EUROPEAN UROLOGY 63 (2013)

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1 EUROPEAN UROLOGY 63 (2013) available at journal homepage: Pelvic Pain National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) Symptom Evaluation in Multinational Cohorts of Patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome Florian M.E. Wagenlehner a, *,y, J.W. Olivier van Till b,y, Vittorio Magri c, Gianpaolo Perletti d, Jos G.A. Houbiers b, Wolfgang Weidner a, J. Curtis Nickel e a Department of Urology, Pediatric Urology and Andrology, Justus-Liebig-University, Giessen, Germany; b Global Medical Science, Astellas Pharma Europe, Leiderdorp, The Netherlands; c Urology and Sonography Outpatient Clinic, Azienda Ospedaliera Istituti Clinici di Perfezionamento, Milan, Italy; d Biomedical Research Division, Department of Theoretical and Applied Sciences, Università degli Studi dell Insubria, Busto A./Varese, Italy; e Department of Urology, Queen s University, Kingston, Ontario, Canada Article info Article history: Accepted October 24, 2012 Published online ahead of print on November 2, 2012 Keywords: Chronic prostatitis/chronic pelvic pain syndrome Prostatitis syndrome Chronic Prostatitis Symptom Index NIH-CPSI Pain interference Quality of life Abstract Background: The assessment of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in everyday practice and clinical studies relies on National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) scores for symptom appraisal, inclusion criteria for clinical trials, follow-up, and response evaluation. Objective: We investigated multiple databases of CP/CPPS patients to determine the prevalence and impact of pain locations and types to improve our strategy of individualized phenotypically guided treatment. Design, setting, and participants: Four major databases with CPSI scores for nonselected CP/CPPS clinic patients from Canada, Germany, Italy, and the United States. Outcome measurements and statistical analysis: Individual question scores and subtotal and total scores of CPSI were described and correlated with each other. Ordinal regression analysis was performed to define pain severity categories. Results and limitations: A total of 1563 CP/CPPS patients were included. Perineal pain/ discomfort was the most prevalent pain symptom (63%) followed by testicular pain (58%), pain in the pubic area (42%) and penis (32%); reports of pain during ejaculation and voiding were 45% and 43%, respectively. European patients had a significantly higher number of pain localizations and symptoms compared with North American patients ( p < 0.001). Severity of pain correlated well with frequency of pain (r = 0.645). No specific pain localization/type was associated with more severe pain. Correlation of pain domain with quality of life (QoL) (r = 0.678) was higher than the urinary domain (r = 0.320). Individually, pain severity (r = 0.627) and pain frequency (r = 0.594) correlated better with QoL than pain localization (r = 0.354). Pain severity categories results for NIH-CPSI item 4 (0 10 numerical rating scale for average pain) were mild, 0 3; moderate, 4 6; severe, 7 10; CPSI pain domain (0 21): mild, 0 7; moderate, 8 13; and severe, Conclusions: Pain has more impact on QoL than urinary symptoms. Pain severity and frequency are more important than pain localization/type. Cut-off levels for disease severity categories have been identified that will prove valuable in symptom assessment and the development of therapeutic strategies. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. y These authors contributed equally to the study. * Corresponding author. Department of Urology, Pediatric Urology and Andrology, Justus-Liebig- University, Giessen, Rudolf-Buchheim-Str. 7, Giessen, Germany. Tel ; Fax: address: Wagenlehner@aol.com (F.M.E. Wagenlehner) /$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

