Chronic scrotal pain syndrome (CSPS): the widespread use of antibiotics is not justified

Transcription

1 IN: ORIGINAL ARTICLE Correspondence: Räto T. trebel, Department of Urology, Kantonsspital Graubünden, Loëstr. 170, 7000 Chur, witzerland. Keywords: anti-bacterial agents, bacterial infections, epididymitis, orchitis, pain, scrotum, testis Received: 11-Feb-2012 Revised: 24-Mar-2012 Accepted: 6-Jul-2012 Chronic scrotal pain syndrome (CP): the widespread use of antibiotics is not justified R. T. trebel,* C. chmidt, J. Beatrice and T. ulser *Department of Urology, Kantonsspital Graubünden, Chur, Department of Urology, GZO Wetzikon, Wetzikon, Department of Urology, pital Uster, Uster, and Department of Urology, University Hospital Zurich, Zurich, witzerland doi: /j x UMMARY Data supporting the widespread use of antibiotics in patients with chronic scrotal pain syndrome (CP) are not available. Therefore, the aim of this study was to investigate the presence of bacteria in the genitourinary tract in patients presenting with CP. From July 2005 to July 2007 we prospectively enrolled patients presenting with CP in our outpatient clinic. The evaluation consisted of a detailed patient s history, physical examination and ultrasound examination of the scrotum. A blood and urinalysis, a Meares-tamey four-glass test for bacterial cultures and PCR testing for Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis and Neisseria gonorrhoeae as well as a semen culture were performed. We assessed the symptom severity with the chronic epididymitis symptom index (CEI) score according to Nickel et al. (J Urol 2002, 167:1701; based on the NIH-CPI). A total of 55 eligible men (median age 34 years) with CP were enrolled in the study. The median CEI score was 17 (range 4 26). The majority of patients (n = 39; 71%) were seen by a general practitioner or an urologist before. Of these, 25 patients (64%) were treated with antibiotics and 26 (67%) with non-steroidal anti-inflammatory drugs, respectively. A significant bacterial colony count in at least one specimen was detected in 21 of 55 patients (38%). The predominantly detected microorganisms were an (11 patients) and coagulase-negative staphylococci (10 patients). Thus, only in 12 of 55 (22%) patients isolated bacteria were considered to be of clinical relevance. No factor or condition predictive for a bacterial aetiology for CP could be identified. In our microbiological assessment of patients presenting with CP we found no evidence for the widely held belief that CP is predominantly the result of a chronic bacterial infection. We therefore conclude that the widespread use of antibiotic agents in the treatment of patients with CP is not justified. INTRODUCTION The chronic scrotal pain syndrome (CP) comprises the clinical diagnoses of idiopathic testicular pain, orchialgia, orchidynia and chronic epididymitis. Nickel et al. (2002) defined it as intermittent or constant scrotal pain over a period of 3 months or longer that significantly interferes with the patient s daily activities and thus prompts him to seek medical attention. In a recent survey among wiss urologists, 98% considered infections to play a role in the aetiology of CP (trebel et al., 2005). Accordingly, up to 82% of patients with CP are treated with an antibiotic agent. This is in accordance with similar findings of Nickel et al. who reported that 74% of affected men in their series were treated with antibiotics (Nickel, 2003). However, evidence-based clinical practice guidelines on the management of patients with CP or data supporting the widespread use of antibiotics are not available (Granitsiotis & Kirk, 2004; Calleary et al., 2009). Therefore, the aim of this study was to investigate how frequently bacteria can be detected in the genitourinary tract in patients presenting with CP and to identify parameters associated with an infectious aetiology. MATERIAL AND METHOD Between July 2005 and July 2007 all patients presenting with CP were prospectively enrolled. The standardized evaluation consisted of a detailed patient s history, physical examination and ultrasound examination of the scrotum. A blood and urinalysis, Meares-tamey four-glass test for bacterial cultures and additional PCR testing for Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis and Neisseria gonorrhoeae as well as a semen culture were performed (Meares & tamey, 1968). A bacterial colony count in any urine sample higher than /ml was considered significant, whereas in semen probes a 2012 American ociety of Andrology and European Academy of Andrology Andrology, 2013, 1,

