Michel A. Pontari

THE NATIONAL INSTITUTES OF HEALTH CHRONIC PROSTATITIS SYMPTOM INDEX: DEVELOPMENT AND VALIDATION OF A NEW OUTCOME MEASURE

AbstractPurpose: Chronic abacterial prostatitis is a syndrome characterized by pelvic pain and voiding symptoms, which is poorly defined, poorly understood, poorly treated and bothersome. Research and clinical efforts to help men with this syndrome have been hampered by the absence of a widely accepted, reliable and valid instrument to measure symptoms and quality of life impact. We developed a psychometrically valid index of symptoms and quality of life impact for men with chronic prostatitis.Materials and Methods: We conducted a structured literature review of previous work to provide a foundation for the new instrument. We then conducted a series of focus groups comprising chronic prostatitis patients at 4 centers in North America, in which we identified the most important symptoms and effects of the condition. The results were used to create an initial draft of 55 questions that were used for formal cognitive testing on chronic prostatitis patients at the same centers. After expert panel review formal...

Ciprofloxacin or Tamsulosin in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Randomized, Double-Blind Trial

Context Although the cause of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is unknown, physicians sometimes try to treat it with antibiotics or -receptor blockers. Contribution In this multicenter, double-blind factorial trial, 196 men with moderately severe CP/CPPS were randomly assigned to 6 weeks of treatment with ciprofloxacin, tamsulosin, both drugs, or placebo. Neither ciprofloxacin nor tamsulosin substantively reduced symptoms. Implications Ciprofloxacin and tamsulosin were not effective treatments for CP/CPPS. Cautions Patients had long-standing, refractory CP/CPPS and received trial treatments for only 6 weeks. Patients with new diagnoses who are given longer courses of the trial treatments might respond differently. The Editors Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder and accounts for approximately 2 million visits to physicians annually in the United States (1). The substantial impact of CP/CPPS includes bothersome lower urinary tract symptoms, sexual dysfunction, reduced quality of life (2-5), and increased health care expenditures (6). The syndrome is diagnosed only on the basis of symptoms, principally pain or discomfort in the pelvic region. No objective measures can help define the disease. Although bacteria can infect the prostate, most men with prostatitis have a negative midstream urine culture, indicating that bacteria may not be the cause of their symptoms (2). Such men are classified as having National Institutes of Health (NIH) category III prostatitis, the most common of the clinically defined prostatitis syndromes (7). It is by no means clear that the disease is characterized by inflammation of the prostate or that the prostate is responsible for symptoms in a substantial proportion of patients. Because of this uncertainty, the term CP/CPPS is used. Chronic prostatitis/chronic pelvic pain syndrome is commonly seen by primary care practitioners, internists, and urologists. In the Olmsted County Study of Urinary Symptoms and Health Status Among Men (8), a population-based study in Olmstead County, Minnesota, the overall prevalence rate of a physician-assigned diagnosis of prostatitis was 9%. Population-based surveys of symptoms have estimated that the prevalence of the syndrome ranges from 9% to 12% among men (9, 10). It is difficult to estimate the proportion of patients with symptoms lasting longer than 3 months whose disorder remains refractory to empirical therapy. These patients are commonly seen by urologists, but whether they represent a minor subpopulation of the overall symptomatic group or make up the majority of patients is unknown. We chose to study these patients because they present with a troubling, long-standing problem and are usually treated with agents of unclear benefit. Even if a relatively large number of men whose symptoms last 3 months or more are cured by standard empirical therapy and the clinical scenario we describe is uncommon, men with refractory symptoms still present a substantial problem to internists and urologists who have little information to guide therapy. Because the cause of CP/CPPS is unknown, affected men receive many empirical therapies. The 2 most common treatments prescribed by physicians are antimicrobial agents and -adrenergic receptor antagonists (2), although there is little objective evidence to support their use (11). Quinolones, such as ciprofloxacin, are commonly used to treat CP/CPPS because of their excellent penetration into the prostate and broad spectrum of coverage for uropathogens and other organisms traditionally believed to be associated with the syndrome (12). Tamsulosin, an -blocker, is an effective treatment for lower urinary tract symptoms in men with benign prostatic hyperplasia, and it has been hypothesized that tamsulosin may improve these symptoms in men with CP/CPPS. This randomized clinical trial was designed to evaluate whether ciprofloxacin or tamsulosin reduces symptoms of long-standing CP/CPPS of at least moderate severity, typical of the 488 men in our Chronic Prostatitis Cohort Study (2). The primary purpose of the trial was to test the most common prescription treatments given to men with CP/CPPS, who are commonly seen in our referral-based urologic practices. Methods Organization The Chronic Prostatitis Collaborative