2 954 EUROPEAN UROLOGY 63 (2013) Introduction 2.1. Statistical methods Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a frequently occurring disease [1,2] with a complex and heterogeneous etiology. The syndrome is characterized by pelvic pain, voiding symptoms, and additional phenotypic signs that are still poorly defined. Specific biomarkers for diagnosis and disease severity assessment are not available. The current diagnosis and clinical monitoring of CP/CPPS patients is based on multiple investigations including structured symptom assessment and the exclusion of obvious etiologic causes such as bacterial pathogens. To structure the assessment of CP/CPPS patients, the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) was developed in 1999 [3]. The NIH-CPSI is a formally developed and psychometrically validated instrument for the evaluation of CP/CPPS symptoms. It contains 13 items that are scored in three discrete domains: pain, urinary symptoms, and the impact on quality of life (QoL). In early studies, the NIH-CPSI was shown to be reliable and valid [4]. The NIH-CPSI total score and pain and QoL subscores are responsive to change [5]. A re-scored questionnaire was also evaluated, and although the rescored NIH-CPSI provided better face validity than the standard score, additional calculation efforts were required that yielded only marginal improvements in performance [6]. The original NIH-CPSI therefore currently provides a valid assessment tool and outcome measure in the management of men with CP/CPPS, which is also commonly used in clinical trials [7 12], as well as in the evidencebased evaluation of treatment effects [13 15]. However, patient cohorts included in clinical trials are often highly selected populations and do not necessarily reflect the clinical situation. Treatment strategies currently follow a more individualized, phenotypically based approach, where symptom quality assessment and the impact on health are drivers of patient management [16 19]. In this study we assessed the symptom characteristics of a multinational unbiased, nonselected population of CP/ CPPS patients by NIH-CPSI; investigated the prevalence and impact of symptoms on QoL in this cross-sectional clinical population of CP/CPPS patients; and established cut-off values for pain severity categories. 2. Materials and methods Four major databases with CPSI scores for nonselected CP/CPPS clinic patients from Canada, Germany, Italy, and the United States/Canada were included in this investigator-initiated nonprofit study. Of 1638 patients, 1563 patients (95.4%) with complete data from the NIH-CPSI score were selected for further analysis. The individual question (Q) scores, subdomain scores, and total scores of the NIH-CPSI questionnaire are described. The pain localization (Q1A, Q1B, Q1C, Q1D), pain symptom (Q2A, Q2B), and pain quality questions (Q3 [pain frequency], Q4 [pain severity]) were related to each other. The impact of pain and voiding symptoms was calculated by correlating the individual question scores and subdomain scores with the QoL questions and subdomain. Validated NIH-CPSI translations in German or Italian were administered to European patients [20,21]. Averages of these ordinal scores are shown as means (standard deviation [SD]) to allow for comparison with literature, but also as median (interquartile range [IQR]). For a comparison of independent samples, the nonparametric Mann-Whitney U test was used (a two-sided p value <0.05 was considered statistically significant). The chi-square test was calculated to test the null hypothesis for independence of pain symptoms versus urinary symptoms or QoL, and the nonparametric Spearman rank correlation (r) coefficient was used to investigate the relationship between two ordered