eau-ebu update series 5 (2007) 1–15 available at www.sciencedirect.com journal homepage: www.europeanurology.com Chronic Prostatitis Syndrome: A Common, but Poorly Understood Condition. Part I Michele Pavone-Macaluso * Chair of Urology, Paolo Giaccone Polyclinic Hospital, University of Palermo, via del Vespro 129, 90127 Palermo, Italy Article info Abstract Keywords: Chronic prostatitis Pelvic pain Chlamydia Interstitial cystitis Classification Chronic Prostatitis Syndrome (CPS) is a frequent disease. Before the PSA era, data from various sources showed that there were more outpatient visits for CPS than for BPH or prostate cancer. CPS has a very negative impact on the patients’ quality of life. However, this debilitating disease stimulates relatively little enthusiasm in the urological world. The classification proposed by the National Institutes of Health is widely adopted. The disease is described as ‘‘Chronic Prostatitis/Chronic Pelvic Pain Syndrome’’ and considers four categories. Category III includes Chronic Inflammatory Prostatitis and Prostatodynia. Universally accepted guidelines for diagnostic work-up are not available; so that the number of cases diagnosed as Chronic Bacterial Prostatitis differs significantly according to the investigations employed by various working groups. The role of Chlamydia and Ureaplasma as causative agents for CPS is still controversial, although many data are in favour of their responsibility in a relatively high number of patients with CPS. Diagnosis of CPS rests fundamentally on symptoms and on the physician’s clinical judgement. CPS and interstitial cystitis may share common pathogenetic mechanisms. The first part of this review covers epidemiology, definition, classification, aetiology and physiopathology, natural history, complications, clinical manifestations and diagnostic work-up. Treatment will be dealt with in a subsequent review article. # 2006 European Association of Urology and European Board of Urology. Published by Elsevier B.V. All rights reserved. * Tel. +39 091 655 2403; Fax: +39 091 655 2439. E-mail address: [email protected]. 1. Introduction Many patients suffering from chronic prostatitis syndrome (CPS) attend urologic outpatient clinics. They often present with difficult diagnostic and therapeutic problems and suffer from a debilitating disease. It is strange or even paradoxical that this topic has attracted relatively little attention in the urologic literature and in the medical world at large. At the 98th Congress of the French Urological Association (AFU) held in Paris in 2004, there was only one contribution on CPS from among 284 accepted abstracts. In that presentation, Delavierre [1] emphasised that, from 1927 to 2004, of 62 official 1871-2592/$ – see front matter # 2006 European Association of Urology and European Board of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eeus.2006.10.002 2 eau-ebu update series 5 (2007) 1–15 reports presented annually at the AFU meetings, not a single one was devoted to prostatitis. Delavierre’s review showed that: A questionnaire on CPS was mailed to 810 members of the AFU. Only 15% replied. They consider the problem of great social importance, but: They are not aware of the pertinent literature on this topic. They do not follow the traditional diagnostic guidelines. Almost every patient is treated with antibiotics. The same situation holds true in Italy. Such a lack of interest, at least in many European countries, is intriguing and not justified, especially because a possible association between chronic prostatitis and prostate cancer has been suggested in several reports [2,3]. Apparently there is a greater awareness of the problem in the United States; 19 of 1725 abstracts accepted for presentation at the annual meeting of the American Urological Association (AUA), in Atlanta, Georgia (May 20–25, 2006), were devoted to the chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). In Europe eight contributions on CPS were presented at the meeting of the European Urological Association (EAU) held in Paris in 2006 (abstracts 901–908). Furthermore, an International Consensus Conference on prostatic diseases was held in Paris in 2005. Proper consideration was given to some aspects of CPS, including diagnostic procedures and the role of chlamydia. Unfortunately, the proceedings are not yet available. This shows that, at least in some countries, there has been a growing interest about prostatitis in recent years, matching the surge of renewed interest for benign prostatic hyperplasia (BPH) that occurred about 20 years ago. Few data exist about the real incidence of CPS, and no uniformly accepted definition, classification, and guidelines for diagnostic work-up are available, to such an extent that prostatitis has been termed ‘‘a wastebasket of clinical ignorance.’’ In a very provocative and stimulating paper, Nickel [4] described prostatitis as the ‘‘black sheep’’ or ‘‘poor cousin’’ of the family of diseases affecting the prostate. The reluctance of many urologists to become involved with this problem may be related to the fact that these patients seldom show a full response to treatment, are frustrated themselves, and often produce frustration in the treating physician. To quote Nickel’s words [4], ‘‘Most urologists freely acknowledge that they would be happy never to see another patient with prostatitis in their office again; others simply refuse to see these patients. Many ignore the real issue, dispensing their ‘antibiotic of the month’, and quickly discharge the patients, hoping that, if they ignore them, they will not return. This approach has resulted in frustration and even anger on the part of the patients as they either shop around for a compassionate urologist or suffer without help from the established medical community.’’ Collins et al [5] state that ‘‘certainly for many patients prostatitis is the most important disease of the prostate gland.’’ The negative impact on a patient’s quality of life is not inferior to what is observed in patients suffering from a recent myocardial infarction, unstable angina or active Crohn disease. It is clear that insufficient time, resources, finances, and scientific scrutiny are being used on research and management of prostatitis. Even the recent EAU guidelines do not consider CPS as a topic to be dealt with as a specific matter, but vague information is given in the guidelines on chronic pelvic pain [6] and genitourinary Infections [7]. It is timely, therefore, to present an updated review of the literature, discuss the main controversial points, and present some personal views and results. We will not deal with either acute prostatitis or rare, specific conditions such as eosinophilic or granulomatous prostatitis, and diseases produced by gonococci, mycobacteria, parasites, fungi, and viruses (including human immunodeficiency). 2. Epidemiology As already noted, clear epidemiologic data on CPS are lacking, due to the fact that there is no uniform definition of this condition. Chronic prostatitis is more frequent than is commonly thought. As Roberts et al [8] point out, one report of autopsy studies [9] found a prevalence of 6.3% histologic inflammation of the prostate, whereas in another series [10] this figure was as high as 44%. It should be noted, however, that although prostatitis means literally an inflammation of the prostate gland, conditions falling within the definition of ‘‘prostatitis syndrome’’ on merely clinical grounds may not be associated with inflammation. This is why we have preferred the term ‘‘chronic prostatitis syndrome’’ (CPS) and will discuss the clinical disease rather than the histologic findings. Statistics from the National Kidney and Urologic Disease Advisory Board [11] and the National Center for Health Statistics [12] in the United States have shown the following: eau-ebu update series 5 (2007) 1–15 3 Prostatitis ranked fourth among the 20 principal diagnoses made by the physicians referring patients to urologists. Symptoms due to CPS accounted for 25% of urologic outpatient visits. In 1985 there were more office visits for CPS than for BPH or prostate cancer. most diagnoses of type III CPS (78%) are made by non-urologists, but such diagnoses were not always confirmed by subsequent evaluation by urologists [22]. It should be noted, however, that the latter statement was based on observations made before the prostate-specific antigen (PSA) era and the enormously increased number of visits and consultations made by people concerned about their PSA levels. Statistics should be updated, but the observations made in 1985 remain of interest. Other reports have shown that: A universally accepted definition of CPS has not yet been found. In fact, the term CPS encompasses a variety of conditions, with or without symptoms and with or without proven inflammation. It even includes clinical situations in which the prostate is apparently not involved, so that the term ‘‘chronic pelvic pain’’ is applied in these cases. Contrary to this, it seems that when inflammation is present, it does not involve only the prostate but also neighbouring organs (urethroprostatovesiculitis). If we limit our attention to patients presenting with symptoms, these are not specific. A differential diagnosis with BPH is not always easy, especially in patients aged 55 yr. The two conditions can coexist. According to Alexander and Trissel [22], the disease is defined only by symptoms, principally pain in the pelvic region. These unsolved problems are reflected in the different classifications, which take into consideration the presence or absence of symptoms, infection, and inflammation. Since 1978, the classification proposed by Drach et al [23] has been widely adopted. It was based on the classical test of Meares and Stamey [24] and divided chronic prostatitis into bacterial, nonbacterial, and prostatodynia. The term ‘‘prostatosis’’ was also used in the past to indicate conditions in which no inflammation could be demonstrated, but abnormal physical findings in the prostate, such as induration or tenderness, could be detected [25]. Other workers used it with a different meaning [26]. Because this definition is ambiguous, is based on subjective findings, and has no prognostic difference from prostatodynia, the term ‘‘prostatosis’’ has been gradually abandoned. In 1991, we proposed a new classification [27], which included chlamydiae-associated prostatitis in the category of ‘‘prostatitis of known aetiology’’ and introduced the term prostalgia as a shorter synonym of prostatodynia. Other classifications were subsequently proposed by Roberts et al [8], and the National Institutes of Health (NIH) [28,29] (Table 1). The NIH classification has been submitted to a preliminary validation, but all these classifications need to be field-tested in large prospective studies. 35–50% of men are affected by prostatitis at some time in life [13]. Incidence was 6% in Wisconsin [14] and prevalence was 8% in a population-based study in Olmsted County, Minnesota [15]. Including visits made by general practitioners, a prostatitis diagnosis is made yearly in 1–2 million people in the United States in men 18 yr old or older [5]. The prevalence was 2-fold greater in the south than in the northeast of the United States, but did not vary by race. In this study, the diagnosis of prostatitis was made more frequently in 36–65-yr-old men than in those aged 18–35. This finding is at variance with previous reports indicating that prostatitis is more frequent in younger men [16]. The disease is frequently diagnosed also in China [16] and in Korea [17] where prostate cancer is rare. In a ‘‘prostate awareness’’ experience led in Palermo, we found that 20% of 230 patients seeking advice for prostatic symptoms were suffering from prostatitis [18]. Obviously, in this and other series based on self-reported symptoms, there was considerable overlap with BPH, especially in older people [19], but CPS had many significant