTI, the chief protective mechanism for males is anatomy, while repeated introduction of bacterial pathogens to the urinary tract in females necessitates a finely tuned innate surveillance and defense system as primary protection. Accordingly, traits or interventions which bypass or hamper these defenses represent risk factors for chronic and/or recurrent UTI [13]. As described above, new experimental models that bypass lower anatomic barriers will enable the study of immunologic and other sex differences in cystitis and pyelonephritis. Recent calls by the US National Institutes of Health [4] and in the basic and clinical literature [2], [95], [96] for sex-based research approaches to infectious and other diseases, including a specific focus on UTI [80], [97], should help to accelerate research progress in this arena. Continued work on studying sex differences in these conditions promises to inform the development of novel therapeutics and interventions, yielding better sex-based treatment and prevention strategies for the benefit of all patients.


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[61] Rosen DA, Pinkner JS, Jones JM, Walker JN, Clegg S, Hultgren SJ. Utilization of an intracellular bacterial community pathway in Klebsiella pneumoniae urinary tract infection and the effects of FimK on type 1 pilus expression. Infect Immun. 2008 Jul;76(7):3337-45. DOI: 10.1128/IAI.00090-08
[62] Mulvey MA, Lopez-Boado YS, Wilson CL, Roth R, Parks WC, Heuser J, Hultgren SJ. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science. 1998 Nov;282(5393):1494-7. DOI: 10.1126/science.282.5393.1494
[63] Mysorekar IU, Mulvey MA, Hultgren SJ, Gordon JI. Molecular regulation of urothelial renewal and host defenses during infection with uropathogenic Escherichia coli. J Biol Chem. 2002 Mar;277(9):7412-9. DOI: 10.1074/jbc.M110560200
[64] Justice SS, Hunstad DA, Seed PC, Hultgren SJ. Filamentation by Escherichia coli subverts innate defenses during urinary tract infection. Proc Natl Acad Sci USA. 2006 Dec;103(52):19884-9. DOI: 10.1073/pnas.0606329104
[65] Horvath DJ Jr, Li B, Casper T, Partida-Sanchez S, Hunstad DA, Hultgren SJ, Justice SS. Morphological plasticity promotes resistance to phagocyte killing of uropathogenic Escherichia coli. Microbes Infect. 2011 May;13(5):426-37. DOI: 10.1016/j.micinf.2010.12.004
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[75] Siroky MB. Pathogenesis of bacteriuria and infection in the spinal cord injured patient. Am J Med. 2002 Jul 8;113 Suppl 1A:67S-79S. DOI: 10.1016/S0002-9343(02)01061-6
[76] Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE; Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011 Mar;52(5):e103-20. DOI: 10.1093/cid/ciq257
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[79] Drekonja DM, Johnson JR. Urinary tract infections. Prim Care. 2008 Jun;35(2):345-67, vii. DOI: 10.1016/j.pop.2008.01.001
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[81] van Nieuwkoop C, van't Wout JW, Assendelft WJ, Elzevier HW, Leyten EM, Koster T, Wattel-Louis GH, Delfos NM, Ablij HC, Kuijper EJ, Pander J, Blom JW, Spelt IC, van Dissel JT. Treatment duration of febrile urinary tract infection (FUTIRST trial): a randomized placebo-controlled multicenter trial comparing short (7 days) antibiotic treatment with conventional treatment (14 days). BMC Infect Dis. 2009 Aug;9:131. DOI: 10.1186/1471-2334-9-131
[82] Sonnex C. Influence of ovarian hormones on urogenital infection. Sex Transm Infect. 1998 Feb;74(1):11-9. DOI: 10.1136/sti.74.1.11
[83] Wang C, Symington JW, Ma E, Cao B, Mysorekar IU. Estrogenic modulation of uropathogenic Escherichia coli infection pathogenesis in a murine menopause model. Infect Immun. 2013 Mar;81(3):733-9. DOI: 10.1128/IAI.01234-12
[84] Lüthje P, Brauner H, Ramos NL, Ovregaard A, Gläser R, Hirschberg AL, Aspenström P, Brauner A. Estrogen supports urothelial defense mechanisms. Sci Transl Med. 2013 Jun;5(190):190ra80. DOI: 10.1126/scitranslmed.3005574
[85] Curran EM, Tassell AH, Judy BM, Nowicki B, Montgomery-Rice V, Estes DM, Nowicki S. Estrogen increases menopausal host susceptibility to experimental ascending urinary-tract infection. J Infect Dis. 2007 Mar;195(5):680-3. DOI: 10.1086/511275
[86] Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD005131. DOI: 10.1002/14651858.CD005131.pub2
[87] Hannan TJ, Mysorekar IU, Hung CS, Isaacson-Schmid ML, Hultgren SJ. Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection. PLoS Pathog. 2010 Aug 12;6(8):e1001042. DOI: 10.1371/journal.ppat.1001042
[88] Hannan TJ, Totsika M, Mansfield KJ, Moore KH, Schembri MA, Hultgren SJ. Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol Rev. 2012 May;36(3):616-48. DOI: 10.1111/j.1574-6976.2012.00339.x
[89] Robinson DP, Lorenzo ME, Jian W, Klein SL. Elevated 17β-estradiol protects females from influenza A virus pathogenesis by suppressing inflammatory responses. PLoS Pathog. 2011 Jul;7(7):e1002149. DOI: 10.1371/journal.ppat.1002149
[90] Kadioglu A, Cuppone AM, Trappetti C, List T, Spreafico A, Pozzi G, Andrew PW, Oggioni MR. Sex-based differences in susceptibility to respiratory and systemic pneumococcal disease in mice. J Infect Dis. 2011 Dec;204(12):1971-9. DOI: 10.1093/infdis/jir657
[91] Klein SL. The effects of hormones on sex differences in infection: from genes to behavior. Neurosci Biobehav Rev. 2000 Aug;24(6):627-38. DOI: 10.1016/S0149-7634(00)00027-0
[92] Billington WD. The immunological problem of pregnancy: 50 years with the hope of progress. A tribute to Peter Medawar. J Reprod Immunol. 2003 Oct;60(1):1-11. DOI: 10.1016/S0165-0378(03)00083-4
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[94] Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997 Sep;84(3):223-43.
[95] Pollitzer E. Biology: Cell sex matters. Nature. 2013 Aug;500(7460):23-4. DOI: 10.1038/500023a
[96] Cahill L. A half-truth is a whole lie: on the necessity of investigating sex influences on the brain. Endocrinology. 2012 Jun;153(6):2541-3. DOI: 10.1210/en.2011-2167
[97] den Heijer CD, Penders J, Donker GA, Bruggeman CA, Stobberingh EE. The importance of gender-stratified antibiotic resistance surveillance of unselected uropathogens: a Dutch Nationwide Extramural Surveillance study. PLoS ONE. 2013;8(3):e60497. DOI: 10.1371/journal.pone.0060497

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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Iara Linhares

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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