categorical variables. The closer the value of r to either +1 or 1, the stronger the correlation. The method for determining the optimal cut-off values of pain severity for mild, moderate, and severe pain in CP/CPPS was adapted from Serlin et al. [22] and Jensen et al. [23]. The subject s pain intensity was rated as mild, moderate, or severe using the numerical rating scale (NRS) (Q4; range: 0 10) and the pain domain score (Q1 4; range: 0 21) of the NIH-CPSI and calculating its pain interference. The NIH-CPSI total scores were not examined because the measure for pain interference would be part of the NIH-CPSI total score. Pain interference is the extent to which pain interfered with daily activities and QoL as represented by the QoL/impact domain of the NIH-CPSI (Q7 9), ranging from 0 to 12. Traditionally, on a 0 10 NRS, pain severity of 3 or 4 has been the upper boundary for mild pain, 4 or 5 the lower boundary for moderate pain, 6 or 7 the upper boundary for moderate pain, and 7 or 8 the lower boundary for severe pain. Thus there are four commonly used combinations of these boundary points [22]: CP (cut-off point upper limit of mild/moderate) 3/6: mild 1 3, moderate 4 6, severe 7 10 CP3/7: mild 1 3, moderate 4 7, severe 8 10 CP4/7: mild 1 4, moderate 5 7, severe 8 10 CP4/6: mild 1 4, moderate 5 6, severe 7 10 A series of four analyses were performed using ordinal regression with classification group (mild, moderate, severe) as the grouping variable and pain interference as the dependent variable to determine which cut-offs were most able to distinguish mild from moderate and moderate from severe pain. A similar analysis was performed to identify severity categories of the NIH-CPSI pain domain. Nickel et al. suggested a pain domain score 8 is moderate/severe [1]. The cut-off value between moderate and severe has never been identified. Cut-off point combinations to identify severity categories of the pain domain were set around both tertiles: cutoff points for mild/moderate were analyzed at 6, 7, or 8, and cut-off points for moderate/severe at 13, 14, and 15. Thus nine possible cut-off combinations were analyzed. The chi-square test was applied as an indicator of the degree of relation between the scores in the pain categories and the pain interference. The chi-square statistic indicated the degree of relation between the scores in the pain categories and the pain interference using various cut-off values of pain severity. The most optimal classification strategy (the one that uses cut-offs where the greatest difference in pain interference occurs) could therefore be identified as that classification strategy associated with the largest chi-square value. 3. Results The mean (SD) total NIH-CPSI of the whole group was 20.4 (7.8) and the median (IQR) 21 (15 26) (Fig. 1; Table 1). The differences between North American (n = 379) and European (n = 1184) groups in total CPSI, pain domain (due to a higher number of pain localizations and symptoms in the European patients), and QoL domain scores were

3 [(Fig._1)TD$FIG] EUROPEAN UROLOGY 63 (2013) Fig. 1 Total National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) distribution of all patients (n = 1563; mean: 20.4 [standard deviation: 7.8]). statistically significant ( p < 0.001), except for urinary domain ( p = 0.405) (Table 1). The age difference in patients of different continents was 3.7 yr (95% confidence interval [CI], ; p < 0.001; Table 1). Within the pain domain, the most common localization of pain was the perineum, followed by testicular pain, ejaculatory pain, dysuria, pain in the pubic area, and pain in the tip of the penis (Table 2). There were no significant differences in total CPSI and subscores between the different pain localizations (Table 2). Odds ratios (ORs) (95% CI) for patients with perineal pain also having