Prostatitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

Prostatitis is an inflammation of the prostate gland. Prostatitis has been classified by International Prostatitis Collaboration Network, into 5 subtypes. This classification is on the basis of timing of the symptoms and the presence of bacterial pathogens and other markers of infection and inflammation. The categories include acute bacterial prostatitis, chronic bacterial prostatitis, inflammatory chronic prostatitis/chronic pelvic pain syndrome, non-inflammatory chronic prostatitis/chronic pelvic pain syndrome, and asymptomatic inflammatory prostatitis.^[1] By the help of microscopic histopathological studies, neutrophils or lymphocytes can be seen inside the glands, between the cells of epithelium or inside the stromal component.^[2][3] The most common bacteria causing prostatitis are aerobic gram-negative bacilli, Escherichia coli is responsible for 50-80% incidents of bacterial prostatitis.^[4] Though a single definitive cause has not been established, different theories exist about chronic prostatitis/chronic pelvic pain syndrome pathogenesis including chemical damage owing to reflux or autoimmune process.^[5] Prostatitis must be differentiated from various causes of dysuria including pyelonephritis, cystitis, urethritis, benign prostatic hyperplasia, prostatic abscess, bladder cancer, urinary tract stones, and a foreign body within the urinary tract.^[6] Recurrent urinary tract infections, benign prostatic hyperplasia, urethral strictures, bladder neck hypertrophy, prostatic carcinoma, and catheterization are risk factors for prostatitis. Acute prostatitis usually results in complete recovery without sequelae. If left untreated, patients with acute bacterial prostatitis may progress to develop chronic prostatitis, epididymitis, prostatic abscess, septicemia, urosepsis, urinary retention and metastasis of infection to spinal cord or sacroiliac joint.^[7][8][9] Patients with untreated chronic prostatitis may develop chronic pelvic pain, sexual dysfunction, infertility and recurrent urinary tract infections.^[8][10] Frequency, urgency, burning during urination, nocturia, urinary retention and pain in the genital area, groin, lower abdomen, or lower back may be the presenting features. Other features include fever, nausea, and vomiting in acute infection.^[5] Laboratory findings show an increase in the number of leukocytes on CBC, bacteria on urine culture, elevated C-reactive protein, and transiently elevated PSA (prostate specific antigen) levels in case of bacterial prostatitis. While in chronic bacterial prostatitis negative pre-massage urine culture results, more than 10 to 20 leukocytes per high-power field in both the pre and the post massage urine specimen, bacteriuria in the postmassage urine specimen, and lower leukocyte and bacterial counts in voided bladder urine specimens as compared to bacterial count in post-prostatic massage voided urine or expressed prostatic secretions are seen.^[4][11] The absence of bacterial growth on cultures is diagnostic of chronic nonbacterial prostatitis.^[4] Antimicrobial therapy is indicated for acute and chronic prostatitis.

In 350 BC, the anatomical positioning and existence of the prostate gland was explained by Herophilus. Prostatic incitement was recognised as a cause of prostatitis in 1800. In 1978 Drach et al. gave the basis of the current classification of prostatitis.^[12]

Prostatitis has been classified by International Prostatitis Collaboration Network, into 5 subtypes. This classification is done on the basis of timing of the symptoms and the presence of bacterial pathogens and other markets of infection and inflammation. The categories include:^[1]

• Acute bacterial prostatitis
• Chronic bacterial prostatitis
• Inflammatory chronic prostatitis/chronic pelvic pain syndrome
• Non-inflammatory chronic prostatitis/chronic pelvic pain syndrome
• Asymptomatic inflammatory prostatitis.