2 R. T. trebel et al. bacterial colony count > /ml in pure and > /ml in mixed bacterial cultures were considered significant. The symptom severity was assessed with the chronic epididymitis symptom index (CEI score, appendix 1) according to Nickel et al. (2002), which is based on the NIH-CPI (National Institutes of Health Chronic Prostatitis ymptom Index). It consists of a pain and quality-of-life subscore. By combining the two domains, a total CEI score (range 0 27) can be determined. Patients with an ongoing acute epididymitis, a history of prostatitis or inguinal hernia were excluded. The study was approved by the local ethics committee. tatistical analyses were performed using commercially available statistical software (P; Chicago, IL, UA). For correlation analyses, Fisher s exact test and logistic regression models were applied. A p-value <0.05 was considered significant. REULT Basic data and personal history A total of 55 eligible men presenting to our outpatient clinic were enrolled in the study. Patient characteristics are shown in Table 1. Only 16 (29%) of the men were seeking medical support because of CP for the first time. The majority of patients (n = 39, 71%) had consulted a general practitioner (GP) or an urologist one to eight times (median 2 visits) before presenting to our department. The median time interval between the last visit with the GP or an office urologist was 5.2 weeks (range weeks). The most common previous therapies prescribed were antibiotics (64%) and anti-inflammatory analgesics (67%). Other preceding therapies like acupuncture, injection of local anaesthetics or prescription of anxiolytics were infrequent. Table 1 Basic data and personal history Parameter All patients (n = 55) Patient characteristics Median age (years) (range) 34 (19 54) Median duration of disease (months) (range) 12 (3 240) Median time interval (days) from last 36.3 (3 97) visit at previous physician to first consultation within study centre (n = 39) Median CEI score Total (range) 17 (7 27) Pain subscore (range) 8 (2 15) Quality-of-life subscore (range) 8 (3 12) No. medical history (%) crotal or groin surgery 12 (22) Vasectomy 0 Urinary tract infections 20 (36) Acute epididymitis 10 (18) Urethritis 5 (9) Cystitis 5 (9) Irritative voiding disorder 12 (22) Diabetes mellitus 0 Cardiovascular disease 7 (13) Neurological disorders 11 (20) Depression 11 (20) Allergies 17 (31) exual history (%) No. sexually active 46 (84) No. exclusively heterosexual 54 (98) No. history of sexually transmitted disease 1 (2) Physical and ultrasound examination On physical examination, 40 patients (73%) presented with an isolated uni- or bilateral tenderness of the epididymis and only one patient had an isolated tenderness of the testis. At the time of examination the scrotal palpation was completely indolent in nine patients. A varicocoele testis was detected in eight patients, and in six of these eight patients this diagnosis was missed in the previous assessments. In five of these, the side of the varicocoele testis matched with the side of the complaints. In the ultrasound examination of scrotal contents neither testicular tumours nor structural changes of the epididymis were detected. Blood analysis and urinalysis White blood cell count and C-reactive protein was marginally elevated in five and two patients, respectively. None of these patients with either elevated white blood cell count or C-reactive protein had a significant bacterial colony count or positive PCR testing. Mid-stream urinalysis was negative for leucocyturia in the entire study population. Microbiological assessment A significant bacterial colony count in at least one specimen was detected in 21 of 55 patients (38%). Table 2 details the distribution of positive samples and the detected bacterial species. The predominantly detected microorganisms were alpha-haemolytic streptococci in 11 patients. Neither urine cultures nor PCR testing provided evidence for N. gonorrhoeae or C. trachomatis. PCR testing was positive for Ureaplasma urealyticum in two patients. In patients without previous assessment for CP a significant bacterial colony count was detected in four of 16 patients (25%). Furthermore, seven of 21 (33%) patients with a significant bacterial colony count or positive PCR testing have a positive history for previous urinary tract infections or male accessory gland infection. Correlation of patient characteristics and clinical findings with microbiological test results Patient s characteristics, history and physical examination findings, and CEI score were analysed to test their association with positive or negative microbiological findings. Only the total CEI score and the quality-of-life domain of the CEI showed a statistically significant association with microbiological test results. However, these two parameters were inversely correlated with positive microbiological findings: The higher the total CEI scores (r = 0.33, p = 0.015) or quality-of-life domain (r = 0.37, p = 0.005), the lower the probability for a positive bacterial culture result. DICUION In our microbiological assessment of patients presenting with CP we found no evidence for the widely held belief that CP is predominantly the result of a chronic bacterial infection. Indeed, at most 21% of the patients had a significant bacterial colony count or positive PCR with bacteria considered to be of possible clinical relevance. Moreover, in 13 of 21 patients the significant bacterial colony count or positive PCR was detected in semen specimen only. From studies on male infertility and chronic prostatitis it is known that semen cultures are either vulnerable to bacterial 156 Andrology, 2013, 1, American ociety of Andrology and European Academy of Andrology