dysuria were 1.39 ( ) or ejaculatory pain were 1.77 ( ), with testicular pain and dysuria 1.33 ( ) or ejaculatory pain 1.68 ( ), with pain in the tip of the penis and dysuria 2.77 ( ) or ejaculatory pain 2.29 ( ), and with pain in the pubic area and dysuria 1.59 ( ) or ejaculatory pain 1.90 ( ). Therefore patients with pain in the tip of the penis had proportionately more dysuria and ejaculatory pain. Patients with dysuria also had significantly ( p < 0.001) more ejaculatory pain (OR: 3.15; 95% CI, ). Patients with various positive pain localizations and pain symptoms had approximately the same outcomes in pain severity measured by the NRS in the NIH-CPSI. However, when patients had higher numbers of pain localizations and symptoms, the severity of pain, urinary symptoms, QoL, and overall disease also increased (Table 3) (Spearman rank correlation of number of pain localizations/symptoms with the CPSI total score: 0.611). To evaluate the impact of symptoms on QoL, pain qualities and quantities, and the urinary domain were correlated with the QoL domain, showing that frequency and intensity of pain had the highest impact on QoL (Table 4). The urinary domain did not significantly correlate with QoL (Table 4). In the development of the NIH-CPSI, it Table 1 Databases of patients * Nationality n (%) Age, yr Q4 score Total NIH-CPSI score Pain domain score Urinary domain score QoL domain score All 1563 (100) 47.2 (15.7) 4.0 (2.4) 4 (2 6) 20.4 (7.8) 21 (15 26) 9.4 (4.1) 9 (7 12) 3.9 (2.6) 4 (2 6) 7.1 (2.9) 7 (5 9) Canadian A 136 (8.7) 50.2 (14.1) 3.9 (2.3) 4 (3 5) 19.5 (8.3) 20 (14 24) 9.0 (4.6) 9 (6 12) 4.1 (2.8) 4 (2 6) 6.5 (2.7) 7 (5 8) Canadian/ 243 (15.5) 47.8 (11.3) 3.3 (2.4) 3 (1 5) 16.8 (9.2) 16 (10 23) 7.9 (4.7) 8 (4 11) 3.7 (2.6) 3 (2 6) 5.2 (3.2) 5 (3 7) American B German 249 (15.9) 44.3 (12.1) 5.0 (2.3) 5 (3 7) 23.7 (7.3) 24 (10 28) 11.2 (4.1) 12 (9 14) 3.7 (2.8) 3 (1 6) 8.7 (2.5) 9 (7 11) Italian 935 (59.8) 46.4 (13.6) 3.9 (2.1) 4 (2 5) 20.7 (7.0) 21 (16 25) 9.4 (3.6) 9 (7 12) 4.0 (2.6) 4 (2 6) 7.3 (2.7) 8 (5 9) North American (24.2) 49.0 (12.9) 3.5 (2.4) 3 (2 5) 17.8 (8.9) 17 (11 24) 8.3 (4.7) 8 (5 11) 3.9 (2.7) 3 (2 6) 5.7 (3.1) 5 (3 8) European (75.8) 45.3 (13.6) 4.2 (2.2) 4 (2 6) 21.3 (7.1) 21 (16 26) 9.8 (3.8) 10 (7 12) 3.9 (2.6) 4 (2 6) 7.6 (2.7) 8 (6 10) IQR = interquartile range; NIH-CPSI = National Institutes of Health Chronic Prostatitis Symptom Index; QoL = quality of life; SD = standard deviation. * Mean (SD)/median (IQR). 1 = A plus B; 2 = German plus Italian cohort; A = Canadian prostatitis, interstitial cystitis, and epididymitis cohort [24]; B = Chronic Prostatitis Cohort [25]. Table 2 Distribution of pain localizations and symptoms * Pain localization n (%) Q4 score Total NIH-CPSI score Pain domain score Urinary domain score QoL domain score Perineal (Q1a) 990 (63.3) 4.3 (2.1) 4 (3 6) 22.3 (7.2) 22 (17 27) 10.5 (3.6) 10 (8 13) 4.2 (2.6) 4 (2 6) 7.6 (2.7) 8 (6 10) Testicular (Q1b) 900 (57.6) 4.4 (2.1) 4 (3 6) 22.6 (7.2) 23 (17 27) 10.7 (3.6) 10 (8 13) 4.2 (2.7) 4 (2 6) 7.7 (2.7) 8 (6 10) Tip of penis (Q1c) 506 (32.4) 4.6 (2.2) 4 (3 6) 23.8 (7.5) 24 (18 30) 11.4 (3.8) 12 (9 14) 4.4 (2.7) 4 (2 6) 8.0 (2.7) 8 (6 10) Pubic area (Q1d) 661 (42.3) 4.5 (2.2) 4 (3 6) 23.5 (7.3) 24 (18 29) 11.0 (3.7) 11 (8 14) 4.6 (2.7) 5 (2 7) 7.8 (2.8) 8 (6 10) Dysuria (Q2a) 676 (43.3) 4.6 (2.2) 4 (3 6) 23.8 (7.2) 24 (18 29) 11.3 (3.6) 11 (9 14) 4.5 (2.7) 4 (2 6) 8.0 (2.7) 8 (6 10) Ejaculatory pain (Q2b) 699 (44.7) 4.6 (2.2) 4 (3 6) 23.7 (7.1) 24 (19 29) 11.4 (3.6) 11 (9 14) 4.4 (2.6) 4 (2 6) 7.9 (2.7) 8 (6 10) IQR = interquartile range; NIH-CPSI = National Institutes of Health Chronic Prostatitis Symptom Index; QoL = quality of life; SD = standard deviation. * Mean (SD)/median (IQR). Q1a to Q2b = individual questions of the pain localizations and symptoms of the NIH-CPSI questionnaire.

