Prostate Inflammation

Mark J. Salji^1,2,3, Truls E. Bjerklund Johansen⁴, and Hing Y. Leung^1,2,3,5

¹ Department of Urology, NHS Greater Glasgow and Clyde, Glasgow, UK

² Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

³ Beatson Institute for Cancer Research, Glasgow, UK

⁴ Department of Urology, Oslo University Hospital, Oslo, Norway

⁵ The Beatson West of Scotland Cancer Centre, NHS Greater Glasgow and Clyde, Glasgow, UK

Abstract

Prostatitis is an umbrella term encompassing a spectrum of disease from asymptomatic inflammatory prostatitis to bacterial prostatitis and chronic pelvic pain syndrome. The estimated prevalence is between 10 and 14% [1]. Prostatitis can occur in all age groups but is most common in younger men, causing significant morbidity and subsequent economic impact [2, 3]. Chronic prostatitis has recently been considered an important factor in the progression of benign prostatic hyperplasia (BPH) [4] and is thought to be one of the most common reasons for a man younger than 50 years to go to a urologist. During the last decade, we have seen an increase in the incidence of acute bacterial prostatitis and urosepsis after transrectal ultrasound (TRUS)‐guided prostate biopsies [5].

Keywords prostate; prostatitis; classification; inflammation; abscess

Key Points

Recent classifications of prostatitis describe four distinct categories: (i) acute bacterial prostatitis, (ii) chronic bacterial prostatitis, (iiia) inflammatory and (iiib) non‐inflammatory chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), and (iv) asymptomatic inflammatory (histological) prostatitis.
The Meares and Stamey four‐glass urine collection with microscopy and culture is the gold standard for localisation of infection to bladder, prostate, and urethra.
Intravenous aminoglycosides followed by second‐generation fluoroquinolone antibiotic treatment for two to four weeks is the preferred treatment for acute bacterial prostatitis.
If a prostatic abscess is confirmed on imaging, a transurethral abscess de‐roofing is the preferred drainage method. Surgical treatment options for CP/CPPS remain experimental.

26.1 Classification of Prostatitis

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) updated the classification of prostatitis in 1999 to the current definitions of four distinct categories of prostatitis (summarised in Table 26.1) [6]. Acute and chronic bacterial prostatitis (NIH I/II) are thought to account for only 5–10% of all cases of prostatitis; the remainder are chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) which represents more than 90% of patients with a diagnosis of prostatitis [1].

Table 26.1 Definitions of four distinct categories of prostatitis.

(Source: Adapted from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Classification of prostatitis [6]).

Category	Symptoms / Signs	WBCs in EPS	NIDDK Classification	Description
I	Pain, bacteraemia, leucocytosis with or without systemic sepsis	Positive	Acute bacterial prostatitis	Bacterial infection of the prostate causing systemic sepsis.
II	Intermittent pain, bacteriuria, and pyuria	Positive	Chronic bacterial prostatitis	Intermittent symptoms >3 months. Rare cause of recurrent UTIs.
IIIa	Pain + sterile pyuria	Positive	Inflammatory CP/CPPS	Encompasses >90% of prostatitis diagnosis. Aetiology is unknown. Associated with sexual dysfunction and psychological issues.
IIIb	Pain + no pyuria	Negative	Noninflammatory CP/CPPS
IV	No pain only pyuria with or without bacteriuria	Positive	Asymptomatic inflammatory prostatitis	Incidental evidence of prostatitis on TRUS biopsy

CP, chronic prostatitis; CPPS, chronic pelvic pain syndrome; EPS, expressed prostatic sections; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; TRUS, transrectal ultrasound; UTI, urinary tract infection; WBCs, white blood cells.

26.1.1 Category I: Acute Bacterial Prostatitis

Acute bacterial prostatitis used to be a rare condition, resulting from acute ascending infection of uro‐pathogenic faecal flora, commonly Escherichia Coli; other gram‐negative pathogens include Proteus, Klebsiella, Pseudomonas, and Serratia spp., and rarely, gram‐positive organisms such as Enterococcus faecalis. Urinary tract infections (UTIs), urethral strictures, phimosis, indwelling urethral catheters, instrumentation of the lower urinary track, prostatic stones, and unprotected anal sexual intercourse are predisposing factors.

