[STDs] Atlas of Nongonococcal Urethritis

These are the images, diagnosis and treatment of cases the disease caused by Nongonococcal Urethritis . This is a Nongonococcal Urethritis Disease

Nongonococcal Urethritis 

By definition, nongonococcal urethritis (NGU) is urethritis not caused by Neisseria gonorrhoeae; it is the most common diagnosis among men presenting to STD clinics. The term nonspecific urethritis (NSU) is synonymous with NGU and is used preferentially in some countries. Postgonococcal urethritis is NGU following successful treatment of gonorrhea, with an etiologic spectrum similar to that of de novo NGU, and occurs in about 25% of men with gonorrhea treated with cephalosporins without azithromycin or a tetracycline.

Chlamydia trachomatis causes 25–35% of cases of initial, nonrecurrent NGU, and about 10–20% of

cases are caused by the recently characterized Mycoplasma genitalium. Ureaplasma urealyticum may cause 10–30% of cases, but conflicting data exist. It is only recently that U. urealyticum has been differentiated from the ubiquitous, apparently nonpathogenic U. parvum, and forthcoming research that distinguishes these two organisms may help elucidate the role of U. urealyticum in NGU and other genital disorders. Neither C. trachomatis, M. genitalium, nor U. urealyticum can be identified in half or more of affected men. Trichomonas vaginalis, herpes simplex virus, usually type 1 (HSV-1), and certain strains of adenovirus each account for 2–5% of cases in recent series. Men with NGU with signs that suggest herpes, such as typical cutaneous lesions, prominent erythema and edema of the meatus, or severe dysuria, should be treated with drugs for HSV as well as the usual bacterial etiologies. When urethritis persists or recurs after initial therapy, repeat treatment should include coverage for T. vaginalis. Some men with NGU without an identifiable pathogen give histories of insertive fellatio, without other recent sexual exposures, suggesting that oropharyngeal flora may cause some cases. It is unknown (and unstudied) whether normal or unidentified organisms in partners’ vaginal or rectal flora may explain some cases of NGU. Escherichia coli or other fecal bacteria occasionally cause NGU following insertive anal intercourse. The differential diagnosis of urethritis also includes urethral foreign bodies and periurethral fistulas, but both are rare. Anecdotal reports suggest that NGU is commonly misdiagnosed as a nonsexually acquired urinary tract infection (UTI) by clinicians unfamiliar with the clinical syndrome. However, UTI is rare in men under 40 years old.

The main complications of NGU are those caused or triggered by C. trachomatis, including acute epididymitis and reactive arthritis, but epididymitis has not been linked to nonchlamydial NGU. There is no evidence that urethral stricture results from NGU; most such cases in the pre-antibiotic era probably  were due to gonorrhea or traumatic therapies such as irrigation with caustic compounds like silver nitrate or potassium permanganate. Although C. trachomatis carries obvious health implications for men’s female sex partners, NGU without identified pathogens has not been associated with morbidity in either the female or male partners of affected men. The female partners of men with nonrecurrent NGU should be routinely treated, primarily to cover C. trachomatis and M. genitalium, but the need for treatment is uncertain if these have been excluded and T. vaginalis is absent. It is unknown whether treatment benefits the receptive partners in oral or anal sex, but it is commonly provided.

Persistent or recurrent NGU is a common and often vexing problem for patients and providers alike. Repeated relapses are frequent in some men, often without sexual reexposure, and C. trachomatis or other recognized pathogens are rarely identified. Recurrent NGU occasionally may be associated with

nonbacterial prostatitis or chronic pelvic pain syndrome, but usually the prostate is not involved. There is no evidence that alcohol, highly spiced foods, changes in sexual frequency, or Valsalva maneuver (“strain”) can cause acute or recurrent urethritis, notwithstanding past beliefs to the contrary. A common error in management of men with persistent or recurrent symptoms is failure to document urethral inflammation by examination for urethral leukocytes. Without objective evidence of urethral inflammation, symptoms alone usually are not indications for repeated antibiotic therapy. Even when urethritis is documented, it is possible that some persistent or recurrent cases result from noninfectious immunologic mechanisms. Much about NGU and its related syndromes remains to be explained by future research. For example, there is renewed interest in the relationship between STDs and later prostate gland morbidity because of recent studies showing transient elevations of prostate-specific antigen in some men with gonorrhea or chlamydial urethritis, although not in men with nonchlamydial NGU. 

