Urethritis, Vulvovaginitis, and Cervicitis

Urethritis, Vulvovaginitis, and Cervicitis

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Urethritis, Vulvovaginitis, and Cervicitis Paula K. Braverman

URETHRITIS Urethritis is inflammation of the urethra. The clinical presentation includes dysuria, urinary frequency, and urethral discharge or itching. Neutrophils usually are found in urethral secretions.1 According to the Centers for Disease Control and Prevention (CDC), urethritis is documented by one of the following: visibly abnormal urethral discharge, a positive leukocyte esterase (LE) test result for a man younger than 60 years of age without other urinary tract disease that could cause pyuria, Gram stain of a urethral smear showing at least 2 white blood cells per high-power field (WBCs/HPF), and a positive LE test result for the firstvoid urine or 10 or more WBCs/HPF in the first-void urine sediment.2,3 However, studies have demonstrated that symptoms of urethritis can occur without microscopic evidence of pyuria on the Gram stain of urethral swab specimens or in the first-void urine samples.4,5 It may be difficult to establish the diagnosis of urethritis in women because they may not have localized symptoms and some pathogens simultaneously infect multiple genital areas.6 In the absence of a documented urinary tract infection, female dysuria can represent vulvar inflammation from vaginitis or vulvar dermatoses, interstitial cystitis, or urethral infection with a sexually transmitted infection (STI).6,7

Etiologic Agents Infectious Causes Organisms associated with STIs are the most significant etiologic agents in urethritis. Newer, more sensitive molecular diagnostic testing modalities for STIs have advanced the understanding of specific pathogens that cause urethritis. Male Patients.  Chlamydia trachomatis and Neisseria gonorrhoeae are common causes of urethritis in men.1 N. gonorrhoeae is estimated to cause one third of acute urethritis cases and is differentiated from other agents, which cause nongonococcal urethritis (NGU).8 NGU is the most common clinical STI syndrome in men. Rates of specific etiologic agents vary by geography, socioeconomic factors, age, race, and sexual orientation or practices.1,5,8–14 Coinfection with multiple pathogens can occur, and in 25% to 40% of cases, no pathogen is identified.15 Approximately 15% to 40% of NGU in men is caused by C. trachomatis, 15% to 25% by Mycoplasma genitalium, 10% to 20% by Trichomonas vaginalis, and 10% to 20% by Ureaplasma urealyticum.15,16 There has been confusion in the literature regarding the role of U. urealyticum as a cause of nongonococcal, nonchlamydial infection in men.2,5,11,15,17–23 The genus Ureaplasma has two types: biovar 1 (U. parvum) and biovar 2 (U. urealyticum). Biovar 2 is the biotype most likely

associated with urethritis.15,17–24 Further analysis has revealed that within biovar 2, only specific subtypes may be independently associated with NGU.18 T. vaginalis traditionally was considered a less common cause of urethritis in men. However, a nucleic acid amplification testing (NAAT) such as polymerase chain reaction (PCR) and transcription-mediated amplification (TMA) demonstrate that T. vaginalis is associated with 10% to 20% of cases of urethritis.10,15,25–27 T. vaginalis can be demonstrated in males without clinical signs of urethritis and commonly is associated with other STIs.15,28–30 Herpes simplex virus (HSV) is a less common cause of urethritis in men.5,11,31 Urethritis develops in 30% of men with primary HSV infection and is found in 2% to 3% of cases of NGU.15 Studies reported in 2006 found that HSV-1 was responsible for more cases of NGU than HSV-2 and that HSV-1 was more likely to be associated with men engaging in oral-genital sex and men with male partners.5,11 Infrequent causes of urethritis in men include adenoviruses, Haemophilus species, and Neisseria meningitidis; coliforms can be an etiologic agent in men who have sex with men (MSM).1,5,11,15 Identification of some pathogens associated with urethritis suggests that infection with oropharyngeal flora, which are normal nonpathogenic organisms in monogamous partners, is possible.11 Nonsexually transmitted NGU is associated with urinary tract infection (UTI), bacterial prostatitis, urethral stricture, phimosis, and urethral catheterization.1 In 25% to 40% of cases, the cause of NGU in male patients remains unknown.15 Female Patients.  Urethritis in female patients can be caused by N. gonorrhoeae, C. trachomatis, HSV, and M. genitalium. T. vaginalis typically causes vaginitis in women but is known to infect the urethra and is associated with pyuria.6,7,10,29,32–36