Clinically, sepsis and localised pain (e.g. perineal, suprapubic, penile, or genitalia) can elude to the diagnosis. Some patients may present with significant worsening of lower urinary tract symptoms (LUTS). Acute urinary retention (AUR) is seen in nearly 10% of cases requiring suprapubic or urethral catheterisation. Examination elicits a tender swollen prostate on digital rectal examination (DRE). Urethral catheterization can be extremely painful, and in such cases, suprapubic catheterization is recommended. Prostatic massage is contraindicated because it can provoke septicaemia. Bed rest, analgesia, and laxatives are also an important part of the management to aid recovery.

Today, acute prostatitis is seen more often due to an increasing number of transurethral ultrasound (TRUS) biopsies being taken. Patients must be informed about this complication before TRUS biopsy, and in case of a febrile reaction, they should be hospitalised as an emergency for intravenous treatment with antibiotics [7].

Acute prostatitis can lead to the chronic form or to abscess formation if antibiotics treatments fail. Abscess should be considered if symptoms persist despite appropriate antibiotics, especially in patients who are diabetic, or those who are immunocompromised, have renal failure, or are catheterised.

26.1.2 Category II: Chronic Bacterial Prostatitis

This form of prostatitis accounts for about 10% of cases and can be associated with recurrent UTIs. Similar organisms may be isolated as in acute prostatitis. The infection is thought to occur in the peripheral zone as ductal drainage here allows more reflux. Infected urine refluxes into the prostatic ducts that drain into the posterior urethra, causing oedema and inflammation, which can obstruct the ducts, leading to deep rooting and trapping of bacteria. It can also be associated with prostatic calculi, creating a nidus for recurrent infection. Patients may complain of painful ejaculation, perineal or suprapubic pain, and obstructive LUTS lasting for more than three months.

26.1.3 Category IIIa: Inflammatory Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Category IIIb: Non‐inflammatory

Categories IIIa/b together represent about 90% of patients with a diagnosis of prostatitis. Prostatitis is most common between the ages of 36 and 65 years [3]. Its aetiology remains unclear; however, high‐pressure voiding and reflux of urine into prostatic ducts, nonculturable microorganisms [8], autoimmune disease [9], and neuropathic and interstitial cystitis‐like processes have been suggested. Symptoms include localised pain, pain with ejaculation, LUTS, and erectile dysfunction lasting for more than three months. Diagnosis of inflammatory prostatitis (NIH IIIa) justifies using a test course of antibiotics, which may be prolonged in the case of symptom relief. Diagnosis is made by means of microscopy (two‐glass or four‐glass tests) in patients presenting with chronic pelvic pain and negative culture tests.

The inflammatory subset (NIH IIIa) is characterised by leucocytes in expressed prostatic secretions (EPS) or postmassage urine. Associated LUTS, sexual dysfunction, and mental health problems are common and can have a huge impact on the patients’ quality of life (QoL). The Chronic Prostatitis Symptom Index (NIH‐CPSI) was developed to quantify three symptom domains: pain, LUTS, and QoL and is useful in both clinical practice and research to quantify these symptoms [6].

26.1.4 Category IV: Asymptomatic Inflammatory (Histological) Prostatitis

Approximately 20% of asymptomatic infertile men have evidence of prostatitis in EPS or semen. Histological evidence of inflammation in prostatic biopsies signifies asymptomatic inflammatory prostatitis. Patients lack any LUTS or pain, and no treatment is required.

26.2 Investigations

26.2.1 Microbial Localisation

The four‐glass urine collection method described by Meares and Stamey in 1968 remains the gold standard of investigation [10]. This involves collecting urine and EPS for microscopy and culture from the urethra, prostate, and bladder as outlined in Table 26.2.

Table 26.2 Four‐glass urine collection method and interpretation of cultures, as described by Meares and Stamey [10].

