Introduction
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition that significantly reduces men's quality of life and often frustrates physicians due to a lack of highly effective treatment. Its prevalence is 8.2% or even higher [1—3].
Acute and chronic bacterial prostatitis are the most well-studied entity; they are caused by known uropathogens and are relatively well treated. However, they account for no more than 10% of all prostatitis cases. However, sexually transmitted infections (STIs) are the most important risk factor for chronic prostatitis. Neisseria gonorrhoae and Trichomonas vaginalis can cause direct inflammatory damage to the prostate. Enough evidence on the contribution of Chlamydia trachomatis, Mycoplasma genitalium, Ureaplasma spp. is available, but the exact pathophysiological pathways of prostate damage in these cases have not been studied.
Nonbacterial prostatitis, or CPPS, is diagnosed when a four- or two-glass test using pre- and post-massage samples does not reveal a relevant bacterial agent and an increased leucocyte count in the prostate secretion of men with CP/CPPS of IIIA category is observed. Standard treatment with fluoroquinolone antibacterials is often ineffective, suggesting an unidentified etiological agent, possibly of viral origin.
With the introduction of molecular genetic techniques, an era of rigorous urogenital sample testing for a wide range of STIs has dawned. Our previous studies have shown that some herpesviruses (Epstein-Barr virus [EBV], cytomegalovirus [CMV], and human herpes virus type 6 [HHV-6]) are associated with urogenital tract diseases, such as inflammation of accessory genital glands (prostate, seminal vesicles, seminal duct, and epididymis) and infertility [4, 5].
Other studies showed similar results [6—8].
Thus, herpesvirus-associated CP/CPPS are becoming more common in the clinical practice of specialists involved in the treatment of STIs and their complications. Thus, it is crucial to describe a clinical characterization of CP/CPPS associated with HEB, CMV and HBV-6.
Materials and methods
A total of 287 males with CP/CPPS were included; 103 had type IV–VI herpesviruses detected in urogenital specimens (group I), and in 184 males, no herpesviruses were detected (group II). The diagnosis and severity of the disease were verified according to the guidelines of the European Association of Urology (Rees). Qualitative polymerase chain reaction (PCR) with Lytech primers was used to detect STIs. Detection of type IV-VI herpesviruses was performed using quantitative real-time PCR by InterLabService Ltd. Urinary and erectile dysfunctions were assessed using the international validated IPSS and IIEF-5 questionnaires; mental status was assessed using the Hospital Anxiety and Depression Scale (HADS). The following instrumental studies were performed: uroflowmetry (Laborie Urocap III, Canada) and transrectal ultrasound scanning (GE Voluson 730 Expert, USA).
Results
The age of the included 287 males with underlying CP/CPPS ranged from 23 to 65 years (mean 37.1±11.2 years), the history of disease duration ranged from 1 to 23 years (mean 7.5±6.7 years), and the symptoms duration at the time of presentation ranged from 3 to 12 months. Twenty-three patients were in a sterile marriage.
Molecular genetic examination revealed STIs in 14 patients: Chlamydia trachomatis (4 subjects), Trichomonas vaginalis (2 subjects), M. genitalium (3 subjects) and U. urealyticum (5 subjects). Urethritis was verified in 9 patients according to clinical and laboratory criteria: Chlamydia trachomatis (3 subjects), Trichomonas vaginalis (1 subject), M. genitalium (2 subjects), U. urealyticum (3 subjects). In all 9 cases of urethritis, the leukocyte count did not exceed 20 per power field, which corresponded to low-grade inflammation [9].
In 5 of these 9 patients, scanty serous discharge with a tendency to self-limiting is observed. However, urethral symptoms (dysuria, burning, urethral discomfort) without microscopic confirmation of urethritis were noted in 5 of 14 patients with STI.
Patients of different groups did not differ in age, duration of disease (7.5±10.6 years), duration of symptoms (4.7±3.8 months), presence of intercurrent diseases (54.7%), etc. Statistical processing revealed that 38 (36.9%) out of 103 patients in group I reported a history of chronic prostatitis treatment; in group II — 41 (22.3%) out of 184. The difference between the groups was significant (p=0.008).