correlates that aided in its recognition [20]. Diagnosis of CPS is made even more often in Canada where, following the pioneering work of Nickel, author of many articles and editor of an exhaustive book on prostatitis [21], there is a greater awareness of this syndrome. In fact, urologists in Canada see an average of 22 patients with prostatitis per month. The odds of a diagnosis of prostatitis were 13-fold greater at visits to urologists compared to visits to primary care physicians in a report from Boston [5]. Conversely, data from Oregon seem to indicate that 3. Definition and classification 4 eau-ebu update series 5 (2007) 1–15 Table 1 – NIH classification and definition of the categories of ‘‘prostatitis’’ NIH classification Category Category Category Category I II III IIIa Category IIIb Category IV Definition Acute bacterial prostatitis Chronic bacterial prostatitis Chronic abacterial prostatitis/CPPS Inflammatory CPPS Noninflammatory CPPS Asymptomatic inflammatory prostatitis Acute infection of the prostate gland Chronic or recurrent infection of the prostate No demonstrated infection White cells in semen and/or EPS or voided bladder urine (VB3) after prostatic massage No white cells in semen/EPS/VB3 No subjective symptoms detected. Inflammation shown either by prostate biopsy or the presence of white cells in EPS/semen during evaluation for infertility or other disorders. NIH = National Institutes of Health; CPPS = chronic pelvic pain syndrome; EPS = expressed prostatic secretions; VB = urine specimen after prostatic massage. The aforementioned classifications are based on the following assumptions: 1. The presence of bacteria in the prostatic fluid, in the semen, and in the urine after prostatic massage, or even in the prostatic tissue, demonstrates that symptoms and abnormal findings (eg, asthenospermia) are due to bacterial infection of the prostate. An even greater difficulty regards the interpretation of the presence of unusual bacteria such as Chlamydia, Mycoplasma, or Ureaplasma organisms. 2. The presence of leukocytes either in semen or in expressed prostatic fluid demonstrates inflammation. 3. The failure to identify either bacteria or leukocytes rules out infection and inflammation. Unfortunately, none of these criteria has ever been conclusively demonstrated. This is the main reason why the term ‘‘chronic pelvic pain’’ (category III CPS) was substituted for the old terms ‘‘chronic abacterial prostatitis’’ (category IIIa) and ‘‘prostatodynia’’ (category IIIb). The fact that both conditions are pooled together in the same category III is due to Table 2 – Histopathologic classification of prostatic inflammatory infiltrates Anatomic location Glandular Periglandular Stromal Extent Focal Multifocal Diffuse Grade Mild Moderate Severe Differential cell types the fact the members of the Chronic Prostatitis Collaborative Research Network felt that the presence or absence of demonstrable inflammation does not modify symptomatology, prognosis, or response to treatment. This new term recognises the limited understanding of the causes of CPS and the possibility that organs other than the prostate may be involved. Exclusion criteria are active urethritis, urogenital cancer, urethral stenosis, and neurogenic bladder. This classification has certain merits and has been widely adopted, but many authors still prefer the old descriptive terms rather than the numerical figures. The diagnostic modalities to differentiate between the various categories of CPS will be discussed in the paragraph devoted to diagnostic work-up. Another classification (Table 2) is based on histopathologic pattern [30], but this can apply only to cases in which inflammation is present and either biopsies or surgical specimens are available for examination. It does not apply to most clinical cases. The proponents suggest that a standardised framework to describe histopathologic prostate inflammation will prove useful in evaluating prostate disease, but they admit that its correlation with clinical chronic prostatitis ‘‘has not yet been completely defined and even less is known about asymptomatic inflammatory prostatitis associated Table 3 – International Continence Society classification of chronic pelvic pain syndrome Urologic Vesical Urethral Penile Prostatic Scrotal Gynaecologic Anorectal Neurologic Muscular eau-ebu update series 5 (2007) 1–15 5 Table 4 – Aetiology Bacteria recognized as aetiologic agents for chronic bacterial prostatitis Gram-negative Gram-positive Potential aetiologic candidates Corynebacteria Other gram-positive strains Chlamydia trachomatis Mycoplasma genitalium Ureaplasma urealyticum Anaerobes Viruses Controversial role of bacterial products with BPH, prostate cancer and infertility.’’ Despite the fact that chronic pelvic pain is included as category III in the NIH classification of prostatitis, this concept has undergone a further development by the International Continence Society (ICS), whose classification distinguishes between the various organs or apparatuses that may be affected by a painful sensation (Table 3) [31]. Hakenberg and Wirth [32] and Oberpfenning et al [33] add additional categories, namely, dermatologic, orthopaedic, oncologic, psychosomatic, psychiatric, and pain from other rare causes. In a workshop attended by Italian urologists in 2001, it was felt that the ICS classification should be incorporated in the current classifications of chronic pelvic pain. 4. Aetiology and physiopathology In the category of chronic bacterial prostatitis, many bacterial species can be isolated from expressed prostatic fluid, urine specimens after massage, or semen (Table 4). Most workers agree that gram-negative bacteria can be responsible for chronic bacterial prostatitis, but the aetiologic role of gram-positive cocci (other than Streptococcus faecalis) is accepted by some authors and denied by others. A difficult problem lies in the fact that prostatic fluid and semen have intrinsic antibacterial properties and may hamper bacterial growth in vitro. For this reason several authors have tried to identify ‘‘bacterial signals,’’ such as products of bacterial genes, 16S rRNA sequences [34], or bacterial DNA sequences [35]. Using these techniques, Tanner et al [36] found positive bacterial signals in 65% of patients with chronic prostatitis. Patients with positive signals (but negative cultures) responded to antibiotics. Unexpectedly, a wide diversity of Corynebacterium species was found in high proportion compared to other bacteria [36]. Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa Streptococcus faecalis (Enterococcus) Staphylococcus saprophyticus, S. epidermidis, S. aureus Using the same materials and various isolation techniques, Chlamydia trachomatis has been isolated by various workers and considered of aetiologic significance. As already mentioned, in our experience chlamydiae were present in a high percentage of patients with CPS. The fact that symptoms and sperm abnormalities can improve or disappear after specific treatment and eradication of the infection has prompted us to consider chlamydia as an aetiologic factor in CPS, but the role of C. trachomatis, Mycoplasma hominis, Mycoplasma genitalium, and Ureaplasma urealyticum in CPS is still controversial, despite many arguments indicating they may be causative agents. For a thorough discussion and bibliography the reader is referred to the detailed reviews by Domingue [37] and Doble [38]. The evidence is particularly suggestive with regard to chlamydiae. Not only anti-chlamydiae 1gA in prostatic fluid with >10 leukocytes per high-power field (hpf) were found in 29% of cases, but the specific antibodies were also present in serum and ejaculate [39]. C. trachomatis was also detected by in situ hybridisation (biotin-labelled DNA probe) on paraffin-embedded biopsy specimens [40] and by polymerase chain reaction (PCR) in urine and semen [38]. The same controversies still exist with regard to the pathogenic role of mycoplasma [37,41], with special reference to U. urealyticum [42,43]. Lack of uniform data and opinions may depend on the difficulty in the identification of these microorganisms, so that they are seldom submitted to routine investigation. In our practice, search for Chlamydia and Ureaplasma organisms is advised for all patients with CPS. If Chlamydia and Ureaplasma organisms are isolated and considered as putative causative agents, it seems more logical to include such cases under the heading of chronic bacterial rather than nonbacterial prostatitis, as suggested in our own classification [27]. 6 eau-ebu update series 5 (2007) 1–15 The pathogenesis of bacterial prostatitis is unknown. According to Schaeffer [44], ascending urethral infection after vaginal or rectal inoculation of the urinary meatus during sexual intercourse is likely to play an important role, sometimes as a complication of urethritis. Haematogenous or lymphatic spread may also occur. Pathogenesis is even more obscure for category III prostatitis. Chronic bacterial prostatitis can follow acute prostatitis, be due to indwelling catheters, or appear ex novo. The formation of biofilms may play an important role in maintaining chronic infection in prostatitis secondary to catheters or stones [45]. A pathogenic role has been attributed, for both bacterial and nonbacterial prostatitis, to reflux of urine in the prostatic ducts [46]. Deposition of uric acid crystals in the prostatic parenchyma has been advocated for abacterial prostatitis, whereas autoimmune processes can be responsible also for prostalgia [47]. Tension of pelvic floor muscle may be due to a psychosomatic mechanism, but it is very difficult to ascertain whether anxiety is primitive or secondary to the persistence of such a stressful condition. Many problems still remain unanswered. 5. Natural history and complications Little is known about the natural history of CPS. In 2006, the results of a 2-yr follow-up of 445 patients were presented [48]. The study showed that CPS is characterised by substantial variation in symptoms within and among subjects. Contrary to a commonly held opinion, there was no evidence that the disease worsens significantly with the passage of time and about one third of men with long-standing symptoms showed a moderate to marked improvement during the follow-up period. None of the analysed factors predicted for response and no conclusion was drawn about the question why responding patients got better. Response may be due either to the treatment received or to other causes, such as natural fluctuations or changes in life stress, general health, or other unknown reasons. In nonresponding patients, complications may be encountered. Infertility, if not present at the beginning, may become prominent later on. Chronic bacterial prostatitis may be the cause of persistence of bacteria and lead to recurrent urinary tract infections. There is a hint that chronic prostatitis may predispose to prostatic cancer, but this awaits definitive confirmation. Finally, the development of severe anxiety and depression may be the most common and most distressful of longterm complications. 