Sample	Localisation	Method	Active UTI or acute prostatitis All samples positive (NIH I)	Chronic bacterial prostatitis (NIH II)	CP/CPPS and AIP All samples negative (NIH IIIa/b and IV)
VB1	Urethra	1st 10 ml urine	> 10³ CFU ml⁻¹^a		< 10³ CFU ml⁻¹
VB2	Bladder	2nd 10 ml urine	> 10³ CFU ml⁻¹^a		< 10³ CFU ml⁻¹
EPS	Prostate	EPS fluid	> 10³ CFU ml⁻¹^a	> 10x CFU ml⁻¹ of VB1	< 10³ CFU ml⁻¹
VB3	Prostate	3rd 10 ml urine	> 10³ CFU ml⁻¹^a	> 10x CFU ml⁻¹ of VB1	< 10³ CFU ml⁻¹

^a Greater than 10³ CFU per ml is usually considered a positive sample. EPS must be greater than 10 times the CFU ml⁻¹ of VB1 for the diagnosis of chronic bacterial prostatitis (NIH II) [6].

AIP, asymptomatic inflammatory prostatitis; CFU, colony‐forming unit; CP, chronic prostatitis; CPPS, chronic pelvic pain syndrome; EPS, expressed prostatic secretions; NIH, National Institutes of Health; UTI, urinary tract infection.

An alternative to this method is the two‐glass technique suggested by Weidner in 1985. This assumes that urethritis can be ruled out clinically and that postprostatic massage urine reflects the EPS. This simpler technique involves only pre‐ and postprostatic massage urine samples and correlates with the four‐glass technique in 90% of cases [8].

26.3 Imaging

Further imaging may be indicated in persisting acute and chronic bacterial prostatitis (NIH I/II) and when a prostatic abscess is suspected. Magnetic resonance imaging (MRI) or high‐resolution computed tomography (CT) of the pelvis provides a noninvasive method to image the prostate. MRI is preferred for its soft‐tissue differentiation and lack of exposure to ionising radiation in young patients (Figure 26.1). Despite associated discomfort, TRUS may allow transrectal or perineal aspiration of a prostatic collection [11]. Additional imaging in chronic prostatitis remains debatable; however, some series have suggested that low signal intensity (SI) regions in T2‐weighted images can be correlated to regions of histologically confirmed chronic prostatitis from TRUS biopsy [12].

Image described by caption. — **Figure 26.1** Contrast‐enhanced magnetic resonance imaging (MRI) showing multiple prostatic abscesses. T1‐weighted coronal image with a low attenuation region highlighted in the left lobe of the prostate representing a prostatic abscess (a). T2‐weighted coronal image showing the corresponding high attenuation abscess region (b).

26.4 Serum Prostate Specific Antigen

Prostate‐specific antigen (PSA) testing is not recommended for patients with suspected prostatitis. It is certainly not advised in the acute setting. The level of PSA does not appear to correlate well with resolution of prostate inflammation, and its use is to be avoided in acute febrile prostatitis [13].

26.5 Histology

Suspected prostatitis is not an indication for prostate biopsy. However, inflammatory prostatitis is often seen in diagnostic prostatic biopsies for prostate cancer due to elevated PSA levels. The biopsy shows regions of microscopic inflammation characterised by diffuse inflammatory infiltrates. Retrospective studies have shown that most patients with CP or CPPS have only mild inflammation, the extent of which does not correlate with the severity of symptoms, suggesting an alternative aetiology may play a greater role than inflammation alone [14].

26.6 Treatment Options

In the acute setting, patients who are septic might need hospitalisation and intravenous antibiotics and analgesics. Once the patients is stable and well, oral antibiotics can be given. While in the chronic forms, it can be beneficial for the patient to have a multidisciplinary approach with a focus on the predominant symptom and the impact on QoL. Psychiatric teams, psychologists, and physiotherapists can help with counselling, education, biofeedback techniques, stress and anxiety relief, pelvic floor exercises, or even support groups. The pain team can be of vital help for pain management.

26.6.1 Antibiotics

Antibiotics for acute and chronic bacterial prostatitis are broad spectrum with activity against gram‐positive and ‐negative pathogens. The intravenous aminoglycoside, gentamycin with a broad‐spectrum penicillin or a third‐generation cephalosporin, is administered in the acute setting in patients who are unwell with urosepsis. Otherwise current recommended regimens use the second‐generation fluoroquinolones (i.e. ciprofloxacin, ofloxacin, and norfloxacin) [15, 16]. The optimal duration of treatment for acute prostatitis (NIH I) remains unclear but is commonly in the region of four weeks to prevent progression to chronic prostatitis.