4 956 EUROPEAN UROLOGY 63 (2013) Table 3 Number of pain localizations and pain symptoms with corresponding pain intensity (0 10 numerical rating scale), and pain, urinary, and quality-of-life domain scores * n y No. of patients (%) Q4 (NRS) score Total NIH-CPSI score Pain domain score Urinary domain score QoL domain score 0 79 (5.1) 0.9 (1.6) 0 (0 1) 7.4 (5.1) 7 (3 10) 1.5 (2.2) 0 (0 2) 2.4 (2.0) 2 (1 4) 3.5 (2.7) 3 (1 5) (15.7) 3.3 (2.0) 3 (2 5) 15.5 (6.1) 15 (10 20) 6.5 (2.8) 6 (4 8) 3.2 (2.6) 3 (1 5) 5.8 (2.8) 6 (4 8) (24.7) 3.7 (2.0) 4 (2 5) 18.2 (5.7) 18 (14 22) 8.1 (2.6) 8 (6 10) 3.5 (2.4) 3 (2 5) 6.6 (2.7) 7 (5 9) (21.6) 4.2 (2.1) 4 (3 6) 21.2 (5.8) 21 (17 25) 9.9 (2.8) 9 (8 12) 3.8 (2.4) 4 (2 6) 7.5 (2.7) 8 (6 9) (16.4) 4.5 (2.1) 4 (3 6) 24.0 (6.1) 24 (20 29) 11.5 (2.8) 11 (10 13) 4.5 (2.6) 5 (2 6) 8.0 (2.5) 8 (6 10) (11.3) 5.1 (2.0) 5 (4 7) 26.8 (6.0) 26 (23 31) 13.1 (2.7) 13 (11 15) 5.0 (2.7) 5 (3 7) 8.7 (2.5) 9 (7 11) 6 81 (5.2) 5.6 (2.3) 6 (4 8) 30.4 (6.3) 30 (27 35) 15.1 (3.1) 16 (12 18) 6.0 (2.7) 6 (4 8) 9.3 (2.3) 10 (9 11) IQR = interquartile range; NIH-CPSI = National Institutes of Health Chronic Prostatitis Symptom Index; NRS = numerical rating scale; QoL = quality of life; SD = standard deviation. * Mean (SD)/median (IQR). y Number of pain localizations (Q1a d) and symptoms (Q2a, Q2b). Table 4 Correlation of pain localizations, symptoms, frequency, severity, and urinary domain with quality-of-life domain and overall quality of life Parameter QoL domain Overall QoL (Q9) Chi-square test Spearman r Chi-square test Spearman r Pain localizations Pain symptoms Pain localizations and symptoms Pain frequency Pain intensity Pain frequency and intensity Pain domain Urinary domain QoL = quality of life. Table 5 Chi-square test values of ordinal regression analyses comparing pain interference of (a) pain severity (numerical rating scale 0 10) with quality of life (QoL) domain scores of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) patients, classified as mild, moderate, and severe, using four classification procedures, and (b) the pain domain score (range: 0 21) with QoL domain scores of CP/CPPS patients, classified as mild, moderate, and severe, using nine classification procedures a. Classification procedures Chi-square test CP3/6 618 CP3/7 589 CP4/6 561 CP4/7 557 b. Classification procedures Chi-square test CP6/ CP6/ CP6/ CP7/ CP7/ CP7/ CP8/ CP8/ CP8/ CP = cut-off point of upper limit of mild/moderate. was shown that overall QoL was best captured with this item: How would subjects feel if they were to spend the rest of their life with their pelvic symptoms just as they had been during the last week (Q9) [3]. Table 4 shows that pain frequency and pain severity had the biggest impact on overall QoL (Q9), whereas pain localizations or symptoms and urinary symptoms had a rather small impact. The disease severity categories (mild/moderate/severe) based on pain interference (QoL domain) scores using the pain NRS (Q4) predicted the largest differences in the QoL domain between the classification groups using the cut-offs mild, 0 3; moderate, 4 6; and severe, 7 10 (Table 5). The disease severity categories using the full pain domain score predicted the largest differences using the cut-offs 0 7 for mild pain, 8 13 for moderate pain, and for severe pain (Table 5). Applying these cut-offs to our patient sample, 45.0% (n = 703) and 31.9% (n = 499) of patients could be grouped in the mild pain category using NRS or the pain domain score, respectively, 39.1% (n = 611) and 52.2% (n = 816) in the moderate category, and 15.9% (n = 249) and 15.8% (n = 248) in the severe category. Corresponding QoL domain scores (median [IQR]) increased from mild, moderate, to severe disease severity categories: 5 (3 7), 8 (6 9), and 10 (9 11), respectively (NRS categories); 5 (3 6), 8 (6 9), and 11 (9 12), respectively (pain domain categories).