The pathogenesis of prostatitis is not completely understood. An infection ascending from the urethra, chemical damage caused by the reflux of urine through the ejaculatory ducts and prostatic ducts and autoimmune involvement are a few possible theories related to the pathogenesis of various types of prostatitis.^[6][11] Chronic prostatitis/chronic pelvic pain syndrome is thought to be caused by an abnormality in the hypothalamic-pituitary-adrenal axis and hormonal derangements involving the adrenocortical hormone. These changes can stem from variable response to stress, neurogenic inflammation, and myofascial pain syndrome. On microscopic examination, neutrophils or lymphocytes can be seen inside the prostatic gland, among the cells of the epithelium or inside the stromal component of the gland.^[2][3]

The most common bacteria causing prostatitis are aerobic gram-negative bacilli, Escherichia coli is responsible for 50-80% incidents of bacterial prostatitis.^[4]Though a single definitive cause has not been established, different theories exist about chronic prostatitis/chronic pelvic pain syndrome pathogenesis including chemical damage owing to reflux or autoimmune process.^[5]

Prostatitis must be differentiated from various entities on the basis of dysuria that include cystitis, pyelonephritis, benign prostatic hyperplasia, prostatic abscess, bladder cancer, urinary tract stones, and a foreign body within the urinary tract.^[6]

In men who are younger than 50 years of age, prostatitis is the most common problem related to the urinary tact. Prostatitis is the 3rd most common urinary diagnosis made in men aged more than 50 years. There are almost 2 million health care visits yearly, associated with prostatitis. Chronic prostatitis is the most commonly seen type of prostatitis.^[5]

Common risk factors in the development of prostatitis include recurrent urinary tract infections, urethral strictures, hypertrophy of the neck of the bladder, prostatic carcinoma, benign prostatic hyperplasia,use of alcohol, smoking and history of foley catheterization.

If left untreated, patients with acute bacterial prostatitis may progress to develop chronic prostatitis, prostatic abscess, septicemia, urosepsis, urinary retention and metastasis of infection to spinal cord or sacroiliac joint.^[7][8] Patients with untreated chronic prostatitis may develop chronic pelvic pain, sexual dysfunction, infertility, severe urinary frequency and urgency, and recurrent urinary tract infections.^[8][10] Complete recovery without sequelae is usual among patients with acute prostatitis. Patients with chronic prostatitis have a gradual recovery and relapse is common.^[13]

United States preventive task force (USPSTF) has no guidelines till date for the screening of prostatitis in men.

There is no gold standard for the diagnosis and evaluation of patients presenting with prostatitis. The evaluation of a patient with acute and chronic bacterial prostatitis consists of history and physical examination and urine culture for lower urinary tract localization cultures, respectively. The evaluation of chronic pelvic pain syndrome includes tests which can be broadly divided into mandatory, recommended and optional.

A detailed and thorough history from the patient is necessary. Specific areas of focus when obtaining a history from the patient include previous history of sexually transmitted diseases, any new sexual partners, known urogenital disorders, and recent catheterization or other genitourinary instrumentation.^[4][14] Common symptoms of acute and chronic bacterial prostatitis include urinary frequency, urinary urgency, burning during urination, nocturia, urinary retention and pain in the genital area, groin, lower abdomen, or lower back. Symptoms of acute prostatitis may also include fever, nausea, and vomiting.^[5]

Patients with chronic prostatitis are usually well-appearing. Patients with acute prostatitis may appear ill and have systemic symptoms such as fever, chills, and nausea.^[6][5] In acute prostatitis, palpation of the prostate reveals a tender and enlarged prostate.^[11][6] In chronic prostatitis, palpation of the prostate reveals a tender and soft (boggy) prostate gland.^[6] A prostate massage should never be done in a patient with suspected acute prostatitis, since it may induce sepsis.