3 INFECTION IN PATIENT WITH CHRONIC CROTAL PAIN YNDROME Table 2 Distribution of positive specimens and isolated bacteria Patient Positive specimen Isolated bacteria CFU/mL CCR History of UTI or MAGI 15 VB3 Citrobacter koseri Corynebacterium glucoronolyticum > 16 Enterococcus sp. > Yes Yes (epididymitis) 17 Corynebacterium glucoronolyticum Unclear Yes (urethritis) 18 > No No 21 VB1, VB2 Lactobacillus sp. Lactobacillus sp. No No 24 Coagulase-negative taphylococcus Corynebacterium sp. Yes Unclear 28 VB1 Enterococcus sp. Yes Yes (UTI) 29 Coagulase-negative taphylococcus No Yes (urethritis) 30 Mycoplasma hominis Yes Yes (epididymitis) Ureaplasma urealyticum 33 Corynebacterium glucoronolyticum > Unclear No 39 Beta-haemolytic treptococcus B Yes No 42 Unclear No Coagulase-negative taphylococcus Neisseria sp. 44 No No Coagulase-negative taphylococcus 45 No Yes (UTI) Coagulase-negative taphylococcus 46 VB1, 2, 3 Yes No Beta-haemolytic treptococcus B Enterococcus Gardnerella vaginalis Ureaplasma urealyticum 47 Coagulase-negative taphylococcus No Yes (epididymitis) 49 EP Coagulase-negative taphylococcus No No 50 VB1 No No VB3 Coagulase-negative taphylococcus 51 VB2 Coagulase-negative taphylococcus No No 52 VB2 EP EP Beta-haemolytic treptococcus B Coagulase-negative taphylococcus Coagulase-negative taphylococcus Yes No 54 Enterococcus sp. No No Yes No Pat: Patient ID; VB1: First voided urine; VB2: Mid-stream urine; EP: Expressed prostatic secretion; VB3: Postprostatic massage urine; : emen culture; CCR: considered clinically relevant; UTI: urinary tract infection; MAGI: male accessory gland infection (e.g. epididymitis, prostatitis). contamination or poorly associated with symptoms (Korrovits et al., 2006). Another indication for a possible bacterial contamination is the frequent isolation of (11 patients) and coagulase-negative taphylococci (10 patients) usually not considered as a pathogen in the genitourinary tract in otherwise healthy patients. The clinical relevance of Corynebacterium glucuronolyticum, which was isolated in four patients, remains open to debate as well. ome authors consider these bacteria as a part of the normal periurethral flora and thus are considered common urinary contaminants (Montagnini paine et al., 2000; Damirayakhian et al., 2006). Considering these facts, the ratio of patients suffering from CP related to chronic bacterial infections probably turns out to be even smaller. Nevertheless, more than one third of our patients had experienced a urinary tract infection before, in particular an acute epididymitis (Table 1). Therefore, this suggests a potential role of post-infectious alterations in the aetiology of CP. In patients with a history of a previous urinary tract infection or male accessory gland infection (MAGI) the isolated bacterial strains within the study assessment were different from the previous strains or types except for one patient (patient 15 in Table 2). This supports the notion that rather than a recurrent or chronic infection, postinfectious inflammatory reactions might play a role in CP. To further elucidate this hypothesis assessing cytokine levels in seminal plasma could be a next step to help better understand underlying causes of CP (Martinez-Prado & Camejo Bermúdez, 2010). With regard to our study population, the previous treatment with antibiotics was most probably unnecessary in many of our study patients. Moreover, this treatment neither eliminated nor improved their symptoms sufficiently, which is reflected by the multiple consultations with different doctors. Thus, the treatment of the symptoms summarized as CP is a challenging problem for urologists (Nickel et al., 2002; Nickel, 2003; trebel et al., 2005; trom & Levine, 2008). This perception is supported by our data, demonstrating that CP has a considerable impact on the quality of life of afflicted patients. This is emphasized by the high average CEI score of 17 patients. Accordingly, Nickel et al. (2002) found a similarly high average 2012 American ociety of Andrology and European Academy of Andrology Andrology, 2013, 1,