Consensus for the treatment of chronic prostatitis (NIH II) is a similarly prolonged treatment course of at least four weeks. Up to 80% of patients are rendered free of infection by culture following treatment with fluoroquinolones, while the infection‐free rate is lower with trimethoprim at about 40% after similar treatment duration [17]. Both of these antibiotics are able to penetrate into the deep prostatic tissue. Trimethoprim has no activity against Pseudomonas and some Enterococci and Enterobacteriaceae.

More recently, resistance to ciprofloxacin is becoming more common and may result in greater use of third‐generation fluoroquinolones such as levofloxacin [18]. Toxicity (including prolonged QT syndrome), side effects (including tendon rupture), and drug interactions (including Warfarin) of fluoroquinolones should be considered carefully when prescribing prolonged courses.

Tetracyclines and macrolides also have good prostatic penetration and are used if culture sensitivity dictate it.

26.6.2 Tamsulosin and Finasteride

The use of alpha‐blockers may have a role in reducing symptom recurrence and bacteriuria in chronic bacterial prostatitis, with one retrospective study suggesting a reduction of as much as 50%. They can also be of use in treating the obstructive LUTS element of CP/CPPS (NIH IIIa/b). By improving urinary flow, reducing reflux, and therefore inflammation, a 5‐alpha reductase inhibitor has also been shown to possibly have a role in the management of CP/CPPS. A small placebo randomised controlled trial [19] showed a beneficial effect in inflammatory CP/CPPS (NIH IIIa), with 33% of men improving in NIH‐CPSI by > 25% (defined as a responder) at six months compared to 16% responding with placebo, but this was not statistically significant. There may be an additive effect in combining finasteride and Tamsulosin in CP/CPPS, but it is currently only recommended in patients with concurrent benign prostatic hyperplasia (BPH) [20] as prostatitis can lead to BPH disease progression.

26.6.3 Pain Relief

A stepwise approach is taken with analgesics to help alleviate pain. Chronic pain may respond to neuro‐modularity therapies such as amitriptyline, gabapentin, and pregabalin.

26.6.4 Pentosan Polysulphate

This is a heparin‐like molecule which resembles aminoglycosides and is thought to provide a barrier‐like protection on the uro‐epithelium. Its use is more common for interstitial cystitis. A randomised controlled trial for treatment of CP/CPPS with pentosan polysulphate was negative when compared to placebo [21].

26.6.5 Other Therapies

Because CP/CPPS is a common but poorly understood ‘condition’, and there is little proof to support the effectiveness of conventional therapies, many alternative treatments have been suggested. Herbal supplements such as quercetin and acupuncture have been used with limited evidence of efficacy [22]. Biofeedback, psychotherapy and relaxation exercises including lifestyle changes have also been tried. In 1999, Nickel advocated ‘triple‐therapy’, combining an alpha blocker, a nonsteroidal anti‐inflammatory, and a muscle relaxant such as diazepam as initial treatment for noninflammatory CP/CPPS (NIH IIIb) [23].

26.7 Upoint Phenotypic Classification of CP/CPPS

This clinical tool has been developed to further classify CP/CPPS into six phenotypic domains [24]. Theory behind this is that patients with CP/CPPS are a heterogeneous group, and as discussed previously, the aetiology remains unclear and may include many different causal factors. Failure to show a benefit in many randomised trials in CP/CPPS cohorts have led to the conclusion that to successfully treat these patients, they must be further characterised phenotypically. This developed into the ‘Snowflake Hypothesis’ in which patients with CP/CPPS can be classified by six domains (the six points of a snowflake, Figure 26.2). These are urinary, psychosocial, organ specific, infection, neurologic/systemic pain and tenderness of skeletal muscle (UPOINT). One study in a cohort of 90 men with documented CP/CPPS suggested that only 22% are positive for only one domain and the proportion positive for each domain was urinary (52%), psychosocial (34%), organ specific (61%), infection (16%), neurologic/systemic pain (37%), and tenderness of skeletal muscle (53%) [25].

