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

Authors


Correspondence:

Räto T. Strebel, Department of Urology, Kantonsspital Graubünden, Loëstr. 170, 7000 Chur, Switzerland.

E-mail: raeto.strebel@ksgr.ch

Summary

Data supporting the widespread use of antibiotics in patients with chronic scrotal pain syndrome (CSPS) are not available. Therefore, the aim of this study was to investigate the presence of bacteria in the genitourinary tract in patients presenting with CSPS. From July 2005 to July 2007 we prospectively enrolled patients presenting with CSPS 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-Stamey 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 (CESI) score according to Nickel et al. (J Urol 2002, 167:1701; based on the NIH-CPSI). A total of 55 eligible men (median age 34 years) with CSPS were enrolled in the study. The median CESI score was 17 (range 4–26). The majority of patients (= 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 Alpha-haemolytic Streptococcus (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 CSPS could be identified. In our microbiological assessment of patients presenting with CSPS we found no evidence for the widely held belief that CSPS 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 CSPS is not justified.

Introduction

The chronic scrotal pain syndrome (CSPS) 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 Swiss urologists, 98% considered infections to play a role in the aetiology of CSPS (Strebel et al., 2005). Accordingly, up to 82% of patients with CSPS 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 CSPS 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 CSPS and to identify parameters associated with an infectious aetiology.

Materials and methods

Between July 2005 and July 2007 all patients presenting with CSPS 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-Stamey 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 & Stamey, 1968). A bacterial colony count in any urine sample higher than 104/mL was considered significant, whereas in semen probes a bacterial colony count >104/mL in pure and >105/mL in mixed bacterial cultures were considered significant.

The symptom severity was assessed with the chronic epididymitis symptom index (CESI score, appendix 1) according to Nickel et al. (2002), which is based on the NIH-CPSI (National Institutes of Health Chronic Prostatitis Symptom Index). It consists of a pain and quality-of-life subscore. By combining the two domains, a total CESI 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. Statistical analyses were performed using commercially available statistical software (spss; Chicago, IL, USA). For correlation analyses, Fisher's exact test and logistic regression models were applied. A p-value <0.05 was considered significant.

Results

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 CSPS for the first time. The majority of patients (= 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 0.4–14 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
ParameterAll patients (= 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 visit at previous physician to first consultation within study centre (= 39)36.3 (3–97)
Median CESI score
 Total (range)17 (7–27)
  Pain subscore (range)8 (2–15)
  Quality-of-life subscore (range)8 (3–12)
No. medical history (%)
 Scrotal or groin surgery12 (22)
  Vasectomy0
 Urinary tract infections20 (36)
  Acute epididymitis10 (18)
  Urethritis5 (9)
  Cystitis5 (9)
 Irritative voiding disorder12 (22)
 Diabetes mellitus0
 Cardiovascular disease7 (13)
 Neurological disorders11 (20)
 Depression11 (20)
 Allergies17 (31)
Sexual history (%)
 No. sexually active46 (84)
 No. exclusively heterosexual54 (98)
 No. history of sexually transmitted disease1 (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.

Table 2. Distribution of positive specimens and isolated bacteria
PatientPositive specimenIsolated bacteriaCFU/mLCCRHistory of UTI or MAGI
  1. Pat: Patient ID; VB1: First voided urine; VB2: Mid-stream urine; EPS: Expressed prostatic secretion; VB3: Post-prostatic massage urine; S: Semen culture; CCR: considered clinically relevant; UTI: urinary tract infection; MAGI: male accessory gland infection (e.g. epididymitis, prostatitis).

15VB3

Alpha-haemolytic Streptococcus

Citrobacter koseri

Corynebacterium glucoronolyticum

104

>105

104

YesNo
16S Enterococcus sp.>105YesYes (epididymitis)
17S Corynebacterium glucoronolyticum 104–105UnclearYes (urethritis)
18SAlpha-haemolytic Streptococcus>104NoNo
21

VB1, VB2

S

Lactobacillus sp.

Lactobacillus sp.

104

105

NoNo
24S

Alpha-haemolytic Streptococcus

Coagulase-negative

Staphylococcus

Corynebacterium sp.

105

105

105

UnclearNo
28VB1 Enterococcus sp.104–105YesYes (UTI)
29SCoagulase-negative Staphylococcus104–105NoYes (urethritis)
30S

Mycoplasma hominis

Ureaplasma urealyticum

Alpha-haemolytic Streptococcus

105

104

105

YesYes (epididymitis)
33S

Corynebacterium glucoronolyticum

Alpha-haemolytic Streptococcus

>105

104

UnclearNo
39SBeta-haemolytic Streptococcus B104YesNo
42S

Alpha-haemolytic Streptococcus

Coagulase-negative Staphylococcus

Neisseria sp.