Research Network, a consortium sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), conducted the trial. Urologists and their clinical associates recruited patients at 10 sites in the United States and 1 site in Canada. The NIDDK established an independent data and safety monitoring board to review the progress, safety, and final analysis of the trial. The individual institutional review boards at each of the 10 participating clinical centers approved the study, and all men gave written informed consent. Participants The design of this trial has been described in detail previously (13). Participating urologists recruited both newly referred patients and patients with established CP/CPPS from their referral-based clinical practices at 10 tertiary medical centers in North America. Trial referrals came from primary care providers, internists, and other urologists. The primary diagnostic criterion was pain or discomfort in the pelvic region for at least 3 months in the previous 6 months. Severity of symptoms was assessed by using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) (14, 15). This instrument is a validated questionnaire, completed by the patient, consisting of 4 questions about pain, 3 about voiding symptoms, and 2 about quality of life. The scores in these 3 individual domains (pain, voiding, and quality of life) are combined without weighting to yield the NIH-CPSI total score. Eligible men were required to have at least moderate symptoms, defined as an NIH-CPSI score of at least 15 of 43 possible points, at the time of randomization. We excluded men who had a documented urinary tract infection (midstream urine culture > 100000 colonies/mL) within the past 3 months, a history of active genital herpes within the previous year, a history of genitourinary cancer, inflammatory bowel disease, active urethral stricture, prostate or bladder surgery, or neurologic disease affecting the bladder. We used ligase chain reaction to screen for Chlamydia in urethral urine samples and excluded men whose tests yielded positive results. Previous treatment with antimicrobial agents or -adrenergic receptor blockers, including the study drugs, had to be completed at least 4 weeks before eligibility screening. Additional details of the eligibility criteria are available elsewhere (13). Study Design and Interventions Men were randomly assigned in equal proportions within a 2 2 factorial design to receive placebo; ciprofloxacin alone, 500 mg twice daily; tamsulosin alone, 0.4 mg once daily; or a combination of both drugs (Table 1). Patients were treated for 6 weeks, at which time the primary end point was assessed. Symptoms at 9 and 12 weeks after randomization (6 weeks after completion of treatment) were also assessed to evaluate longer-term treatment response. The 2 baseline screening contacts and the primary end point contact at 6 weeks were clinic visits; interim contacts at 3, 9, and 12 weeks were conducted by telephone. Table 1. Study Design Each patient was randomly assigned by computer. A permuted block randomization schedule with varying block sizes was used, stratified by clinical site. The research pharmacist at each site provided the blinded study drugs in 2 tamper-evident bottles. All clinical investigators, research nurses, and patients were blinded to treatment assignments until all patients had completed follow-up. Outcomes The primary outcome was the change in the NIH-CPSI total score from baseline to 6 weeks. The NIH-CPSI was administered at each of the 2 baseline screening visits, 1 to 3 weeks apart, and every 3 weeks thereafter until 12 weeks. The average of the 2 scores before randomization was used as the baseline score. Evaluation of the responsiveness of the NIH-CPSI indicates that a 4-point change on a scale of 0 to 43 points represents a difference detectable by the patient. Secondary outcomes included changes in the pain, voiding, and quality-of-life subscales of the NIH-CPSI; physical and mental summary scores on the Medical Outcomes Study 12-Item Short-Form Health Survey (16); and a 7-point patient-reported global response assessment. Responders for the global response assessment were defined as men reporting that they were markedly improved or moderately improved at 6 weeks compared with baseline. Men for whom the global response assessment was missing were considered nonresponders and were included in the denominator for the assessment of response rates. Adverse events were monitored throughout the study and graded according to the National Cancer Institute Common Toxicity Criteria (ctep.cancer.gov/reporting/ctc.html). Patients were asked at each contact to report any adverse events that had occurred since the previous contact. The questions were open-ended, and researchers did not ask about any specific categories of adverse events. All events, regardless of whether they were expected reactions to the study drugs, were recorded. Attribution to treatment was also assessed. However, because it was difficult to determine whether certain adverse events, such as pain, were related to treatment or to CP/CPPS, all events were analyzed. Statistical Analysis For each of the 2 primary treatment comparisons, the recruitment goal of 184 patients provided 80% power, at a 2-sided significance level of 5%, to detect a 4-point treatment difference in the NIH-CPSI total score between baseline and 6 weeks. We recognized that although patients could detect this difference, most might not perceive it as a major improvement. However, we did not want to miss even a minor change in