Schematic illustrating the ‘Snowflake Hypothesis’ comprising 6 symptom domains combining into the clinical presentation of CP/CPPS: Urinary, tenderness, psychosocial, organ specific, infection, etc. — **Figure 26.2** UPOINT phenotypic classification of CP/CPPS the ‘Snowflake Hypothesis’ comprises six symptom domains combining into the clinical presentation of CP/CPPS.

A prospective study of 100 patients with CP/CPPS treated with this multimodal approach has shown promising results with more than half improving in NIH‐CPSI by greater than 50% with an average follow up period of 50 weeks. Specific treatment regimens employed for each positive domain included urinary (α‐blocker or antimuscarinic), psychosocial (stress reduction/psychological support), organ specific (quercetin), infection (antibiotics), neurological/systemic pain (amitriptyline or pregabalin), and tenderness of skeletal muscle (pelvic floor physiotherapy) [26]. An online algorithm based tool for urologists has been created to enter patient factors and provide the UPOINT phenotype [27] with suggested therapies to help manage this difficult condition using a multimodal and multidisciplinary approach.

26.8 Surgical Options

Transurethral resection or deroofing can be useful to drain a prostatic abscess (Figure 26.3). Transurethral resection of the prostate (TURP) may provide a benefit in chronic bacterial prostatitis (NIH II) due to drainage of abscesses and removal of prostatic calculi, but this has not yet been proven. A modified TURP technique, avoiding resection of the bladder neck and anterior zone for prostatic abscess drainage, has been suggested to minimise any risk of incontinence, which may in part be due to bladder overactivity [28]. It is recommended that TURP is reserved only for refractory cases of chronic prostatitis and in the context of trials. A combination of prostatic massage and antibiotic therapy regimens may also improve symptoms in the short term, but its longer‐term efficacy remains unproven [29].

26.9 Heat Therapies

Transurethral microwave thermotherapy (TUMT) involves increasing the temperature of the prostate, which is thought to have a numbing effect on prostatic sensory nerves resulting in symptom relief. It has been shown in a small randomised double‐blind sham controlled trial to provide a beneficial effect in CP/CPPS (NIH IIIa/b) by reducing symptom score from 48.4 to 27.3 over three months using a validated severity index (0–100); this is a statistically significant improvement compared to sham [30]. Responders were then followed up for 21 months without deterioration in symptoms, suggesting long‐term maintenance of the effects [30]. Transurethral needle ablation (TUNA) of the prostate has also been shown to provide improvement in symptom score in a study of 32 patients with inflammatory CP/CPPS. Symptoms resolved in 60% of patients at six months and reduction in leucocytes present in EPS was seen in all patients [31]. Despite promising results, studies are small, and these forms of thermotherapy remain experimental.

26.10 Prostate Tuberculosis

Prostate tuberculosis (PTB) is a form of extrapulmonary tuberculosis (EPTB) and rare in developed countries, accounting for only 2–5% of all cases of EPTB. Before anti‐tuberculosis (TB) drugs, the prevalence of PTB was much greater because it is spread by sexual transmission [32]. In patients with active TB and LUTS, a diagnosis of PTB should be considered. An early diagnosis can be aided by TRUS biopsy staining for acid‐fast bacilli as well as TB culture or polymerase chain reaction (PCR) of prostate tissue. Treatment with standard anti‐TB combination therapy with the addition of ofloxacin to better penetrate prostate tissue showed improvements in pain, dysuria, and negative cultures following therapy at eight months in a 2014 Russian study of 93 patients with suspected PTB [33]. By the time granuloma cavitation develop in the prostate, the disease cannot be fully cured with antimicrobial therapy. This late presentation is pathognomonic and may also present with a cold abscess draining into the rectum via a fistula tract.

26.11 Summary

Recent years have seen changes in the presentation and forms of prostatitis with acute prostatitis becoming more important as a complication of TRUS‐guided prostate biopsies. This may lead to urosepsis and require emergency hospitalisation and intravenous treatment with broad‐spectrum antibiotics.

CP/CPPS is as a common disease of younger men which may cause significant morbidity but remains poorly understood. There is limited evidence to support current treatments and surgery is reserved as a last resort. Further knowledge of the basic underlying processes may help to develop novel treatments and guide the management of these patients.