Noninfectious Causes In men and women, urethritis can accompany noninfectious systemic diseases such as Stevens-Johnson syndrome, or it can result from chemical irritation.1,6

Epidemiology One half of new STIs occur in adolescents and young adults between the ages of 15 and 24 years.37 Population-based data for this age group derived from the National Health and Nutrition Examination Survey (NHANES) showed the prevalence of C. trachomatis was 1.7% among males and 3.2% among females (2005–2008 data); prevalence of N. gonorrhoeae was 0.3% among males and 0.6% among females (1999–2008

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PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION G  Genitourinary Tract Infections

data); and prevalence of T. vaginalis was 0.9% among males and 1.5% among females (2001–2004 data).37 Other studies have demonstrated that prevalence rates of T. vaginalis infection increase with age; they are highest among black women, lower among black men, and lowest among whites.38,39 Similar ethnic or racial differences have been found for C. trachomatis and N. gonorrhoeae.40 Data from several studies, including the CDC’s 2013 sexually transmitted disease (STD) surveillance report, illustrate that the STI rates vary by specific populations.25,38,40,41 Youth in correctional facilities and the National Job Training Program have among the highest STI rates.2,40,41 Sexual practices and behavior can influence the epidemiology of urethritis. Urethritis due to C. trachomatis, N. gonorrhoeae, or HSV among adolescent women correlates with having new sex partners.6 Adenovirus and HSV-1 have been associated with oral-genital contact and having a male partner, whereas M. genitalium and C. trachomatis have been associated with vaginal sex.5 In one study, N. gonorrhoeae and U. urealyticum urethritis were found in heterosexual men, C. trachomatis urethritis was associated with MSM, and T. vaginalis was more common in men older than 30 years of age.42 Urethritis due to STI pathogens also can occur in prepubertal boys and, less frequently, in prepubertal girls. In this age group, transmission commonly results from sexual abuse with genital-to-genital contact (see Chapter 54).

Clinical Manifestations and Differential Diagnosis Symptomatic urethritis in adolescent males is characterized by dysuria, urethral discharge, or urethral pruritus. Discharge can be mucoid, mucopurulent, or purulent. Gonococcal urethritis compared with NGU usually has a shorter incubation period, more acute onset, and more profuse discharge (Table 51.1).1 Discharge in patients with NGU can be so scant that it is only noticed in the morning or is apparent as crusting on the meatus or as stains in underwear.1 Urethral infection with N. gonorrhoeae and the various organisms causing NGU also can be asymptomatic.43 Urethritis must be differentiated from UTI, particularly in adolescent boys with dysuria but no discharge. In contrast to UTI, frequency,

TABLE 51.1  Clinical Manifestations of Nongonococcal and Gonococcal Urethritis Characteristic

Nongonococcal Urethritis

Gonococcal Urethritis

Incubation period

2–3 weeks

2–6 days

Onset

Insidious

Abrupt

Dysuria

+, may wax and wane

++, continuous

Discharge

Scant to moderate, may be absent

Profuse, absent in <10%

+, modest discomfort; ++, more severe discomfort.

hematuria, and urgency are uncommon in urethritis. However, if the male adolescent is sexually active, pyuria is more likely to be caused by urethritis than UTI because UTI is uncommon in this age group. A focused STI history (see Chapter 49) and thorough medical history can help establish relative risks of urethritis and UTI. In adolescent girls, dysuria is the cardinal feature of urethritis, which must be differentiated from acute bacterial cystitis and vulvovaginitis (Table 51.2). The literature differentiates internal and external dysuria. Internal dysuria is pain that is felt internally during voiding. External dysuria is discomfort that is felt as urine passes over the labia.7 Internal dysuria, urinary frequency, and isolation of more than 102 uropathogens per milliliter of voided urine suggest acute bacterial cystitis; isolation of 102 or fewer uropathogens per milliliter suggests acute urethritis due to STI pathogens.6 Pain that is felt internally only at the end of urination is consistent with bacterial cystitis.7 External dysuria can occur with vulvovaginitis. Female adolescents can have vaginitis alone or a concurrent UTI and may not be able to adequately distinguish between internal and external dysuria.7,44 Any female patient suspected of having urethritis requires an STI-directed history and physical examination to identify other STIs or STI syndromes (e.g., pelvic inflammatory disease [PID]). In prepubertal boys and girls, urethritis due to STI pathogens can manifest with dysuria and urethral or vaginal discharge. There may be vague lower abdominal pain, unwillingness to void, and in boys, irritation in the distal urethra or meatus. Dysuria in a prepubertal child is much more likely to be caused by UTI than urethritis associated with STI. Urethritis is more probable in the setting of a discharge or a history of sexual abuse, especially if genital-to-genital contact has occurred.