The laboratory tests used in the diagnosis of prostatitis are CBC, urinalysis, serum PSA (prostate-specific antigen) levels, urine culture, postvoid residual volume levels, 2-glass pre and post-prostatic massage test, Stamey-Meares four-glass test, and a semen analysis.^[4][5][6] Laboratory findings consistent with the diagnosis of acute prostatitis include increased leukocytes on complete blood picture, bacteria seen on urine culture, elevated C-reactive protein, and transiently elevated PSA (prostate specific antigen) levels. Laboratory findings consistent with the diagnosis of chronic bacterial prostatitis include negative pre-massage urine culture results, more than 10 to 20 leukocytes per high-power field in both the pre and the post massage urine specimen, bacteriuria in the postmassage urine specimen, and lower leukocyte and bacterial counts in voided bladder urine specimens as compared to bacterial count in post-prostatic massage voided urine or expressed prostatic secretions.^[4][11] The absence of bacterial growth on cultures is diagnostic of chronic nonbacterial prostatitis.^[4]

CT scan in a patient with prostatitis shows edema of the prostate gland with diffuse enlargement, mostly in the peripheral zone. An abscess may be seen as a rim enhancing hypodensity which can either have single or multiple loci. Ultrasound can be used to diagnose prostatitis. On ultrasonography, focal hypoechoic area in the periphery of the prostate represents prostatitis. Fluid collection can show abscess formation. Colour doppler ultrasound may also prove to be very effective. MRI can also be used to diagnose prostatitis. Though it is not used commonly, its utilisation when suspecting alternate diagnosis like prostatic carcinoma etc is very important. MRI in case of a patient wit prostatitis depicts diffuse enlargement of the gland.^[15][6][16]

Antimicrobial therapy is indicated for acute and chronic prostatitis. Patients are generally treated in an outpatient setting unless severe disease (e.g. bacteremia) is suspected. Empirical therapy for both acute and chronic prostatitis includes monotherapy with either ciprofloxacin, levofloxacin, or TMP-SMX for at least 6 weeks. When culture results are obtained, antimicrobial therapy may be narrowed down to cover the causative pathogen more adequately. Addition of alpha blocker may be considered for the symptomatic management of bacterial prostatitis. Inflammatory prostatitis may be treated with NSAIDs, allopurinol, or cernilton.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2]

In 350 BC, the anatomical positioning and existence of the prostate gland was explained by Herophilus. Prostatic incitement was recognised as a cause of prostatitis in 1800. In 1978 Drach gave the basis of the current classification of prostatitis.

• In 350 BC, Herophilus first explained the anatomical existence of the prostate gland.^[1]
• In 1800, the most common cause of prostatitis was identified to be incitement of the prostatic gland by exertion, instrumentation, alcohol or intercourse.^[1]
• In 1815, Legneau elaborated the prostatic inflammation for the first time.^[1]
• In 1906, Young analysed the prostatic fluid for the first time.^[1]
• In 1968, Meares and Stamey differentiated the aetiology of prostatitis by using multi glass test.^[2]

• In 1978, Drach first explained the current classification system.^[3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D., Usama Talib, BSc, MD [2]

Prostatitis has been classified by International Prostatitis Collaboration Network, into 5 subtypes. This classification is done on the basis of timing of the symptoms and the presence of bacterial pathogens and other markers of infection and inflammation. The categories include acute bacterial prostatitis, chronic bacterial prostatitis, inflammatory chronic prostatitis/chronic pelvic pain syndrome, non-inflammatory chronic prostatitis/chronic pelvic pain syndrome, and asymptomatic inflammatory prostatitis.^[1][2]

Prostatitis has been classified by International Prostatitis Collaboration Network, into 5 subtypes. This classification is done on the basis of timing of the symptoms and the presence of bacterial pathogens and other markers of infection and inflammation. The categories include:^[1]

• Acute bacterial prostatitis: Acute symptoms with evidence of bacterial infection.^[3]
  • Emphysematous prostatitis: This is characterised by presence of air in the prostate. It is found in diabetic or immunocompromised individuals and Klebsiella is the most common cause.^[4][5]
• Chronic bacterial prostatitis: Chronic symptoms with evidence of bacterial infection.^[6]
• Inflammatory chronic prostatitis/chronic pelvic pain syndrome: Chronic symptoms with inflammation but without any evidence of bacterial infection.^[7]
  • Non Granulomatous prostatitis: All forms of prostatitis without the presence of granulomatosis are included in this category.
  • Granulomatous prostatitis: This type of prostatitis can result from a systemic granulomatous disease or malakoplakia or intravesical BCG for transitional cell bladder carcinoma. It has high PSA levels and may be confused initially with prostatic cancer.^[8][9][10]
  • IgG4 related prostatitis: It is the inflammation of the prostate in a person with IgG4 related disease.^[11]
• Non-inflammatory chronic prostatitis/chronic pelvic pain syndrome: Chronic symptoms with neither inflammation nor evidence of bacterial infection.^[12]
• Asymptomatic inflammatory prostatitis: No symptoms with evidence of inflammation (incidental finding).^[13]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D. Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