Quality of Life Is Impaired in Men with Chronic Prostatitis: The Chronic Prostatitis Collaborative Research Network

OBJECTIVE: Health-related quality of life (HRQOL) impairment may be a central component of chronic prostatitis for men afflicted with this condition. Our objective was to examine HRQOL, and factors associated with HRQOL, using both general and condition-specific instruments.DESIGN: Chronic Prostatis Cohort (CPC) study.SETTING: Six clinical research centers across the United States and Canada.PARTICIPANTS: Two hundred seventy-eight men with chronic prostatitis.MEASUREMENTS AND MAIN RESULTS: The Short Form 12 (SF-12) Mental Component Summary (MCS) and Physical Component Summary (PCS), and the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) were measures used. CPC subjects’ MCS scores (44.0±9.8) were lower than those observed in the most severe subgroups of patients with congestive heart failure and diabetes mellitus, and PCS scores (46.4±9.5) were worse than those among the general U.S. male population. Decreasing scores were seen in both domains with worsening symptom severity (P<.01). History of psychiatric disease and younger age were strongly associated with worse MCS scores, whereas history of rheumatologic disease was associated with worse PCS scores. Predictors of more severe NIH-CPSI scores included lower educational level and lower income; history of rheumatic disease was associated with higher scores.CONCLUSIONS: Men with chronic prostatitis experience impairment in the mental and physical domains of general HRQOL, as well as condition-specific HRQOL. To optimize the care of men with this condition, clinicians should consider administering HRQOL instruments to their patients to better understand the impact of the condition on patients’ lives.

LEUKOCYTE AND BACTERIAL COUNTS DO NOT CORRELATE WITH SEVERITY OF SYMPTOMS IN MEN WITH CHRONIC PROSTATITIS: THE NATIONAL INSTITUTES OF HEALTH CHRONIC PROSTATITIS COHORT STUDY

PURPOSE We examine whether leukocytes and bacteria correlate with symptom severity in men with chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS All 488 men screened into the National Institutes of Health Chronic Prostatitis Cohort Study before close of recruitment on August 22, 2001 were selected for analysis. The National Institutes of Health Chronic Prostatitis Symptom Index, including subscores, were used to measure symptoms. Urethral inflammation was defined as white blood cell (WBC) counts of 1 or more (1+) in the first voided urine. Participants were classified as category IIIa based on WBC counts of 5 or more, or 10 or more (5+, 10+) in the expressed prostatic secretion, or 1+ or 5+ either in the post-expressed prostatic secretion urine (voided urine 3) or semen. Uropathogens were classified as localizing if the designated bacterial species were absent in voided urine 1 and voided urine 2 but present in expressed prostatic secretion, voided urine 3 or semen, or present in expressed prostatic secretion, voided urine 3 or semen at 2 log concentrations higher than at voided urine 1 or 2. Associations between symptoms, and inflammation and infection were investigated using generalized Mantel-Haenszel methods. RESULTS Of all participants 50% had urethral leukocytes and of 397 with expressed prostatic secretion samples 194 (49%) and 122 (31%) had 5+ or 10+ WBCs in expressed prostatic secretion, respectively. The prevalence of category IIIa ranged from 90% to 54%, depending on the composite set of cut points. None of the index measures were statistically different (p >0.10) for selected leukocytosis subgroups. Based on prostate and semen cultures, 37 of 488 men (8%) had at least 1 localizing uropathogen. None of the index measures were statistically different (p >0.10) for selected bacterial culture subgroups. CONCLUSIONS Although men with chronic prostatitis routinely receive anti-inflammatory and antimicrobial therapy, we found that leukocytes and bacterial counts as we defined them do not correlate with severity of symptoms. These findings suggest that factors other than leukocytes and bacteria also contribute to symptoms associated with chronic pelvic pain syndrome.