Laboratory Findings and Diagnosis Male Patients.  For male patients, specimens are obtained to document urethritis and to detect common causes such as N. gonorrhoeae and C. trachomatis. The definitive diagnosis is enhanced if the patient has not voided recently; examination in the morning before voiding is ideal.1 A meatal swab specimen of a discharge can be taken for Gram stain; the finding of gram-negative intracellular diplococci of the typical kidney bean morphology pattern (Fig. 51.1) or at least 2 neutrophils per oil immersion field (×1000) is diagnostic of urethritis.1,2 A Gram stain smear is sensitive and specific in diagnosing gonococcal urethritis if intracellular diplococci are detected. If the Gram stain is equivocal, negative, or unavailable and the criteria for urethritis are met, NAAT for N. gonorrhoeae and C. trachomatis is indicated.2 In all patients, regardless of whether N. gonorrhoeae is suspected by Gram stain, a first-voided urine or urethral specimen should be obtained for detection of C. trachomatis by NAAT. The optimal specimen from male patients is a first-voided urine.2,45 NAAT for N. gonorrhoeae and C. trachomatis may detect infection in male patients with symptoms of urethritis but no objective evidence of urethral inflammation.2 The diagnosis of T. vaginalis in men is more challenging than in women. Wet mount preparation of a urethral smear detects only 30% of T. vaginalis infections in men.28 Culture can be performed on urine, semen, or urethral specimens and appears to yield better results if

TABLE 51.2  Distinguishing Features of Urethritis, Acute Bacterial Cystitis, and Vulvovaginitis in Adolescent Females Feature

Urethritis

Acute Bacterial Cystitis

Vulvovaginitis

Symptoms

Internal dysuria

Internal dysuria, frequency, urgency, hematuria

External dysuria, vaginal discharge, vulvar burning, itching

Duration of symptoms

Often ≥7 days

Usually ≤4 days

Varies with cause

Signs

Mucopurulent cervicitis Vulvar lesions

Suprapubic tenderness

Vulvar lesions and inflammation, vaginal discharge

Epidemiologic associations

New sex partner Previous STI Sexual partner with STI

Previous cystitis Onset of symptoms within 24 hours of intercourse Use of diaphragm Use of a spermicide

History of genital herpes Sex partner with genital herpes Antibiotic use Previous vulvovaginitis Candidiasis

STI, sexually transmitted infection. Modified from Holmes KK, Stamm WE, Sobel JD. Lower genital tract infection syndromes in women. In: Holmes KK, Sparling PF, Mardh P-A, et al. (eds). Sexually Transmitted Diseases, 4th ed. New York, McGraw-Hill, 2008, pp. 987–1016.

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Urethritis, Vulvovaginitis, and Cervicitis

A

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available. Specific testing of men for T. vaginalis should be considered for cases of nongonococcal urethritis in high-prevalence areas or populations.2 Cultures for U. urealyticum are not available readily, and M. genitalium is difficult to isolate.1,32,51 In research studies, both are diagnosed and evaluated using NAAT. However, these tests are not cleared for use by the US Food and Drug Administration (FDA), and management relies on the clinical presentation and exclusion of other causes.2 Female Patients.  Endocervical or vaginal and urethral specimens should be obtained for NAAT for N. gonorrhoeae and C. trachomatis in adolescent girls with urethritis because concurrent infection is common.2,6 Urinalysis and urine culture also are indicated because simultaneous UTI and STI can occur in sexually active females.7 Urine testing using NAAT for C. trachomatis and N. gonorrhoeae is not as sensitive as endocervical specimen testing.2,45 Studies using NAAT for vaginal specimens have shown good correlation with cervical specimens, and the vaginal specimens can be collected by the healthcare personnel or the patient.2,45 T. vaginalis can be diagnosed by a variety of methods, including wet mount preparation, culture, nucleic acid probe, immunochromatographic capillary flow dipstick technology, and NAAT.2,25,48,49,52,53 As for male patients, wet mount microscopy has poor sensitivity compared with other methods.2 NAAT for T. vaginalis (e.g., strand displacement amplification [SDA]), and TMA are FDA cleared for use in women for endocervical, vaginal, or urine specimens.2,48,52

