Nongonococcal Urethritis

Etiology

The most common cause of NGU is Chlamydia trachomatis, which accounts for 15% to 40% of NGU cases.[2] The second most common cause is Mycoplasma genitalium, which accounts for 15% to 20% of NGU cases; although widespread testing for mycoplasma is not available.[3] Less common causes of NGU include infection with Trichomonas vaginalis, herpes simplex virus, Epstein Barr virus, and Adenovirus. Enteric bacteria is an uncommon cause of NGU that is typically seen in males who practice insertive anal intercourse. In almost half of all cases of NGU, an etiology is not identified.[2]

Epidemiology

Urethritis is the most common sexually transmitted infection in men with gonorrhea and chlamydia representing the primary pathogens. The Center for Disease Control and Prevention (CDC) does not publish rates of urethritis as a syndrome. The CDC instead breaks down sexual infection rates down by etiology. Chlamydia is the most commonly reported sexually transmitted infection in the United States with over 1,500,000 new cases in 2016. Rates of new diagnoses continue to rise annually with an estimated increase of 4.7% from 2015 to 2016. Trends show that rates of chlamydia in females are 2 times higher than that of males. Rates are highest among adolescents and young adults. Racial disparities exist, and blacks are 5.6 times more commonly affected with chlamydia when compared to whites. Gonorrhea cases are more commonly seen in males, and there were an estimated 468,000 new cases of gonorrhea in 2016. Like with chlamydia, infections rates are higher in adolescents and young adults; the African American race is also disproportionately affected.

Pathophysiology

The most common cause of NGU is chlamydia. C. trachomatis typically infects columnar epithelial cells at mucosal sites. It replicates in host cells eventually causing cell death.[4] Other causes of NGU are less well described.

Histopathology

Microscopic evaluation of NGU reveals polymorphonuclear leukocytes without the presence of intracellular gram-negative diplococci on gram stain.

The most common cause of NGU, C. trachomatis, is an intercellular bacterium. The cell wall in C. trachomatis lacks peptidoglycan. The absence of peptidoglycan makes C. trachomatis not visible on Gram stain and makes beta-lactam antimicrobials ineffective.[5]

History and Physical

Patients present with complaints of dysuria, pruritus, penile burning, and urethral discharge. Urethral discharge can be purulent, mucoid or watery. Discharge in NGU is sometimes scant and only noted as crusting at the meatus or staining of the underwear.

Not all men with urethritis have symptoms, and over 40% of cases of all cases of NGU are asymptomatic.[6]

Patients who present with regional lymphadenopathy, constitutional symptoms, or vesicles may have urethritis from HSV NGU.

Physical examination may reveal penile discharge. Differentiating between gonococcal and non-gonococcal urethritis is difficult based on clinical examination of discharge. NGU tends to be mucoid or clear, compared to gonococcal urethritis which is more commonly purulent; however, this generalization is not reliable.

Men with urethritis can also present with fever, testicular pain, testicular swelling, sore throat, rectal pain, or rectal discharge. Differential diagnoses of these symptoms would include other infectious processes such as epididymitis, pharyngitis, or prostatitis, and these should be considered accordingly.

Conjunctivitis can accompany urethritis caused by gonorrhea, chlamydia, or Adenovirus.

Some patients with NGU can also present with reactive arthritis, which is characterized by urethritis, uveitis, and arthritis. This constellation of symptoms is typically associated with the HLA-B27 gene.[1]

Evaluation

Urethritis can be diagnosed with any of the following:

• Mucoid, mucopurulent, or purulent discharge on examination
• Gram stain of urethral secretions demonstrating equal to 2 white blood cells (WBC) per oil immersion field
• Positive leukocyte esterase test on urinalysis or microscopic examination of sediment from a spun first-void urine demonstrating equal to 10 WBC per high-power field

The diagnosis of NGU requires the exclusion of gonorrheal infection. This can be achieved with a gram stain that lacks gram-negative diplococci or by any negative gonorrhea test (culture, nucleic acid testing, among others).[7]

In men at high risk for infection, if symptoms are present but none of these criteria are met, a presumptive diagnosis can be made, and empiric treatment started. These patients should be treated with a drug regimen for both chlamydia and gonorrhea.[8]

Patients should also have a nucleic acid amplification test (NAAT) performed for chlamydia, gonorrhea, and trichomoniasis. In urethritis, NAAT testing is recommended over culture because of its high sensitivity and specificity. NAAT testing for M. genitalium exists but is not widely available.[1]

Treatment / Management

Empiric treatment for urethritis should be started at the time of diagnosis, before results of testing for a specific etiology. Treatment should be based on whether the gonococcal infection has been evaluated by microscope:

Presumptive Treatment of NGU with Microscope

Recommended Regimens

• Azithromycin 1 g orally in a single dose, or
• Doxycycline 100 mg orally twice a day for 7 days

Azithromycin and doxycycline are both highly effective for the treatment for chlamydial urethritis. Urethritis associated with M. genitalium responds better to azithromycin, although azithromycin resistance is increasing.

Presumptive Treatment of NGU without Microscope

When Gram stain is not available gonorrheal infection cannot be ruled out. These patients should be treated with a drug regimen effective against both chlamydia and gonorrhea.

Recommended Regimens

• Ceftriaxone 250 mg IM

PLUS

• Azithromycin 1 g orally in a single dose, or
• Doxycycline 100 mg orally twice a day for 7 days

Recurrent or Persistent NGU

Recurrent or persistent symptoms can be common following treatment for NGU with the recommended regimen. Patients should first be evaluated for adherence to prior treatment and re-exposure to disease. If they continue to have evidence of urethritis (discharge on exam, elevated WBC on a microscope, or leukocyte esterase on urinalysis) therapy should be directed towards M. genitalium. M. genitalium is the most common cause of persistent or recurrent NGU.

Recommended Regimens

• If azithromycin was not used for initial exposure:
• Azithromycin 1 g orally once  
• If azithromycin was used for initial exposure
• Moxifloxacin 400 mg orally daily for 7 days
• In either instance, metronidazole 2 g orally once should be given in areas where T. vaginalis is prevalent.[1]

Differential Diagnosis

The differential diagnosis of patients presenting with dysuria includes:

• Prostatitis
• Epididymitis
• Vaginitis
• Cystitis

Typically, patients with another diagnosis present with other clinical findings; however, any of these conditions may also co-exist with urethritis.[9]

Treatment Planning

Partner management is recommended for patients with urethritis regardless of whether specific etiology is identified. Sexual partners within 60 days should be referred for complete STI evaluation and treatment with the same treatment regimen as the original patient.[1]

Prognosis

NGU is generally a self-limited disease and resolves, even without therapy, with no complications in most cases.

Complications

Complications for NGU in men are rare but include epididymitis, prostatitis, abscess formation, and reactive arthritis. One percent to 2% of males with NGU develop epididymitis. One percent to 2% develop conjunctivitis. Urethral stricture or stenosis is possible after NGU due to post inflammatory scar formation but is rare.

Complications in women are more common than in men (10% to 40%). Women with urethritis can potentially develop pelvic inflammatory disease, infertility, and ectopic pregnancy.[10]

Children born to mothers with chlamydia urethritis can potentially develop complications including conjunctivitis, iritis, and pneumonia. Routine treatment of all newborns with antibiotic eye ointment has significantly decreased the incidence of these.[11]

Chlamydia urethritis can also cause lymphogranuloma venereum, a genital ulcer disease which presents as lymphadenitis or lymphangitis and can lead to lymphatic obstruction, strictures or fistulas.[1]