In addition, a history of urethral STIs was reported in 47 (45.6%) of 103 patients in group I; and 51 (27.7%) of 187 patients in group II (p=0.003). Thus, men with CP/CSTB associated with type IV-VI herpesviruses were on average twice as likely to have a history of CP and urethral STI treatment.
It is worth noting that infertility as a comorbidity was observed in 23 males: 8 (7.8%) in group I and 15 (8.2%) in group II.
Patients complained of pain in the perineum — 192 (66.9%), scrotum — 58 (20.2%), penis — 36 (12.5%), below the waist or suprapubic region — 33 (11.5%). Pain appeared or increased during (or after) urination in 27 (15.4%) patients and ejaculation in 16 (8.7%).
Disease severity was assessed by the total NIH-CPSI score. Thus, 89 patients had mild symptoms (NIH-CPSI < 15 points), 186 patients had moderate symptoms (with NIH-CPSI 15—29 points), and 12 patients had severe symptoms (NIH-CPSI > 30 points). The mean NIH-CPSI score was 24.3±4.2. It is important to note that there were no differences in the frequency of complaints and severity of CP/CPPS between the groups.
CP/CPPS symptoms have a significant impact on patients' mental wellbeing. In this regard, it seems important to assess the main indicators of mental health — depression, and anxiety, which were determined using the Hospital Anxiety and Depression Scale (HADS) (Table 1).
Table 1. Psychosocial disorders in Group I and II patients
|
Condition |
Group I (n=103) |
Group II (n=184) |
p |
|
Depression |
|||
|
n (%) |
73 (70.9) |
83 (45.1) |
0.001a |
|
scores |
7.4±2.9 |
6.8±2.3 |
|
|
Anxiety |
|||
|
n (%) |
29 (28.2) |
31 (16.8) |
0.02b |
|
scores |
5.8±3.9 |
6.1±3.7 |
Note. aχ2=17.669, the critical value of χ2 at significance level is 6.635; bχ2=5.426, the critical value of χ2 at significance level is 3.841.
Data analysis showed that signs of subclinical depression were significantly more common in group I (73/70.9%) vs. group II (83/45.1%). Similarly, subclinical anxiety was significantly more common in group I (29/28.1%) vs. group II (31/16.8%).
Results
Morphological parameters of the prostate (volume, homogeneity of tissues, presence of calcinates, foci of fibrosis, and cysts) were determined in all patients using transrectal Doppler ultrasound. The normal volume of the prostate gland does not exceed 20 cm3. However, with aging and inflammatory diseases due to tissue swelling, prostate enlargement is often observed. Several diseases were ruled out using transrectal Doppler ultrasound: abscess, cancer, benign prostatic hyperplasia, etc. To assess bladder disturbances, the residual urine volume after micturition was measured using the bladder ultrasound. The study data are summarized in Table 2.
Table 2. Morphological parameters assessment of the prostate and bladder in groups I and II patients
|
Parameter |
Group I (n=103) |
Group II (n=184) |
p |
|
Prostate volume, cm3 |
21.1±5.2 |
23.1±6.1 |
>0.05 |
|
Prostate calcinates |
82 (79.6%) |
136 (73.9%) |
>0.05 |
|
Prostate focal fibrosis |
43 (41.7%) |
96 (52.2%) |
>0.05 |
|
Prostate cysts |
10 (9.7%) |
20 (10.9%) |
>0.05 |
|
Abnormal ultrasound of the seminal vesicles |
18 (25.2%) |
33 (17.9%) |
>0.05 |
|
Residual urine, mL |
29.7±18.1 |
31.2±16.8 |
>0.05 |
The analysis of the results showed that the most common ultrasound sign of CP/CPPS is prostate calcinates. The ultrasound pattern of vesiculitis was observed in 17.9—28.1% of patients.
An important instrumental examination in patients with CP/CPPS is uroflowmetry, which reflects urinary dysfunction due to infravesical obstruction by an enlarged prostate. Table 3 presents uroflowmetry parameters in patients of the two groups.