Treatment

B

C FIGURE 51.1  (A) Gram stain of urethral discharge from an male adolescent with urethritis shows multiple neutrophils and intracellular diplococci with the kidneybean morphology typical of Neisseria gonorrhoeae (magnification ×1000). (B) Gram stain of vaginal fluid from an adolescent with bacterial vaginosis shows clue cells and squamous vaginal epithelial cells covered with coccobacilli, which gives them a stippled or granular appearance. Notice the absence of rods with blunt ends (i.e., lactobacilli) (magnification ×2000). (C) Wet mount of vaginal secretions from a female adolescent with bacterial vaginosis shows clue cells. Notice the stippled epithelial cells with ragged (i.e., bacteria-covered), ill-defined borders (magnification ×200).

multiple sites are tested.2,29,46 The InPouch culture system (BioMed Diagnostics, San Jose, CA) is equivalent to the gold standard Diamond media, and urethral or urine sediment specimens can be inoculated.25 However, studies have shown that NAAT is superior to a wet mount preparation or culture to detect T. vaginalis in male patients.10,26,28,29,47–49 Although the TMA test is approved only in the United States for female specimens, it may be used in laboratories that have conducted validation procedures on male specimens.2,46,50 T. vaginalis PCR is not commercially

Initial treatment for male patients can be based on Gram stain results (Table 51.3).2 Patients with evidence of N. gonorrhoeae by Gram stain should be treated with dual single-dose therapy, including intramuscular ceftriaxone and oral azithromycin to reduce the development of antimicrobial-resistant N. gonorrhoeae. Although oral cefixime can be substituted for ceftriaxone, it is not the first-line drug due to resistance patterns and poor efficacy if there is a concomitant pharyngeal infection.2 All patients with negative Gram stain results should be tested for C. trachomatis and treated if positive. For NGU, a single dose of azithromycin may be preferred over a 1-week course of doxycycline in adolescents because of adherence.2 Single-dose azithromycin is also preferred because it is most effective in treating M. genitalium, which is the most common cause of persistent and recurrent NGU.2 Confirmed cases of N. gonorrhoeae or C. trachomatis must be reported to the local health authorities, and sexual partners should be contacted for assessment and treatment. Immediate follow-up and repeat testing for N. gonorrhoeae or C. trachomatis urethritis in adolescents are not recommended routinely if appropriate treatment is completed, signs and symptoms disappear, and no re-exposure to an untreated partner occurs. However, because of the high rate of reinfection after initial treatment, repeat testing for N. gonorrhoeae and C. trachomatis is recommended in 3 months.2 If symptoms persist despite good adherence and no re-exposure and the person meets diagnostic criteria for persistent or recurrent NGU, further management is indicated. Treatment without signs for urethral inflammation has not been demonstrated to be effective.2,54,55 M. genitalium is the most common cause of persistent or recurrent NGU.2 If doxycycline was used initially, single-dose azithromycin should be tried because it is more effective than multidose doxycycline for this organism.2 However, resistance has developed to azithromycin, and studies have demonstrated treatment failure in men treated with both single-dose and extended-dosing regimens of azithromycin, possibly related to the selection of resistant organisms with the common use of single-dose azithromycin for treatment of N. gonorrhoeae and C. trachomatis. Seven days of moxifloxacin (400 mg daily) is effective for treatment failures for M. genitalium.2,16,51,54–57 Fluoroquinolone resistance has also been demonstrated.57,58 For male patients with persistent urethritis, culture of a urethral specimen or first-void urine for T. vaginalis should be performed because of the high prevalence of T. vaginalis infection among men with nongonococcal, nonchlamydial urethritis and coinfection with these organisms. If there has been laboratory validation, testing of urethral or urine specimens with NAAT is preferred.2 If T. vaginalis is diagnosed, metronidazole or tinidazole is prescribed (see Chapter 274). Current CDC guidelines recommend presumptive treatment with metronidazole or tinidazole in