EPIDEMIOLOGY

Incidence and Prevalence

• Accurate data unavailable

• Accounts for 10–30% of new problem visits by men to STD clinics

Transmission

• Initial episodes of NGU usually are acquired sexually, but exceptions may occur

• Oral-genital exposure probably accounts for some cases of nonchlamydial NGU

• Recurrent or persistent NGU probably results primarily from relapse, but reinfection often cannot be

excluded

Age

• Most cases age 15–35 years

• All ages susceptible

Sex and Sexual Orientation

• By definition, NGU occurs only in men

• Mucopurulent cervicitis may be female counterpart in some instances 

• In MSM, C. trachomatis accounts for <10% of cases, and many cases are associated with oral-genital exposure 

HISTORY

Incubation Period

• Typically 1–3 weeks

Symptoms

• Urethral discharge is the primary symptom

• Dysuria usually is mild, often absent; sometimes described as urethral itching or tingling

• Severe dysuria suggests viral etiology (HSV, adenovirus)

• Urinary urgency, frequency, or pelvic or perineal pain are uncommon; they suggest cystitis, chronic

pelvic pain syndrome, or prostatitis

Epidemiologic History

• Usually new sex partner, but exceptions are common

• Some cases occur in monogamous men, perhaps caused by partners’ normal vaginal, rectal, or oral flora

PHYSICAL EXAMINATION

• Urethral discharge

° Typically mucoid or mucopurulent; occasionally purulent

° Variable in amount, from spontaneous to scant amounts expressed by urethral compression; may be apparent only after several hours without urination

° Some patients lack demonstrable discharge

• Scant clear mucus sometimes is observed normally in men without urethritis, especially after sexual arousal or prolonged interval since urination

• Occasional meatal erythema or edema (“meatitis”), especially in cases associated with HSV or adenovirus

• HSV urethritis may be associated with localized tenderness along penile shaft at sites of intra-urethral herpetic lesions

• Penile venereal edema (painless edema of penis, without erythema) sometimes accompanies urethritis or genital herpes

DIAGNOSIS

Documentation of Urethritis

• Clear history of abnormal urethral discharge; or observation of abnormal discharge (see History and

Physical Examination) 

and

• Evidence of inflammatory response in the urethra:

° Gram-stained smear of external urethral exudate or endourethral swab, showing elevated PMNs

or

° Positive leukocyte esterase test on initial 30 mL of voided urine

Microbiologic Tests

• Tests for C. trachomatis and N. gonorrhoeae, preferably by NAAT (see Chaps. 3 and 4)

• Testing for M. genitalium by NAAT not yet routinely recommended nor widely available, but may

become useful

• Testing for T. vaginalis by NAAT not yet routinely recommended nor widely available, but may become useful

• Tests for U. urealyticum are not recommended

• Urine culture for uropathogens may be useful in selected settings, e.g., for NGU following insertive

anal intercourse or if urgency or urinary frequency are present

• Test for HSV (NAAT or culture) if clinical findings or exposure suggest herpes

Recurrent or Persistent NGU

After symptomatic resolution, urethritis recurs within 6 weeks in 10–20% of men following chlamydial NGU and in 20–30% after nonchlamydial NGU.

• Confirm urethral inflammation by Gram-stained smear showing PMNs or positive leukocyte esterase test

• Microbiologic evaluation

° Repeat NAATs for C. trachomatis and N. gonorrhoeae rarely are productive unless patient reexposed to untreated partner

° NAAT for T. vaginalis may be useful if available

° Urine culture for uropathogens may be useful

° Tests for M. genitalium or U. urealyticum are not readily available in most settings but may be useful in some patients

TREATMENT

Initial NGU*

Treatments of Choice

• Azithromycin 1.0 g PO, single dose

• Doxycycline 100 mg PO bid for 7 days

Alternative Regimens

• Erythromycin base 500 mg PO qid (or equivalent alternate erythromycin formulation) for 7 days

• Ofloxacin 300 mg PO bid for 7 days

• Levofloxacin 500 mg PO once daily for 7 days 

Suspected HSV Urethritis

A viral etiology of NGU, often due to HSV or adenovirus, is suggested by presence of mucocutaneous lesions consistent with genital herpes, or by severe dysuria, prominent erythema or edema of the meatus, or conjunctivitis.