5 EUROPEAN UROLOGY 63 (2013) Discussion With the novel phenotype-directed treatment approaches in CP/CPPS patients [16 18], it is of interest to define the most important phenotypes to be treated. In this multicenter multinational study, 1563 nonselected CP/CPPS clinic patients from Canada [24,25], Germany [17], Italy [17], and the United States [25] were evaluated to determine the prevalence of pain localizations and symptoms, pain quality and quantity, urinary symptoms, and the impact of pain on QoL using the NIH-CPSI items. This unique patient cohort had the advantage of not undergoing selection processes by inclusion and exclusion criteria defined by different study designs but were unselected patients, seen and diagnosed with CP/CPPS by expert urologists. The difference between patients from North America and Europe could be explained in various ways: (1) North American patients were significantly older than European patients, and younger age has been associated with more CP/CPPS symptoms [26] and worse QoL [27]. (2) The NIH- CPSI exhibited different test reliability and internal consistency in different languages: The German translation showed a lower internal consistency of the pain domain than the original English and the Italian versions with Cronbach a values of 0.60, 0.86, and 0.84, respectively [3,20,28]. (3) Almost 75% of the included patients were from Europe, introducing a possible bias. The statistical evaluations showed that pain had more impact on QoL than urinary symptoms. This is in line with study findings on the responsiveness of the NIH-CPSI, showing that total, pain, and QoL scores were more responsive than the urinary score in those patients who improved [5]. Urinary symptoms are cited in the NIH-CPSI in only 2 of 13 items, possibly underrepresenting this phenotype domain [3]. However, in the development process of the NIH-CPSI, the urinary questions were derived from the 7-item American Urological Association symptom index [29], selecting the two questions having a higher correlation with the CP/CPPS group compared with the benign prostatic hyperplasia (BPH) and control groups [3]. Regarding pain perception, pain severity and frequency are more important than pain localization or pain symptoms. Furthermore, the impact of pain on the patient s daily activities is important information to be acquired because it enables the practicing urologist to judge the disabling aspects of the disease. This impact is frequently evaluated by measuring pain interference, which describes the extent to which pain interferes with daily activities or QoL. QoL is a prominent item in the NIH-CPSI questionnaire, depicted by three questions (Q7, Q8, Q9) forming the QoL domain (ranging from 0 to 12). Research among people with different chronic pain conditions, such as cancer pain, back pain, or amputation pain, suggests that the degree of pain interference with QoL varies with the different types of pain [23]. Therefore each chronic pain condition has to be evaluated separately. It has also been shown that the association between pain intensity and pain interference is nonlinear, which means that pain begins to have a serious impact on QoL when it reaches a certain threshold level, and frequently a second pain threshold can be identified that, once reached, shows an even greater proportional negative impact on QoL, which supports the potential clinical utility of classifying pain as mild, moderate, or severe [23]. A study in young men showed that relative to men with mild pain, men experiencing moderate or severe pain had a 4- to 16- fold risk of poor QoL [30]. Research on the management of chronic pain has shown that clinicians can make more informed decisions regarding the goals of treatment when using pain