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PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION G  Genitourinary Tract Infections

TABLE 51.3  Recommended Treatment of Urethritis in Postpubertal Children and Adolescents Gram Stain

Suggested Treatment

RESULTS AVAILABLE Increased Neutrophils

Gram-Negative Intracellular Diplococci

Present

Presenta

Treat for gonococcal and chlamydial urethritis. For Neisseria gonorrhoeae: for postpubertal children >45 kg and adolescents, ceftriaxone (250 mg IM once) or cefixime (400 mg PO once) and azithromycin (1 g PO once) For Chlamydia trachomatis: for postpubertal children ≥8 years and adolescents, azithromycin (1 g PO once) or doxycycline (100 mg bid PO for 7 days)

Present

Absent

Treat for nongonococcal urethritis. Azithromycin (1 g PO once) or doxycycline (for 7 days) or ofloxacin (300 mg PO bid for 7 days) or levofloxacin (500 mg PO once daily for 7 days) or erythromycin base (500 mg PO qid for 7 days) or erythromycin ethylsuccinate (800 mg PO qid for 7 days)

Absent

Absent

Defer treatment until microbiologic results are available, or if patient is high risk by history and follow-up cannot be ensured, treat for gonococcal and chlamydial urethritis

RESULTS NOT AVAILABLE Urethral discharge

—

Treat for gonococcal and chlamydial urethritis

No urethral discharge

—

Defer treatment until microbiologic results are available, or if patient is high risk and follow-up cannot be ensured, treat for gonococcal and chlamydial urethritis

RECURRENT OR PERSISTENT URETHRITIS —

—

Azithromycin (1 g PO once) if not used for initial episode; for failure, moxifloxacin (400 mg PO qd for 7 days) to cover Mycoplasma genitalium; metronidazole (2 g PO once) or tinidazole (2 g PO once) to cover Trichomonas vaginalis

a Gram stains are considered inadequate to evaluate prepubertal children for N. gonorrhoeae. IM, intramuscularly; IV, intravenously; PO, orally. Data from Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015;64(RR- 3):1–137.

cases of persistent urethritis in areas of high prevalence for men who have sex with women.2 U. urealyticum can be difficult to eradicate, and resistance to tetracyclines has been demonstrated.1,51 Patients who do not respond to therapy should be referred to a urologist. Female patients with findings suggesting bacterial cystitis can be treated presumptively for UTI. However, if urethritis is suspected, a single dose of azithromycin (1 g) or a 7-day course of doxycycline (100 mg twice per day) is indicated pending results of urine culture and STI testing.2 If symptoms of dysuria due to vulvovaginitis are found, treatment should be directed at the cause. Although the CDC’s 2015 STD treatment guidelines do not specifically discuss persistent urethritis in females, treatment of M. genitalium should be considered when other causes have been ruled out, and ideally, testing for this organism should be done.35

Complications Complications of urethritis include disseminated gonococcal infection (0.5% to 3%) and reactive arthritis syndrome (i.e., Reiter syndrome). In male patients, epididymitis (1% to 2%) and, rarely, prostatitis and balanoposthitis also occur.1,16 Female patients with N. gonorrhoeae, C. trachomatis, and M. genitalium infection also are at risk for PID and infertility.7,16,36,59 M. genitalium has been associated with preterm birth and spontaneous abortion.2,59 In male and female patients, STIs associated with urethritis increase susceptibility to infection with, viral shedding, and transmission of HIV.2,60,61

Prevention Correct and consistent use of condoms is the most effective means of preventing and reducing transmission of the STIs associated with urethritis.

VULVOVAGINITIS Vulvovaginitis (i.e., inflammation of the vagina or vulva) is a common gynecologic problem in prepubertal and adolescent girls. The cause,

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pathogenesis, and management are substantially different for the two age groups.7 Vaginitis and vulvitis are a continuum in young children, whereas they are distinct clinical entities in adolescents.