4 R. T. trebel et al. CEI score of 13.8 in their group of 50 patients with chronic epididymitis. The fact that the majority of patients we examined had consulted physicians one to eight times before being referred to our department underlines the considerable burden of disease for these patients. Owing to the fact that the CP is associated with a high burden of disease and its infrequent association with a bacterial infection, parameters to predict an infectious aetiology would be of help in the management of this disease. We tested several clinical parameters for their association with a bacterial infection. However, we found only two parameters that were significantly associated with the outcome of the microbiological results: The total CEI score and the quality-of-life domain of the CEI. However, their inverse correlation was not very strong, and therefore probably not of help to base clinical decisions upon these parameters. We are aware of the fact that the small number of patients in the subgroups limits our results. Another limitation is the fact that our study population represents a pre-selected group of patients, as many of them have been seen by a doctor previously. However, we observed no differences in the CEI score or detection rate of bacteria between patients with and without previous assessment of their CP. Nevertheless, our results should not be generalized to a population of men presenting themselves with CP for the first time to a doctor. Noteworthy is the fact that the detection of a varicocoele was missed in six patients in previous medical assessments. Patients with a varicocoele complain frequently about scrotal pain (Chen & Chen, 2011). Thus, examining patients with scrotal pain should always include an assessment for varicocoele. The fact that this pathology was not recognized warrants education of general practitioners. ome authors argue that in association with elevated cytokine levels any detected microorganisms are indicative for the presence of an infection, at least in patients with chronic pelvic pain syndrome (Korrovits et al., 2006). Moreover, several authors support the notion that elevated cytokines (e.g. interleukin-6 and interleukin-8, tumour necrosis factor-a) are surrogate markers for an infectious and/or inflammatory aetiology in patients suffering from chronic pelvic pain syndrome and/or infertility (Khadra et al., 2006; Mazzoli et al., 2007; Lotti et al., 2011). Haidl et al. demonstrated a relationship between elevated cytokines such as interleukin-6 and interleukin-8 and sperm quality in men with fertility problems (Haidl et al., 2008; La Vignera et al., 2011). In addition, Martinez-Prado and Camejo Bermudez demonstrated a correlation between elevated interleukin-6 and interleukin-8 and the presence of pathogens and leucocytes in semen (Martinez-Prado & Camejo Bermúdez, 2010). To our knowledge, however, so far no studies have been reported testing this theory in patients with CP. Therefore, we renounced to test for parameters of inflammation such as cytokines at this point in time of our study. Thus, for this study we considered that only positive cultures or PCR results justify an antibiotic treatment in patients with CP not suffering from infertility. Likewise, we did not evaluate the presence of leucocytes in seminal specimen. This fact, however, is another limitation of our study as several studies demonstrated that the leucocyte concentration in the ejaculate is correlated with the presence of bacteria and thus is a wellestablished parameter in the assessment for MAGI (Hosseinzadeh et al., 2004; Lackner et al., 2006; La Vignera et al., 2011). In summary, our study confirms that: 1The CP is associated with a high level of discomfort for the patients. 2A bacterial aetiology is infrequently encountered in patients with CP. Our study emphasizes the need for trials testing new therapeutic and diagnostic approaches to counsel and treat patients suffering from CP. One potential next step to further elucidate the knowledge about CP is to design a study with assessment for leucocyte concentration in the ejaculate in conjunction with established inflammatory parameters, such as interleukins, elastase and tumour necrosis factor-a. In addition, the presented results should help to reduce the uncritical prescription of antibiotics particularly in the light of increasing resistance of bacteria to antibiotics and its associated morbidity such as septicaemia after prostate biopsy (Patel et al., 2011). CONCLUION We conclude that the widespread use of antibiotic agents in the treatment of patients presenting with CP is not justified. ACKNOWLEDGEMENT The study was designed by R, C and JB collected the data and performed the statistical analyses. C and R wrote the manuscript. All authors revised the manuscript critically before submission. In addition, we would like to thank Damina Balmer for her excellent assistance in the preparation of the manuscript. We are grateful for the excellent support we received from Malgorzata Roos