105

105

105

UnclearNo
44S

Alpha-haemolytic Streptococcus

Coagulase-negative Staphylococcus

105

104

NoNo
45SAlpha-haemolytic Streptococcus105NoYes (UTI)
  Coagulase-negative Staphylococcus105  
46

VB1, 2, 3

S

Beta-haemolytic Streptococcus B

Enterococcus

Gardnerella vaginalis

Ureaplasma urealyticum

105

105

105

105

YesNo
47SCoagulase-negative Staphylococcus104–105NoYes (epididymitis)
49EPSCoagulase-negative Staphylococcus104NoNo
50

VB1

VB3

Alpha-haemolytic Streptococcus

Coagulase-negative Staphylococcus

104

104

NoNo
51VB2Coagulase-negative Staphylococcus105NoNo
52

VB2

EPS

EPS

S

Alpha-haemolytic Streptococcus

Beta-haemolytic Streptococcus B

Coagulase-negative Staphylococcus

Coagulase-negative Staphylococcus

104

104

105

104

YesNo
54S

Enterococcus sp.

Alpha-haemolytic Streptococcus

105

105

YesNo

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 CSPS 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 CESI score were analysed to test their association with positive or negative microbiological findings. Only the total CESI score and the quality-of-life domain of the CESI showed a statistically significant association with microbiological test results. However, these two parameters were inversely correlated with positive microbiological findings: The higher the total CESI scores (r = −0.33, = 0.015) or quality-of-life domain (r = −0.37, = 0.005), the lower the probability for a positive bacterial culture result.

Discussion

In our microbiological assessment of patients presenting with CSPS we found no evidence for the widely held belief that CSPS 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 contamination or poorly associated with symptoms (Korrovits et al., 2006). Another indication for a possible bacterial contamination is the frequent isolation of Alpha-haemolytic Streptococcus (11 patients) and coagulase-negative Staphylococci (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. Some authors consider these bacteria as a part of the normal periurethral flora and thus are considered common urinary contaminants (Montagnini Spaine et al., 2000; Damirayakhian et al., 2006). Considering these facts, the ratio of patients suffering from CSPS 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 CSPS. 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, post-infectious inflammatory reactions might play a role in CSPS. To further elucidate this hypothesis assessing cytokine levels in seminal plasma could be a next step to help better understand underlying causes of CSPS (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 CSPS is a challenging problem for urologists (Nickel et al., 2002; Nickel, 2003; Strebel et al., 2005; Strom & Levine, 2008). This perception is supported by our data, demonstrating that CSPS has a considerable impact on the quality of life of afflicted patients. This is emphasized by the high average CESI score of 17 patients. Accordingly, Nickel et al. (2002) found a similarly high average CESI 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 CSPS 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 CESI score and the quality-of-life domain of the CESI. 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 CESI score or detection rate of bacteria between patients with and without previous assessment of their CSPS. Nevertheless, our results should not be generalized to a population of men presenting themselves with CSPS 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.

Some 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-α) 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 CSPS. 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 CSPS 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 well-established 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:

  1. The CSPS is associated with a high level of discomfort for the patients.

  2. A bacterial aetiology is infrequently encountered in patients with CSPS.

Our study emphasizes the need for trials testing new therapeutic and diagnostic approaches to counsel and treat patients suffering from CSPS. One potential next step to further elucidate the knowledge about CSPS 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-α. 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).

Conclusion

We conclude that the widespread use of antibiotic agents in the treatment of patients presenting with CSPS is not justified.

Acknowledgements

The study was designed by RS, CS and JB collected the data and performed the statistical analyses. CS and RS 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 Social 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.

Appendix

Appendix 1

CESI Score

1. How often have you had pain or discomfort in the scrotal/testicular area over the last week?

0 ○ Never, 1 ○ Rarely, 2 ○ Sometimes, 3 ○ Often, 4 ○ Usually, 5 ○ 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)?

○0 ○1 ○2 ○3 ○4 ○5 ○6 ○7 ○8 ○9 ○10

3. How much have your symptoms kept you from doing the kind of things you would usually do, over the last week?

0 ○ None, 1 ○ Only a little, 2 ○ Some, 3 ○ A lot

4. How much did you think about your symptoms over the last week?

0 ○ None, 1 ○ Only a little, 2 ○ Some, 3 ○ 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 ○ Delighted, 1 ○ Pleased, 2 ○ Mostly satisfied, 3 ○ Mixed (about equally satisfied and dissatisfied), 4 ○ Mostly dissatisfied, 5 ○ Unhappy, 6 ○ Terrible

Scoring the CESIScore (range)
Pain: total of items 1 and 20–15
Quality of life impact: total of items 3, 4 and 50–12
Total: pain score plus quality of life impact0–27

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