Vulvovaginitis in Prepubertal Girls Etiologic Agents and Epidemiology Prepubertal girls can have specific or nonspecific vaginal infections.7 Several factors predispose young girls to vulvovaginal irritation, including proximity of the vagina to the rectum, poor hygienic practices, lack of protective labial fat pads and pubic hair, and lack of an estrogen effect on vaginal mucosa.7,62 Prepubertal girls are more likely than postpubertal girls to experience vulvar irritation and trauma from soaps, bubble baths, and clothing.7 The lack of estrogen effect in prepubertal girls promotes an environment with a neutral pH, predisposing to overgrowth with a variety of potential pathogens.6,62 Vaginal microbial infections that are not STIs usually are caused by respiratory tract and enteric pathogens. T. vaginalis is rare in prepubertal children because lack of estrogen makes the vagina resistant to this infection.7 Isolation of Gardnerella vaginalis in prepubertal vaginitis is not diagnostic of bacterial vaginosis (BV) but has been reported in prepubertal girls after sexual assault.7 Candida vulvovaginitis is not common in prepubertal girls unless there are other risk factors, such as antibiotic use, diabetes mellitus, immunosuppression, or use of diapers; 3% to 4% of prepubertal girls have Candida spp. as part of normal vaginal flora.7,62 Although prepubertal vulvovaginitis is not often sexually transmitted, sexual abuse must be considered if pathogens such as C. trachomatis, N. gonorrhoeae, T. vaginalis, human papillomavirus (HPV), or HSV are identified.7,62 Attributing HPV to sexual abuse rather than vertical transmission or inoculation from caregivers and autoinoculation is challenging because of the lack of studies in this age group regarding incubation, latency to clinical presentation, and cutoff ages for vertical transmission.62 Similar to the cervical epithelium of postpubertal girls, the cuboidal vaginal epithelium of prepubertal girls is susceptible to N. gonorrhoeae and C. trachomatis.6 Other causes of vulvovaginitis include foreign body, vulvar skin disorders, and allergic reactions (Box 51.1).

Urethritis, Vulvovaginitis, and Cervicitis

BOX 51.1  Etiologic Factors in Prepubertal Vulvovaginitis NONSPECIFIC CAUSES Contact or Allergic Reactions (Common) • • • •

Bubble-bath preparations Shampoos, soaps Laundry detergents Clothing (e.g., nylon undergarments)

Physical Factors (Common) • Foreign body • Sand (e.g., sandbox) • Poor hygiene (e.g., wet diapers) SPECIFIC MICROBIOLOGIC CAUSES Not STI Related • • • • • • • • • • •

Shigella spp. Yersinia enterocolitica Enteric bacilli Staphylococcus aureus Group A Streptococcus Haemophilus influenzae Enterobius vermicularis Moraxella catarrhalis Streptococcus pneumoniae Neisseria meningitidis Candida spp.

Possibly STI Related (Less Common) • • • •

Neisseria gonorrhoeae Chlamydia trachomatis Trichomonas vaginalis Herpes simplex virus

Vulvar Skin Disorders • Eczema • Psoriasis STI, sexually transmitted infection.

Clinical Manifestations, Differential Diagnosis, and Clinical Approach The clinical features of vulvovaginitis in children include vaginal discharge, vulvar irritation, pruritus, dysuria, bleeding, genital inflammation, and foul smell.7,62 When associated with a foreign body, the discharge can be profuse, foul smelling, and blood tinged.7 Parents often are unaware that the child has inserted something into the vagina. In Enterobius vermicularis–associated vulvovaginitis, recurrent symptoms and vulvar or anal pruritus are common. Discharge can be bloody in cases of vulvovaginitis caused by Shigella spp. or Streptococcus pyogenes infection.6,7,62 Bleeding also should raise concern about trauma. Diffusely hyperemic vulvar mucosa suggests streptococcal vulvovaginitis. Discharge associated with gonococcal infection is commonly green and purulent, whereas discharge is less common with chlamydial infection. All prepubertal children with vulvovaginitis require a careful history and physical examination. Vaginitis due to S. pyogenes can occur after a pharyngeal or skin infection in the patient or family members. Finding a sibling with an STI raises concern about sexual abuse by someone associated with the family.7,62 Gynecologic examination includes abdominal inspection and palpation. In a gentle and supportive manner, inspection of the perineal skin, vulva, and perirectal and genital areas is performed to detect excoriation, erythema, ulcers, or structural abnormalities. Visualization of the vagina and cervix without instrumentation usually is possible with the patient in the knee-chest position.7 This facilitates detection of a foreign body, especially if a magnifying lens or