Interstitial Cystitis/Painful Bladder Syndrome and Associated Medical Conditions With an Emphasis on Irritable Bowel Syndrome, Fibromyalgia and Chronic Fatigue Syndrome

PURPOSE We characterized and compared the impact of clinical phenotypic associations between interstitial cystitis/painful bladder syndrome and controls in relation to potentially related conditions, particularly irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. MATERIALS AND METHODS Female patients with interstitial cystitis/painful bladder syndrome and controls with no interstitial cystitis/painful bladder syndrome completed a biopsychosocial phenotyping questionnaire battery which included demographics/history form, self-reported history of associated conditions, and 10 validated questionnaires focused on symptoms, suffering/coping and behavioral/social factors. RESULTS Questionnaires were completed by 205 patients with interstitial cystitis/painful bladder syndrome and 117 controls matched for age. Prevalence of self-reported associated condition diagnosis in interstitial cystitis/painful bladder syndrome vs controls was irritable bowel syndrome 38.6% vs 5.2%, fibromyalgia 17.7% vs 2.6% and chronic fatigue syndrome 9.5% vs 1.7% (all p <0.001). In the interstitial cystitis/painful bladder syndrome cohort 50.3% reported no other associated condition, 24.4% had interstitial cystitis/painful bladder syndrome + irritable bowel syndrome only, 2.5% had interstitial cystitis/painful bladder syndrome + fibromyalgia only, 1.5% had interstitial cystitis/painful bladder syndrome + chronic fatigue syndrome only, while 20.2% had multiple associated conditions. As the number of associated conditions increased (ie localized, regional, systemic), pain, stress, depression and sleep disturbance increased while social support, sexual functioning and quality of life deteriorated. Anxiety and catastrophizing remained increased in all groups. Symptom duration was associated with this apparent phenotypic progression. CONCLUSIONS Irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome are more prevalent in patients with interstitial cystitis/painful bladder syndrome than in asymptomatic control subjects, and result in significant impact. There are at least 3 distinct clinical phenotypes based on identification of overlapping syndrome patterns. A suggestion that remains to be proven with longitudinal studies is that there may be progression over time from an organ centric to a regional and finally to a systemic pain syndrome with progression of symptom severity, and deterioration of cognitive and psychosocial parameters.

Alfuzosin and Symptoms of Chronic Prostatitis–Chronic Pelvic Pain Syndrome

BACKGROUND In men with chronic prostatitis-chronic pelvic pain syndrome, treatment with alpha-adrenergic receptor blockers early in the course of the disorder has been reported to be effective in some, but not all, relatively small randomized trials. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of alfuzosin, an alpha-adrenergic receptor blocker, in reducing symptoms in men with chronic prostatitis-chronic pelvic pain syndrome. Participation in the study required diagnosis of the condition within the preceding 2 years and no previous treatment with an alpha-adrenergic receptor blocker. Men were randomly assigned to treatment for 12 weeks with either 10 mg of alfuzosin per day or placebo. The primary outcome was a reduction of at least 4 points (from baseline to 12 weeks) in the score on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) (range, 0 to 43; higher scores indicate more severe symptoms). A 4-point decrease is the minimal clinically significant difference in the score. RESULTS A total of 272 eligible participants underwent randomization, and in both study groups, 49.3% of participants had a decrease of at least 4 points in their total NIH-CPSI score (rate difference associated with alfuzosin, 0.1%; 95% confidence interval, -11.2 to 11.0; P=0.99). In addition, a global response assessment showed similar response rates at 12 weeks: 33.6% in the placebo group and 34.8% in the alfuzosin group (P=0.90). The rates of adverse events in the two groups were also similar. CONCLUSIONS Our findings do not support the use of alfuzosin to reduce the symptoms of chronic prostatitis-chronic pelvic pain syndrome in men who have not received prior treatment with an alpha-blocker. (ClinicalTrials.gov number, NCT00103402.)

Clinical phenotyping in chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis: a management strategy for urologic chronic pelvic pain syndromes.

The urologic chronic pain conditions such as chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis are syndromes whose evaluation and management are controversial. Part of the difficulty in diagnosis and therapy is the heterogeneity of etiologies and symptoms. We propose a six-domain phenotype, which can classify these patients clinically and can direct the selection of therapy in the most evidence based multimodal manner. The domains are urinary, psychosocial, organ specific, infection, neurologic and tenderness of skeletal muscles. This system is flexible and responsive to new biomarkers and therapies as their utility and efficacy are proven.

A randomized placebo-controlled multicentre study to evaluate the safety and efficacy of finasteride for male chronic pelvic pain syndrome (category IIIA chronic nonbacterial prostatitis)

To determine if finasteride can reduce symptoms in men with a clinical diagnosis of chronic nonbacterial prostatitis (National Institutes of Health, NIH, category IIIA chronic pelvic pain syndrome, CPPS) compared with placebo.