The pathogenesis of prostatitis is not completely understood. An infection ascending from the urethra, chemical damage caused by the reflux of urine through the ejaculatory and prostatic ducts and autoimmune involvement are a few possible theories related to the pathogenesis of various types of prostatitis.^[1][2] Chronic prostatitis/chronic pelvic pain syndrome is thought to be caused by an abnormality in the hypothalamic-pituitary-adrenal axis and hormonal derangements involving the adrenocortical hormone that can stem from variable response to stress, neurogenic inflammation, and myofascial pain syndrome. On microscopic examination, neutrophils or lymphocytes can be seen inside the prostate gland, among the cells of the epithelium or inside the stromal component of the gland.^[3][4]

The exact pathogenesis of acute prostatitis is not fully understood. Possible pathogenesis may include:

• Ascending infection from the urethra and the chemical damage secondary to the reflux of urine through the prostatic and ejaculatory ducts.^[2]
• Virulence factors are exhibited in abundance in the stains of pathogens that cause prostatitis as compared to cystitis or pyelonephritis.^[5][6]

• The pathogenesis of chronic bacterial prostatitis is not very clear but an ascending infection from the distal urethra to the prostate is considered a possibility.^[1]
• Greater ability to form biofilm and virulence factors may be associated with chronic bacterial prostatitis.^[7]
• Seeding from the blood or lymphatics or the bowel may also cause chronic bacterial prostatitis^[8]
• Anatomical abnormality in the intra-prostatic ducts may also account for their increased ability for retrograde spread of infection.^[9][10]

• The symptoms of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) are related to association between physiological factors and dysfunction in the immune, neurological and endocrine systems. Possible mechanisms include hypothalamic-pituitary-adrenal axis dysfunction and abnormalities in adrenocortical hormone, neurogenic inflammation, or myofascial pain syndrome. Abnormal functioning of the local nervous system which may be due to previous trauma, infection, or an anxious disposition and chronic albeit unconscious pelvic tensing may lead to inflammation that is mediated by nerve cells nerve cell related substances (e.g substance P). The prostate (and remaining genitourinary tract: bladder, urethra, testicles) can be inflamed by the chronic activation of pelvic nerves on the mast cells at the end of the nerve pathways.^[3][4]
• Another important theory about non bacterial prostatitis includes the increased content of creatinine, urate and white blood cells due to reflux into the prostatic ducts. These agents can act as chemical agents leading to an inflammatory response.^[11]
• Autoimmune phenomenon has also been proposed in some studies. Infiltration of the stroma and surroundings of the prostatic gland by lymphocytes is seen in such cases.^[12][13]

Asymptomatic prostatitis is characterised by incidental finding of inflammation after a biopsy of prostate done for another reason. It can also be diagnosed by the presence of leukocytes on analysis of semen without the presence of symptoms of prostatic inflammation.^[1]

• Type 3 or chronic inflammatory or non inflammatory prostatitis is associated with polymorphism of IL-10 gene.^[14]
• A genotype that favours decreased IL-10 production and thus a decreased anti-inflammatory effect leading to immunosupression leads to development of prostatitis.^[15]

The following conditions are associated with the development of prostatitis:^{[1][16][17][18]}

• Recurrent urinary tract infections
• Epididymitis
• Benign prostatic hyperplasia
• Urethritis
• Prostatic carcinoma
• Diabetes
• Immunocompromised status
• Urethral strictures
• Bladder neck hypertrophy
• Tuberculosis

The gross pathology in case of prostatitis may yield the following findings:^[19]

• Peripheral zone inflammation can be demonstrated.