6. Clinical manifestations Symptoms from CPS are variable and nonspecific. Some authors [49] have stated that pain, present for 3 mo, is the most common and most typical of all symptoms. The pain is most frequently located in the perineum but other parts of the pelvic region can be affected, including the suprapubic area, penis, urethra, testicles, and sometimes with irradiation to the lower back. Because the vast majority of patients with CPS fall into category III (chronic pelvic pain), pain should be, by definition, the most typical manifestation in the majority of patients. However, the term ‘‘pain’’ has been replaced in some reports by ‘‘pain or discomfort’’ [50], which is a very vague definition. The percentage of pain is lower (25%) in some series [16] than in the original report from Krieger et al [49]. In category IV, CPS symptoms are lacking altogether. A clear definition of symptoms is essential, insofar as the diagnosis of CPS is based on clinical rather than pathologic grounds and little is added by most laboratory tests or imaging investigations. Table 5 shows the symptoms presented in our series of 155 consecutive patients seen at the Outpatient Section of the Urological University Clinic in Palermo, in whom the diagnosis of CPS was made. Pain (or discomfort) is often associated with voiding symptoms, which may be difficult to distinguish Table 5 – Clinical manifestations. In our survey of a sample of 155 patients the following symptoms were reported Frequency Nocturia Urethral burning during micturition Urethral burning independent from micturition Pain during micturition Suprapubic discomfort Suprapubic pain Sensation of reduced urinary flow Pain or discomfort in inguinal, rectal, perineal, or lumbar regions Erectile dysfunction Pain during ejaculation Ejaculatio praecox Haemospermia Anxiety Prostatorrhea n % 88 76 59 57 49 38 41 26 19 24 14 50 26 12 15 9 32 17 19 15 17 12 102 15 12 10 11 8 66 10 eau-ebu update series 5 (2007) 1–15 7 Table 6 – NIH Chronic Prostatitis Symptom Index (NIH-CPSI) from those caused by BPH. However, urgency and pain or burning on urination were more common in men with CPS than in BPH [51,52]. In our own and in other series, sexual disturbances were rather frequent, ranging from erectile dysfunction (ED) to painful ejaculation [53]. ED may have more a psychogenic than an organic pathogenesis. It is well known that severe anxiety is often associated with depression, one of the leading and more invalidating manifestations in CPS [54]. A neurogenic disturbance related to altered expression of nerve growth factor induced by inflammation and tissue injury cannot be ruled out, at least in cases where inflammation is present [55,56]. The question we posed in 1991: ‘‘Prostatitis, prostatosis and prostalgia: psychogenic or organic disease?’’ [27] has not yet found a clear-cut answer to be applied in all cases. Because symptoms are a key feature of this bothersome clinical entity, the NIH and the Chronic Prostatitis Collaborative Research Network developed an index for quantitative measure of symptoms and quality of life (Table 6) [50]. The symptom index is thought to be especially helpful for evaluation of the outcome of therapy. This 9-item questionnaire has been validated in English-speaking countries and translated into several languages, including Italian [57]. It can be self-administered in a few minutes and has replaced previous attempts to develop specific questionnaires, including that proposed by Nickel and Sorensen [58] that was simple and user-friendly but had not been subjected to such an extensive validation. A remarkable result of this index is the confirmation of lack of correspondence between presence of infection or inflammation and type and severity of symptoms. Chronic bacterial and nonbacterial prostatitis show the same symptomatology [59] but may be present without symptoms. 7. CPS and interstitial cystitis: similarities or common pathophysiology? Some symptoms of CPS, especially pelvic pain, may be indistinguishable from those of interstitial cystitis (IC) [60,61]. The latter condition is more frequently seen in women than in men, so that the possibility of IC in men is often disregarded and the diagnosis is missed, especially if non–bladderrelated symptoms are present [62]. Not only is the diagnosis of IC in general made much more frequently than 20 yr ago but, according to Parson [63], a recent survey has shown a female-to-male ratio of 5:1, which is substantially lower than previously believed (10:1). This study has also shown that there was an overlap between men diagnosed 8 eau-ebu update series 5 (2007) 1–15 Table 7 – Items to be considered in the diagnostic workup of chronic prostatitis syndrome Table 8 – Diagnostic work-up: percentage of data obtained in Palermo in 2000 Age Symptoms Pathology Physical examination Urodynamics Urine analysis Digital rectal examination Prostatic massage Simplified Meares-Stamey test Microscopic examination of expressed prostatic fluid Symptom score Test for Chlamydia organisms Test for Ureaplasma organisms Sperm culture Sperm analysis Uroflow Suprapubic echography Transrectal ultrasound Urodynamics Cytology Intravenous pyelography Cystoscopy Biopsy Imaging Intraprostatic pressure Response to ‘‘ad hoc’’ treatment Overall clinical judgement with IC and those diagnosed with prostatitis, suggesting that both conditions may be part of the same disease process probably consisting of a dysfunction of lower urinary epithelium and potassium recycling [64]. Because the number of patients who report a history of prostatitis is higher than that of patients in whom the diagnosis of CPS is confirmed, it is possible that IC may account for this discrepancy. Nickel et al [65], in a Canadian study in outpatients found that, in such cases, IC was even more common than prostatitis. Better diagnostic criteria are needed before a diagnosis of IC is established [66] and some of them, such as intravesical potassium test or cystoscopy under anaesthesia with hydrodistention, are unduly invasive. There is a need for putative, noninvasive markers for IC, such as methylhistamine [67] or nitric oxide [68] assays in urine before a complete assessment for IC is incorporated in the work-up for CPS and specific treatment for IC is instituted in patients with CPS resistant to first-line conventional treatment [69]. 