from the Institute of ocial and Preventive Medicine, Biostatistics Unit, University of Zurich. The authors have nothing to disclose. The study has been funded by the medical faculty of the University of Zurich. REFERENCE Calleary JG, Masood J & Hill JT. (2009) Chronic epididymitis: is epididymectomy a valid surgical treatment?int J Androl 32, Chen LK & Chen. (2011) Risk factors for developing pain in normospermic patients with varicocele. Int J Androl 35, doi: /j x Damirayakhian M, Jeyendran R & Land A. (2006) ignificance of semen cultures for men with questionable semen quality. Arch Androl 52, Granitsiotis P & Kirk D. (2004) Chronic testicular pain: an overview. Eur Urol 45, Haidl G, Allam JP & chuppe HC. (2008) Chronic epididymitis: impact on semen parameters and therapeutic options. Andrologia 40, Hosseinzadeh, Eley A & Pacey AA. (2004) emen quality in men with asymptomatic chlamydial infection. J Androl 25, Khadra A, Fletcher P, Luzzi G, hattock R & Hay P. (2006) Interleukin-8 levels in seminal plasma in chronic prostatitis/chronic pelvic pain syndrome and nonspecific urethritis. BJU Int 97, Korrovits P, Punab M, Türk & Mändar R. (2006) eminal microflora in asymptomatic inflammatory (NIH IV category) prostatitis. Eur Urol 50, La Vignera, Vicari E, Condorelli RA, D Agata R & Calogero AE. (2011) Male accessory gland infection and sperm parameters. Int J Androl 34 (5 Pt 2), e330 e347. doi: /j x. Epub 2011 Jun 22. Review. Lackner JE, Herwig R, chmidbauer J, chatzl G, Kratzik C & Marberger M. (2006) Correlation of leukocytospermia with clinical infection and 158 Andrology, 2013, 1, American ociety of Andrology and European Academy of Andrology

5 INFECTION IN PATIENT WITH CHRONIC CROTAL PAIN YNDROME the positive effect of anti-inflammatory treatment on semen quality. Fertil teril 86, Lotti F, Corona G, Mancini M, Filimberti E, Degli Innocenti, Colpi GM et al. (2011) Ultrasonographic and clinical correlates of seminal plasma interleukin-8 levels in patients attending an andrology clinic for infertility. Int J Androl 34, Martinez-Prado E & Camejo Bermúdez MI. (2010) Expression of IL-6, IL-8, TNF-alpha, IL-10, HP-60, anti-hp-60 antibodies, and antisperm antibodies, in semen of men with leukocytes and/or bacteria. Am J Reprod Immunol 63, Mazzoli, Cai T, Rupealta V, Gavazzi A, Castricchi PR, Mondaini N & Bartoletti R. (2007) Interleukin 8 and anti-chlamydia trachomatis mucosal IgA as urogenital immuno-logical markers in patients with C. trachomatis prostatic infection. Eur Urol 51, Meares EM & tamey TA. (1968) Bacteriologic localization patterns in bacterial prostatitis and urethritis. Invest Urol 5, Montagnini paine D, Mamizuka EM, Pereira Cedenho A & rougi M. (2000) Microbiological aerobic studies on normal male urethra. Urology 56, Nickel JC. (2003) Chonic epididymitis: a practical approach to understanding and managing a difficult urologic enigma. Rev Urol 5, Nickel JC, iemens DR, Nickel KR & Downey J. (2002) The patient with chronic epididymitis: characterization of an enigmatic syndrome. J Urol 167, Patel U, Dasgupta P, Amoroso P, Challacombe B, Pilcher J & Kirby R. (2011) Infection after trans-rectal ultrasonography-guided prostate biopsy: increased relative risks after recent international travel or antibiotic use. BJU Int 109, [Epub ahead of print]. doi: /j X x trebel RT, Leippold T, Luginbuehl T, Muentener M, Praz M & Hauri D. (2005) Chronic scrotal pain syndrome: management among urologists in witzerland. Eur Urol 47, trom KH & Levine LA. (2008) Microsurgical denervation of the spermatic cord for chronic orchialgia: long-term results from a single center. J Urol 180, APPENDIX APPENDIX 1. CEI core 1. How often have you had pain or discomfort in the scrotal/ testicular area over the last week? 0 s Never, 1 s Rarely, 2 s ometimes, 3 s Often, 4 s Usually, 5 s Always 2. Which number best describes your average level of pain or discomfort in the scrotal/testicular area, on the days that you had pain, over the last week (0: no pain, 10: pain as bad as you can imagine)? s0 s1 s2 s3 s4 s5 s6 s7 s8 s9 s10 3. How much have your symptoms kept you from doing the kind of things you would usually do, over the last week? 0 s None, 1 s Only a little, 2 s ome, 3 s A lot 4. How much did you think about your symptoms over the last week? 0 s None, 1 s Only a little, 2 s ome, 3 s A lot 5. If you were to spend the rest of your life with your symptoms just the way they have been during the last week, how would you feel about it? 0 s Delighted, 1 s Pleased, 2 s Mostly satisfied, 3 s Mixed (about equally satisfied and dissatisfied), 4 s Mostly dissatisfied, 5 s Unhappy, 6 s Terrible coring the CEI Pain: total of items 1 and Quality of life impact: total of items 3, 4 and Total: pain score plus quality of life impact 0 27 core (range) 2012 American ociety of Andrology and European Academy of Andrology Andrology, 2013, 1,