• Focal Atrophy (uniform or bilateral atrophy shows effects of hormones or age).

• On microscopic histopathologic exam, acute prostatitis may demonstrate glands containing neutrophils , between the epithelial cells or inside the stroma.^[3][20]

• On microscopic histopathologic exam, chronic prostatitis may shows glands containing lymphocytes, between the epithelial cells or inside the stroma.^[4][20]

• Granulomatous prostatitis a category of chronic prostatitis and on histopathological examination it can show areas of granulomatous changes.^[20]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2] Luke Rusowicz-Orazem, B.S., Usama Talib, BSc, MD [3]

Prostatitis is usually caused by bacterial infection. Fungi may also rarely be responsible for causing prostatitis. Aerobic gram negative bacilliare the most common cause of bacterial prostatitis, with Escherichia coli accounting for 50-80% of cases.^[1] Though a single definitive cause has not been established, different theories exist about chronic prostatitis/chronic pelvic pain syndrome pathogenesis including chemical damage owing to reflux or autoimmune process.Many experts consider both inflammatory an non-inflammatory causes of chronic prostatitis to be non-infectious in nature.^[2]

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. There are no known life-threatening causes of prostaitits.

Bacteria are the most common cause of prostatitis over all. Amongst the bacteria the following are more common causes are:^[3]

• Escherichia coli
• Enterobacteriaceae (Klebsiella, Proteus)
• Enterococci
• Pseudomonas species
• Chlamydia trachomatis
• Ureaplasma urealyticum
• Mycoplasma genitalium
• Neisseria gonorrhoeae

The causes of acute prostatitis include ^[4][5][6]

• Escherichia coli
• Proteus
• Other members of Enterobacteriaceae
  • Klebsiella
  • Enterobacter
  • Serratia
• Pseudomonas aeruginosa
• Gram positive organisms^[7][8]
  • Staphylococcus aureus
  • Enterococci

The causes associated with Chronic bacterial prostatitis include ^{[9][10][11][12][13]}

• Escherichia coli (up to 80% cases)^[14]
• Klebsiella pneumoniae
• Pseudomonas aeruginosa
• Enterococcus faecalis
• Proteus mirabilis
• Less common causes
  • Staphylococcus aureus
  • Streptococcal sp.
  • Mycobacterium tuberculosis
  • Chlamydia trachomatis
  • Mycoplasma
  • Ureaplasma

Many experts consider both these categories to be noninfectious. The non infectious causes of Chronic Prostatitis include^{[15][16][17][18][19]}

• Trauma
• Neurogenic pain
• Autoimmunity
• Higher prostate tissue pressure
• Anxiety

Some studies associated certain organisms with these types of prostatitis and they include:^{[20][21][22][23]}

• Viruses
  • CMV^[24][25]
  • Herpes simplex^[26]
• Fungi^[27]
  • Coccidioides^[28]
  • Aspergillus^[29]
  • Cryptococcus neoformans^[30][31]
  • Histoplasma
  • Blastomyces
  • Candida
  • Paracoccidioides
• Parasites^[32][33]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

• Prostatisis must be differentiated from other diseases that cause lower abdominal pain and fever like appendicitis, diverticulitis, inflammatory bowel disease, cystitis, Colorectal cancer, and endometritis.^{[1][2][3][4][5][6]}

• Prostatitis must be differentiated from various other diseases on the basis of symptoms like dysuria. The differential diagnosis includes acute cystitis, benign prostatic hyperplasia, prostatic abscess, bladder cancer, urinary tract stones, and a foreign body within the urinary tract.^[7]

Prostatitis must be differentiated from:^[7]

• Acute cystitis
• Cervicitis
• Epididymitis
• Syphilis
• Vulvovaginitis
• Benign prostatic hyperplasia
• Prostatic abscess
• Bladder cancer
• Urinary tract stones
• Enterovesical fistula
• Foreign body within the urinary tract