intensity cut-offs [22,23,31]. The categorization cut-off levels found in this cohort of patients with chronic pelvic pain were evaluated using the NRS as well as the full pain domain of the NIH-CPSI. This categorization of patients will greatly help the practicing urologist to phenotype and select those patients that need more intensive treatment, such as combination treatments including peripheral analgesics and antidepressants or anticonvulsants [32]. More intensive pain treatment is therefore important for those patients having moderate and severe pain, which is where more focus is needed, both in clinical routine and research, evaluating new compounds as well as those available compounds in appropriate clinical studies. The results from this study will also provide a valuable and more precise identification of subjects using a NRS or the CPSI in population prevalence assessments of CP/CPPS. In the final validation study for the NIH-CPSI, which included 524 patients with prostatitis syndrome, BPH, and normal controls, it was noted that pain and/or discomfort in the perineum or on ejaculation were the most specific symptoms for a diagnosis of prostatitis syndrome, and a value 4 in the pain domain score was believed to represent a reasonable cut-off point to distinguish patients with prostatitis syndrome from normal controls and those with BPH [1,3]. Based on these studies, patients with possible CP/ CPPS were defined as those with a pain domain score 4, and pain in the perineum and on ejaculation. Many studies on the prevalence of CP/CPPS have been based on this definition [1,33 35]. However, in our sample, 25% of patients (n = 391) did not report these prostatitis-like symptoms. Therefore the NIH-CPSI definitions covered only 75% of patients with a clinical diagnosis of CP/CPPS in our large patient cohort study, which means that the prevalence in uncontrolled populations might be higher than those reported in the literature. 5. Conclusions This large multinational, population-based cohort study in nonselected CP/CPPS patients evaluating NIH-CPSI data showed that pain intensity has the most important impact on QoL. Cut-off levels for pain and disease severity categories have been identified to guide patient categorization for treatment and research. Author contributions: Florian M.E. Wagenlehner had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Wagenlehner, van Till, Magri, Perletti, Houbiers, Weidner, Nickel.

6 958 EUROPEAN UROLOGY 63 (2013) Acquisition of data: Wagenlehner, Magri, Perletti, Nickel. Analysis and interpretation of data: Wagenlehner, van Till, Magri, Perletti, Houbiers, Weidner, Nickel. Drafting of the manuscript: Wagenlehner, van Till. Critical revision of the manuscript for important intellectual content: Wagenlehner, van Till, Magri, Perletti, Houbiers, Weidner, Nickel. Statistical analysis: van Till, Houbiers, Wagenlehner. Obtaining funding: None. Administrative, technical, or material support: Wagenlehner, van Till, Magri, Perletti, Houbiers, Weidner, Nickel. Supervision: Wagenlehner, van Till. Other (specify): None. Financial disclosures: Florian M.E. Wagenlehner certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: J.W. Olivier van Till and Jos G.A. Houbiers are employees of Astellas. Florian M.E. Wagenlehner, J. Curtis Nickel, and Gianpaolo Perletti are members of the Astellas advisory board. The other authors have nothing to disclose. Funding/Support and role of the sponsor: None. Acknowledgment statement: The authors acknowledge Reynaldo Martina for help with the statistical analyses. References [1] Nickel JC, Downey J, Hunter D, Clark J. Prevalence of prostatitis-like symptoms in a population based study using the National Institutes of Health chronic prostatitis symptom index. 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