Table 3. Urine flow rate in patients of I and II groups, mL/sec
|
Parameter |
Group I (n=103) |
Group II (n=184) |
p |
|
Maximum urine flow rate (Qmax) |
11.9±5.1 |
13.8±4.7 |
>0.05 |
|
Average urine flow rate (Qav), mL/s |
7.1±1.9 |
7.5±1.9 |
>0.05 |
Analysis of the results showed that group I patients tended to have more urinary difficulties, but the differences were not significant (p > 0.05)
Uroflowmetry parameters were analyzed separately in patients with at least 5 points in the urinary domain of the NIH-CPSI scale (n=84). In this cohort of patients, the maximum urine flow rate (Qmax) was 13.8±2.6 mL/s, and the average rate (Qav) was 7.5±1.7 mL/s for urine volumes over 200 mL; which was similar to the mean of all 287 patients regardless of their complaints. Thus, it is not appropriate to rely on the patient's complaints (or lack thereof) alone to assess the degree of urinary dysfunction. An objective assessment using uroflowmetry is required.
Discussion
Sexual transmission of herpesviruses is a well-studied phenomenon, but it is difficult to estimate the frequency of this transmission route and its contribution to overall morbidity.
In a study by D.H. Crawford et al. (2002), including over 1000 students in Edinburgh, it was shown that EBV-seropositivity was significantly higher among sexually active individuals (82.7%) than among those who were not sexually active (63.7%); p<0.001). Furthermore, having more sexual partners was a strong risk factor for EBV-seropositivity. Two-thirds of infectious mononucleosis cases were related to sexual contact. Evidence suggests that transmission of EBV occurs during sexual intercourse or related bodily contact [10].
A recent study [11] has also shown that sexual activity significantly affects cytomegalovirus seropositivity in the population. Similar data were obtained for HHV-6 [12].
It is known that EBV, CMV, and HPV have been detected on vaginal ultrasound probes, which also confirms iatrogenic and sexual routes of transmission [13].
The results of our study indicate that patients with a history of herpesvirus types IV-VI had a higher incidence of urethral STIs (45.6% vs. 27.7% in the comparison group) and may have been infected via sexual route.
Clinical data analysis showed that males with virus-associated CP/CPPS were significantly more likely to have a history of CP treatment (36.9% vs. 22.2% in the comparison group). Since antiviral drugs are not included in standard CP/CPPS therapy, relapse of this type of disease seems to be a natural occurrence, which explains the more frequent treatment courses for CP/CPPS associated with types IV-VI herpesviruses.
The routine workup for urethritis includes tests for N. gonorrhoae, T. vaginalis, C. trachomatis, M. genitalium, HSV-1,2 but not for type IV-VI herpesviruses and HPV-HR. Infection with herpesviruses is lifelong. It may explain the higher recurrence rate of nonbacterial prostatitis associated with these viruses after antibacterial treatment usually administered in such cases. It may also explain a more frequent (36.9%) history of CP/CPPS treatment in patients with the viral infection.
According to the published data [14—16], the prevalence of psychosocial disorders in CP/CPPS patients ranges from 42% to 74%. In this study, similar values were obtained in the main group I and in the comparison group II. However, depression and anxiety were more common in patients with virus-associated CP/CPPS, consistent with a more common history of urethral STIs and inadequate standard therapy for virus-associated CP/CPPS in these males.
Conclusion
The study results showed that males with CP/CPPS associated with EBV, CMV, and HHV-6 were significantly more likely to have a history of urethral STIs and therapy courses for CP. It has also been shown that males with CP/CPPS associated with type IV-VI herpesviruses are at higher risk for psychosocial disorders, such as depression and anxiety, which significantly affect the quality of life.
Authors’ contributions
V.P. Kovalyk: conducting clinical and diagnostic studies, following the patients, reviewing of publications and writing the text of case report;
M.A. Gomberg: reviewing of publications and writing the text of case report, scientific advice;
K.I. Yurlov: carrying out quantitative studies for herpes viruses;
A.A. Kushch: carrying out quantitative studies for herpes viruses, scientific advice.
The authors declare no conflict of interest.