How Does the Pre-Massage and Post-Massage 2-Glass Test Compare to the Meares-Stamey 4-Glass Test in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome?

PURPOSE The Meares-Stamey 4-glass test is the standard method of assessing inflammation and the presence of bacteria in the lower urinary tract in men presenting with the chronic prostatitis syndrome. However, most urologists do not use it in daily practice because of the time and difficulty in performing it, as well as the additional expense. We evaluated a simpler test, the 2-glass pre-massage and post-massage test, and compared it with the Meares-Stamey 4-glass test to detect inflammation and bacteria in men with chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS The study population included 353 men enrolled in the National Institutes of Health Chronic Prostatitis Cohort study with baseline leukocyte counts and 2-day bacterial cultures on specimens obtained from a standard 4-glass test (VB1, VB2, expressed prostatic secretions, VB3). The chi-square test was performed to assess associations of white blood cell counts in expressed prostatic secretions and VB3. A receiver operating characteristic curve was constructed to determine the optimal cut point of white blood cells in VB3 in predicting white blood cells in expressed prostatic secretions. Sensitivity and specificity of VB3 cultures predicting expressed prostatic secretions and positive Meares-Stamey results were calculated from 2 x 2 contingency tables. RESULTS Analysis of binary leukocyte outcomes (no white blood cells vs any white blood cells) suggests that white blood cells tend to be present in expressed prostatic secretions when there are any white blood cells in VB3, p <0.0001, the optimal cut point being white blood cell counts of 3 in VB3 (best predictive ability with area under ROC 0.771) to predict 5+ in expressed prostatic secretions with a sensitivity of 76% and specificity of 70%. The optimal cut point of white blood cells in VB3 to predict 10 white blood cells in expressed prostatic secretions was 4 (62% sensitivity and 75% specificity). Uropathogens localizing to expressed prostatic secretions or VB3 confirms a positive 4-glass Meares-Stamey localization test. The sensitivity and specificity of a VB3 localizing culture only in predicting a positive Meares-Stamey 4-glass test result for any uropathogen were 44% to 54% (depending on definition) and 100%, respectively. The pre-massage and post-massage test predicted a correct diagnosis in more than 96% of subjects. CONCLUSIONS The value of localizing leukocytes and uropathogens to prostate specific specimens remains controversial in chronic heavily pretreated patients, but these data may help direct therapy (anti-inflammatory or antimicrobial) when obtained at first presentation. The pre-massage and post-massage test has strong concordance with the 4-glass test and is a reasonable alternative when expressed prostatic secretions are not obtained.

Psychosocial phenotyping in women with interstitial cystitis/painful bladder syndrome: a case control study.

PURPOSE We characterized and compared psychosocial phenotypes in a female interstitial cystitis/painful bladder syndrome cohort and an age matched cohort without that diagnosis. MATERIALS AND METHODS Female patients with interstitial cystitis/painful bladder syndrome and controls without the condition completed a psychosocial phenotyping questionnaire battery, including a demographics/history form and validated questionnaires focused on a range of presenting symptoms, psychosocial parameters and quality of life. Specific measures included interstitial cystitis symptom and problem index, McGill Pain Questionnaire, Medical Outcomes Study Sleep Scale, Center for Epidemiological Studies Depression Scale, State-Trait Anxiety Inventory, Pain Catastrophizing Scale, Female Sexual Functioning Index and Multidimensional Scale of Perceived Social Support and Medical Outcomes Study Short Form-12 quality of life. Direct comparisons and correlations were made to establish group differences and the strength of associations for psychosocial parameters in patients with interstitial cystitis/painful bladder syndrome. RESULTS Questionnaires completed by 207 patients with interstitial cystitis/painful bladder syndrome were compared to those of 117 controls matched for age, partner status and education. Compared to controls patients reported significantly more pain (total, sensory and affective), worse physical quality of life, increased sleep dysfunction, depression, catastrophizing, anxiety, stress and moderately more sexual/social function problems. These suffering, coping and social parameters correlated with the degree of general pain but stress, anxiety, depression and catastrophizing further correlated with IC specific symptoms and strongly with decreased quality of life. Pain was strongly associated with physical quality of life, while depression, catastrophizing and stress, and to a lesser extent social support were associated with poor mental quality of life. CONCLUSIONS Patients with interstitial cystitis/painful bladder syndrome have significant cognitive and psychosocial alterations compared to controls.