• Acyclovir, valacyclovir, or famciclovir (see Chap. 8) in addition to azithromycin or doxycycline

Persistent or Recurrent NGU

• First recurrent or persistent episode†

° If initial episode treated with azithromycin, use doxycycline as above

° If doxycycline used initially, use azithromycin plus

° Metronidazole 2.0 g PO, single dose, or tinidazole 2.0 g PO, single dose

• Subsequent recurrent episodes†

° For second and subsequent recurrences, some experts recommend moxifloxacin 400 mg PO once daily for 7 days.‡

° More prolonged courses (2–6 weeks) of fluoroquinolone antibiotics (e.g., ofloxacin, levofloxacin, ciprofloxacin) have been employed by some clinicians, especially when NGU may be accompanied by prostatitis; no controlled studies are available

° Persistent or recurrent symptoms of urethritis should not be treated with antimicrobial drugs unless urethritis is confirmed by urethral leukocytosis

° Consider evaluation for prostatitis and chronic pelvic pain syndrome

PREVENTION

• As for chlamydial infection and gonorrhea 

• Examine and treat female sex partners of patients with nonrecurrent NGU for presumptive chlamydial infection

• The standard practice is to treat partners of men with initial nonchlamydial NGU, but benefits to prevent either reinfection of the index case or morbidity in partners are unknown

• Repeated treatment generally is not recommended for partners of men with recurrent NGU

• Recommend condoms for new or casual sexual encounters 

15–1. Mucopurulent urethral discharge in NGU  

CASE 1

Patient Profile Age 26, graduate student and teaching assistant, heterosexual

History Urethral “itching” and intermittent urethral discharge for 7 days; began a new sexual relationship 6 weeks earlier

Examination Mucopurulent urethral discharge

Differential Diagnosis Urethritis; probable NGU, rule out gonorrhea

Laboratory Urethral Gram stain showed 15–20 PMNs per 1000× field and scant mixed bacterial flora, without GND; urethral NAATs for C. trachomatis and N. gonorrhoeae (both negative); VDRL and HIV serology negative

Diagnosis Nonchlamydial NGU

Treatment Azithromycin 1.0 g PO, single dose

Other The patient was counseled about the sexually acquired nature of his infection and the need to arrange for examination and treatment of his partner. Expedited partner therapy (EPT) is a consideration for partner management when partners are not likely to attend in person, but has been rigorously studied only for confirmed gonorrhea, chlamydial infection, and trichomoniasis. 

15–2. Chlamydial NGU with scant, clear, mucoid urethral discharge, and slight
meatal erythema.  

CASE 2

Patient Profile Age 34, flight attendant, MSM

History Urethral discharge for 5 days; no dysuria or other symptoms; regularly had unprotected insertive anal and oral sex with his steady partner; occasional sex with other men, usually but not invariably with condoms; denied receptive anal intercourse in preceding year; negative HIV test 4 months earlier

Examination Scant, clear, mucoid urethral discharge; slight meatal erythema

Differential Diagnosis Urethritis: probable NGU, rule out gonorrhea; possible coliform urethritis

Laboratory Urethral Gram stain showed 10–12 PMNs per 1000× field, without GND; urethral NAATs for N. gonorrhoeae (negative) and C. trachomatis (positive); pharyngeal culture for N. gonorrhoeae (negative); urine culture for UTI pathogens (negative); VDRL and HIV serology (both negative)

Diagnosis Chlamydial NGU

Treatment Doxycycline 100 mg PO bid for 7 days

Comment Scant clear appearing urethral moisture was found on examination. Doxycycline was prescribed, rather than azithromycin, to cover both C. trachomatis and some potential causes of coliform urethritis while awaiting urine culture result. Advised to refer partner for evaluation; EPT has not been validated in MSM, in whom high risk for other STDs supports personal examination. 

15-3. Nongonococcal urethritis with prominent meatitis.
Tests for C. trachomatis and N. gonorrhoeae were negative. 

Meatitis, characterized by prominent dysuria and

meatal erythema, raises the probability of viral etiology,
such as HSV or adenovirus. There were no cutaneous
lesions and urethral culture for HSV was negative.  

15–4. Penile venereal edema in a patient with chlamydial NGU  

REFERENCES

H. Hunter Handsfield, MD, Color Atlas & Synopsis of Sexually Transmitted Diseases, Third Edition.