8. Diagnosis There is still no agreement on the criteria to be used for the diagnosis of CPS. No guidelines have been developed so far to provide the clinician with a validated diagnostic work-up schedule [70]. Our diagnostic efforts should be directed not only to establish the diagnosis of CPS in general terms, but also to identify aetiologic agents, if any, to detect signs of inflammation and to classify the patient into one of the four CPS categories. To this purpose, the items listed in Table 7 are usually considered. Table 8 shows the relative frequency with which various diagnostic investigations were performed by us in 155 consecutive patients in 1999–2000 [71]. Distribution of patients among the different categories depends on the classification adopted and on the diagnostic work-up. In most recent reports, the NIH classification is adopted and search of a bacterial aetiology is limited to cultures of expressed prostatic secretion (EPS) or urinary specimens according to the classical or simplified 100% 100% 90% 66% 40% 15% 89% 42% 74% 66% 84% 57% 66% 9% 1.3% 2.6% 8% 0.6% Meares-Stamey test. If these criteria are adopted, the distribution of cases is as follows: Category Category Category Category II III a III b IV 3–10% 5–12% 70–80% 2–10% In our personal experience, using a more extensive diagnostic work-up, which included sperm culture and search for Chlamydia and Ureaplasma species, we have adopted a modified classification [27]. It includes, in addition to cases classified as ‘‘chronic bacterial prostatitis’’ according to the NIH criteria, also a greater number of cases, classified under the heading of ‘‘chronic prostatitis of known bacterial aetiology.’’ Altogether, this enlarged infectious CPS group was significantly greater than NIH category II, as follows: CPS of known bacterial aetiology Chronic abacterial prostatitis (NIH category IIIa) Prostalgia (chronic pelvic pain syndrome, NIH category IIIb) Asymptomatic inflammatory prostatitis (NIH category IV) 66.45% 19.35% 13.55% 0.65% In patients whose disease was classified as CPS of known aetiology, the presumed causative agents consisted of either gram-negative or gram-positive bacteria in 60.09% of cases. Bacteria were more frequently obtained from sperm culture than from EPS or urine after prostatic massage. Chlamydia organisms were more frequently associated with eau-ebu update series 5 (2007) 1–15 ‘‘classical’’ bacteria or Ureaplasma species than isolated as a single agent. Ureaplasma organisms not associated with chlamydiae were found only in 3.88% of cases. Altogether chlamydiae-associated CPS constituted 42.26% of a series of 155 consecutive cases of CPS observed in our outpatient department. These observations account for the fact that most of our CPS patients received antibiotics as the first therapeutic attempt. Of the items listed in Table 7, we have already presented some information about age and symptoms. Physical examination obviously includes a digital rectal examination (DRE) and a prostatic massage to obtain the EPS sample to be submitted to microscopic examination and culture. In our experience, however, even after a prolonged prostatic massage, we were unable to obtain EPS samples in >50% of cases. For clinical purposes, pathology is rarely useful for diagnosis and biopsy is seldom performed (only in 0.6% of cases in our series). Not only is inflammation an extremely common histologic finding in patients with BPH who have no symptoms of prostatitis [72], but if systematic biopsy is prospectively performed in patients with clinical CPS, moderate or severe inflammation was found in a minority of cases [73]. Laboratory data are more frequently obtained. They include urinalysis, cultures for common bacterial flora, as well as Chlamydia and Mycoplasma organisms, microscopic examination of EPS, Meares-Stamey test (usually in a simplified form), sperm culture and sperm analysis, cytology, serum PSA levels, and specific tests for inflammation. We have already mentioned the ongoing research for identification of bacterial products. A careful anamnestic investigation should be obtained, with special reference to previous episodes of urinary tract infection or acute prostatitis, catheterisation or other instrumental manipulations, urethritis, and sexually transmitted diseases. Sexual life should be investigated to obtain not only the history of the patient, but also that of the couple. Obviously, all the symptoms suggestive of a CPS should be asked for and a symptom index is highly recommended. The classical Meares-Stamey test is seldom performed because of cost and complexity (4 specimens are needed for culture: first voided urine, midstream specimen, EPS, and urine after massage). A simplified test has been suggested by Nickel [74] using only two urine specimens, one before and another after prostatic massage. We routinely submit for culture only one urine specimen after prostatic massage. If negative (as happens in >90% of cases), no additional cultures 9 are needed. If positive, we ask the patient to submit for culture a midstream specimen at the next visit, together with a search for Chlamydia and Ureaplasma organisms in urine after massage urine and a semen culture for common pathogens. Semen cultures are considered to be positive if >50,000 colonies/ml are obtained. Such an arbitrary cut-off is challenged by other authors. Physical examination may disclose concomitant pathologies, such as hemorrhoids, epididymitis, and varicocele [75], which are not rarely associated with CPS. Some of these conditions, in addition to prostatic inflammation, may be responsible for infertility often encountered in patients with CPS. Microscopic examination of EPS is still highly recommended although it is seldom performed by general practitioners and even by young urologists who are not very familiar with the microscope. This holds true despite the tendency to consider chronic abacterial prostatitis and prostatodynia to be almost indistinguishable from the clinical standpoint. According to Wright et al [76], microscopic examination of EPS is the essential initial observation to identify prostatic inflammation as well as an important parameter to assess response to treatment. Studies of prostatic inflammation indicated that most healthy men had <10 white blood cells (WBCs)/hpf in the EPS. Inflammatory prostatitis was judged to be present if the EPS contained 10 WBCs/ hpf. The validity of this cut-off level for the number