Prostatitis can be differentiated from other diseases that cause lower urinary tract irritation symptoms, such as: dysuria, urgency and frequency in addition to urethral discharge , the differential list include: urethritis, pyelonephritis, cystitis, cervicitis, vulvovaginitis, epididimitis and syphilis.^{[8][9][10][11]}

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

In men who are younger than 50 years of age, prostatitis is the most common problem related to the urinary tact. Prostatitis is the 3rd most common urinary diagnosis made in men aged more than 50 years. There are almost 2 million health care visits yearly, associated with prostatitis. $84 Million are spent every year on treatment of prostatitis. The most common form of prostatitis is chronic prostatitis/chronic pelvic pain syndrome.^[1][2]

• There are approximately 2 million health care visits related to prostatitis.^[1]

• 15% of the men experience prostatitis at some point in their life^[3]
• According to another estimate the life long prevalence of chronic prostatitis is 1.8% to 8.2%^[4]
• The prevalence of chronic prostatitis/chronic pelvic pain syndrome is 2% to 10%^[5]

• Prostatitis only occurs in men.

• In men who are younger than 50 years of age, prostatitis is the most common problem related to the urinary tact.^[1]
• Prostatitis is the 3rd most common urinary diagnosis made in men aged more than 50 years.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

Common risk factors in the development of prostatitis include recurrent urinary tract infections, urethral strictures, hypertrophy of the neck of the bladder, prostatic carcinoma, benign prostatic hyperplasia,use of alcohol, smoking and history of catheterization.

Common risk factors in the development of prostatitis include:^{[1][2][3][4][5]}

• Recurrent urinary tract infections
• Epididymitis
• Benign prostatic hyperplasia
• Urethritis
• Prostatic carcinoma
• Diabetes
• Immunocompromised
• Urethral strictures
• Bladder neck hypertrophy
• Tuberculosis
• Behcet’s disease^[6]

• Transrectal ultrasonography guided biopsy of the prostate
• Lower urinary tract due to surgery or trauma leading to nerve damage
• Pelvic surgery
• Previous instrumentation or catheterization

• Alcohol
• Smoking
• Immobility
• Prolonged urine holding
• Decreased fluid intake

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2]

United States preventive task force (USPSTF) has no guidelines till date for the screening of prostatitis in men.

The USPSTF has no recommended guidelines for the screening of prostatitis in men.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maliha Shakil, M.D. [2], Usama Talib, BSc, MD [3]

If left untreated, patients with acute bacterial prostatitis may progress to develop prostatic abscess, septicemia, urosepsis, and urinary retention.^[1][2] Patients with untreated chronic prostatitis may develop chronic pelvic pain, sexual dysfunction, infertility, urinary frequency and urgency, and recurrent urinary tract infections.^[2][3]Complete recovery without sequelae is usual among patients with acute prostatitis. Patients with chronic prostatitis have a gradual recovery and relapse is common.^[4]

If left untreated, patients with acute bacterial prostatitis may progress to develop:^[1][2][5]

• Prostatic abscess
• Septicemia
• Urosepsis
• Urinary retention
• Chronic prostatitis

If left untreated, patients with chronic prostatitis may progress to develop:^[2][3]

• Chronic pelvic pain
• Sexual dysfunction
• Infertility
• Difficulty in urinating: frequency, urgency, dysuria
• Recurrent urinary tract infections

Common complications of prostatitis include^{[1][2][3][6][7]}

• Urinary retention
• Sepsis
• Prostatic abscess
• BPH
• Prostatic cancer
• Pelvic pain
• Metastatic infections such as pyogenic vertebral osteomyelitis
• Erectile dysfunction
• Infertility

Patients with acute prostatitis usually recover completely, without a sequelae. Patients with chronic prostatitis gradually recover over time and with time, the rate of relapse is high, reaching up to 50%.^[4]

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