of WBCs in EPS has not been uniformly accepted. The value of such a count is even less if EPS cannot be obtained by prostatic massage and the first voided urine after massage is examined as a substitute for EPS [77]. An increased number of WBCs can be observed in semen but the upper normal value has not been uniformly defined. The presence of cytokines can be an alternative indicator of inflammation [78–80]. Levels of tumor necrosis factor a, interleukin (IL)-1b [78], IL-10 [79], and IL-6 and IL-8 are elevated in some patients with CPS. Miller et al [79] observed a direct correlation between IL-10 levels and severity of pain. Paulis et al [80] found high levels of IL-6 or IL8 or both in 85.5% of men with CPS, whereas the leukocyte count yielded a positive result only in 48% of cases. These studies are of great theoretical interest, but such assays are of no use in daily practice. It should be noted, however, that interleukin, complement, and immunoglobulin determinations in serum and ejaculate reveal an inflammatory process in some cases clinically diagnosed as having noninflammatory chronic pelvic pain syndrome [81]. 10 eau-ebu update series 5 (2007) 1–15 We recommend search for Chlamydia and Mycoplasma organisms in patients who have negative cultures after massage, both in urine after prostatic massage and in semen. We advise neither a search for chlamydiae in urethral swabs, unless there is suggestion of urethritis, nor a determination of antichlamydiae antibodies in serum. Identification of chlamydiae in smears by immunofluorescence has a very low sensitivity, whilst the classical culture in McCoy cells is lengthy and, at least in our hands, is of limited sensitivity and specificity, but it offers the possibility of in vitro sensitivity test to antibiotics. In recent years we have used the PCR technology, which is more expensive, but more rapid and specific [82,83]. We also recommend a regular sperm analysis to be performed routinely, with special reference to sperm count, motility, morphology, and presence or round cells and WBCs. We consider this a necessary step in our work-up, due to the high incidence of infertility in CPS patients [84]. If abnormal, a sperm count should be repeated to monitor treatment outcome [85]. Search for special aetiologic agents, that is, fungi, viruses, anaerobes, mycobacteria, or trichomonas is not performed, unless there is a specific reason to do so. Urinary cytology is requested to rule out urothelial carcinoma in situ if clinically suspected. PSA determination in serum is optional, but frequently asked for. A few reports [86] confirm that PSA can be elevated not only in acute but, to a lesser degree, also in chronic prostatitis, including category IIIb and IV. An investigation by Pansadoro et al [87], involving 72 patients under 50 yr of age, showed an elevated serum PSA level in 71% of patients with acute prostatitis, 15% in patients with category II CPS, and 7% in patients with category III CPS. In CPS, the PSA level (if elevated) was usually between 4 and 20 ng/ml and the free-tototal PSA ratio was relatively low, with intermediate average ratios between those observed for BPH and cancer. Why prostatic inflammation causes an increase in PSA is not clear, but a role can be played by hypervascularity with increased vascular permeability causing leakage, disruption of epithelial integrity, and perhaps enhanced apoptosis. PSA values exceeding 20-fold the normal range can be encountered in acute prostatitis. After successful treatment the decrease in PSA usually occurs starting on the third day, but normalisation may take up to 3 mo or even many years. In some cases, significant PSA elevation may be maintained throughout the patient’s life, as the disease becomes chronic, often asymptomatic, and resistant to treatment. The effect of prostatic calculi on PSA levels is still controversial. The increase in serum PSA in chronic prostatitis is inconstant and often marginal. Nadler et al [88], in 2006, evaluated 421 selected patients with the CPS and 112 age-matched controls. Mean PSA levels were 1.97 2.87 in CPS patients and 1.72 2.93 in controls, with free-tototal PSA ratios of 17.83% and 15.38%, respectively. No additional information was given by analysis of recently discovered PSA isoforms. Patients with chronic inflammatory prostatitis, defined by WBC counts >5/hpf in EPS, had a higher mean PSA (2.47 3.80) and a lower free-to-total PSA ratio (34.65% 18.30%) than NIH category IIIb patients (1.70 2.07 and 40.48% 17.76%, respectively). In the latter group, total PSA never exceeded 4 ng/ml. Different data were reported by Zattoni F, Verona, Italy (personal communication, 2002) who, in a group of 41 patients with elevated PSA, found that those who were affected by CPS had a median PSA value of 11.5 (range 5–19.5). Such values are clearly higher than those obtained by Nadler et al in a highly selected group of patients, many of whom had received previous treatment for their CPS. For many years, a common belief is that patients with inflammatory signs of prostatitis have a larger decrease in serum PSA if treated with antibacterial agents than those affected by prostate cancer. This had led to the concept that, if a reduction of PSA exceeds 50% of the pretreatment value, this may help in differentiating benign from malignant diseases. Because data differ considerably among different workers [89], these criteria should be adopted with great caution and it is doubtful whether this can lead to a significant reduction in the number of prostatic biopsies. Nadler et al [88] concluded that PSA value and the patient’s response to antibiotic treatment should not interfere with the clinician’s approach to screening for prostate cancer. A recent review by Kawakami et al [90] puts forward some interesting questions. Should the description of inflammation on negative (no cancer) biopsies change the need for subsequent biopsies? Should all men be evaluated for asymptomatic prostatitis before biopsy? Should all men with asymptomatic prostatitis be treated with antibiotics before undergoing biopsy? The answer to all these questions is probably no, in view of conflicting opinions and results from antibiotic treatment of such cases. The issues still remain open to debate [91,92]. Regarding non-laboratory investigations of potential clinical usefulness, cystoscopy is not recommended except in case of haematuria and, eau-ebu update series 5 (2007) 1–15 perhaps, according to the clinician’s preference, also for haemospermia. Biopsy, both for histopathology and bacteriology, is not routinely recommended. Other invasive procedures include measurement of intraprostatic pressure under spinal anaesthesia. Despite the stimulating experience reported by a group of Finnish workers [93,94], who found significantly higher pressures in CPS patients compared to the controls, this idea has not been found suitable for clinical use. A complete urodynamic evaluation may improve the diagnostic accuracy in patients with CPS, especially in non-responders after medical therapy [95], but is not recommended for routine work-up. Conversely, we agree with Gobish [96] who is a proponent of uroflowmetry in the assessment of all patients with CPS. It is noninvasive and shows that most patients with CPS, including those with prostatodynia, have abnormal flowmetry parameters. This might help in the identification of the pathophysiologic basis of the symptoms and, accordingly, in the selection of treatment. Imaging plays a secondary role for the diagnostic work-up of patients with CPS. For this indication, traditional radiography, namely, plain abdominal x-ray, intravenous urography, and cystography, has been abandoned. Urethrography may be indicated only if there is a suspicion of a urethral stenosis. There is no role for computed tomography scanning or magnetic resonance imaging [97]. Renal echography is not indicated but ultrasonography of the bladder, including visualisation of the prostate and a measurement of postvoid residual urine, can be a useful addition to diagnostic work-up. There is no consensus on the role of transrectal ultrasonography (TRUS). In our early experience (1988), Di Trapani et al [98], from a comparison between 121 patients with CPS and 20 controls, described that in nearly 90% of the CPS patients echographic abnormalities of some sort were recorded. The most frequent feature was congestion and dilatation of the periprostatic veins and the Santorini plexus. Another common alteration was a nonhomogenous echo pattern with a mixture of hyperechoic and hypoechoic areas. Some alterations of the seminal vesicles was observed in approximately 60% of patients, consisting of distention and elongation of the vesicles and thickening of the vesicular septa, due to inflammatory oedema. Hypertrophy of the bladder neck was observed in one third of patients with CPS. Prostatic calculi or microcalcifications can also be observed but their clinical significance is obscure, because they can be found in normal, asymptomatic subjects. It cannot be ruled out that prostatic calculi 11 may help to maintain local inflammation and produce moderate pain, acting as foreign bodies [99]. Larger calculi are more frequently associated with symptoms. It was noteworthy that these abnormalities detected by TRUS were observed with nearly equal frequencies in all CPS categories, including prostatodynia, suggesting a possible organic pathology also for the latter category of patients. De la Rosette et al [100] confirmed these findings, although they considered them aspecific and suggested that specificity could be improved by Doppler ultrasound, where an increased flow pattern can be visualised. An updated review of the various treatment options will be presented in a subsequent article. 9. Conclusions CPS still remains a difficult and controversial topic. It has been neglected for many years but there is a recent surge of interest, which has led to the formation of specialised working groups. The Chronic Prostatitis Collaborative Research Network has produced important contributions such as the NIH classification and the validated symptom index. 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CME questions Please visit www.eu-acme.org/europeanurology to answer these CME questions on-line. The CME credits will then be attributed automatically. 1. The diagnosis of chronic prostatitis/chronic pelvic pain syndrome is based on: A. Symptomatology B. Biopsy and pathology C. Bacteriology D. Imaging 2. If the classical Meares-Stamey test is adopted and no additional bacteriologic investigations are performed, the cases of chronic bacterial prostatitis represent what percentage of the chronic prostatitis/chronic pelvic pain syndrome: A. 0–5% B. 5–10% C. 20–50% D. >50% eau-ebu update series 5 (2007) 1–15 3. What is the most frequent complication of chronic prostatitis/chronic pelvic pain syndrome: A. Recurrent urinary tract infections. B. Fibrosis and obstruction of the bladder neck. C. Development of prostate cancer. D. Anxiety and depression. 4. The fact that CPS has received relatively little attention in the urologic literature is mainly due to the fact that: A. The condition is relatively rare. B. There is no clear definition. C. There is no impact on survival. D. Doctors often become frustrated and tend to neglect the issue. 5. A causative role for Chlamydia trachomatis in CPS can be suspected when: 15 A. Chlamydiae are present in the vagina of the partner. B. There is a history of acute epididymitis. C. Chlamydiae are shown in swabs from anterior urethra by immunofluorescence. D. Chlamydiae are identified by PCR in postmassage urine or semen. 6. A sperm analysis is useful in the diagnostic workup of patients with CPS, because: A. Asthenospermia is a frequent finding. B. It allows diagnosis in patients with CPS category IV. C. It represents a substitute for expressed prostatic fluid. D. It allows identification of intracellular Chlamydia organisms.