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BOX 51.2  Testing Vaginal Discharge or Aspirate Specimens From Prepubertal Girls With Vulvovaginitis Gram stain for bacteria and white blood cellsa Culture for aerobic and anaerobic bacteria Culture for Neisseria gonorrhoeae and Chlamydia trachomatisb Wet mount to detect clue cellsc or trichomonadsd Potassium hydroxide preparation to detect fungal elementsd and note odor Scotch tape specimen from perianal area in early morning if pinworms are suspected a Gram stain should not be used to diagnose or exclude N. gonorrhoeae in prepubertal children. b Nonculture tests usually are not recommended in cases of abuse due to the risk of falsepositive results, but nucleic acid amplification testing (NAAT) of vaginal or urine specimens may be an acceptable alternative particularly in other circumstances. c Clue cells are stippled epithelial cells whose borders are obscured by adherent bacteria. d Culture also can be performed for Trichomonas vaginalis and yeast. NAAT for Trichomonas vaginalis has not been adequately studied in prepubertal children.

otoscope head is used. Examination with the patient under anesthesia may be necessary in some cases.

Laboratory Findings and Diagnosis Samples of a vaginal discharge are obtained (Box 51.2) using a sterile, saline-moistened swab for potassium hydroxide (KOH) preparation, Gram stain, and culture.62 A vaginal wash using nonbacteriostatic saline or vaginal aspiration using an eyedropper are alternative methods of specimen collection.7,62 However, the latter specimens may not be as sensitive for identification of C. trachomatis if few epithelial cells are collected, which are necessary because the organism is an obligate intracellular pathogen. Culture confirmation of N. gonorrhoeae and C. trachomatis is the most admissible legal evidence for cases of suspected sexual abuse. NAAT for vaginal or urine specimens may be an alternative to culture for testing of vaginal secretions in girls.2 T. vaginalis can be detected in vaginal wash specimens or by culture.7,53 If Enterobius infestation is suspected, the parent is instructed to examine the perianal region at night for the small, white pinworms, and a Scotch tape swab or paddle specimen is collected from the perianal area immediately on the child’s awakening. Samples for culture for yeast should be considered if itching persists or the history suggests risk factors for candidal infection.7,62

Treatment The mainstay of treatment for nonspecific vulvovaginitis is education, attention to personal hygiene, and avoidance of agents such as bubble baths and tight nylon undergarments that provoke the problem.62 Sitz baths in warm water without soap may be helpful. Vitamin A and D ointment or petroleum jelly can protect the vulva, and a short course of 1% hydrocortisone cream can alleviate acute exacerbations of irritant vulvitis.7,62 In severe cases, an estrogen cream may be applied for several weeks to ameliorate symptoms.7,62 If a foreign body is detected, removal usually resolves the problem. Treatment of vulvovaginitis due to specific pathogens is initiated on the basis of the Gram stain, wet mount preparation, culture, or NAAT results. Recommended treatments for N. gonorrhoeae are ceftriaxone alone for patients who weigh 45 kg or less and ceftriaxone along with azithromycin for those who weigh more than 45 kg. For C. trachomatis, erythromycin is given to patients who weigh less than 45 kg, azithromycin for those younger than 8 years of age and who weigh 45 kg or more, and azithromycin or doxycycline for older girls. For Candida, an antifungal agent, such as clotrimazole, is used, or oral fluconazole is used if topical therapy is not effective. Treatment for S. pyogenes is penicillin or amoxicillin. Other antimicrobial agents are chosen on the basis of vaginal bacterial culture results.2,7,62

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PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION G  Genitourinary Tract Infections

Complications The follow-up of children with vulvovaginitis depends on the cause. Fortunately, gonococcal and chlamydial vulvovaginitis rarely are associated with upper tract disease, and impairment of fertility is unlikely if the infection is treated adequately.7 For recurrences due to S. pyogenes, pharyngeal colonization in the patient and carriage in family members are considered.62

Vaginitis in Pubertal Girls Etiologic Agents and Epidemiology Under the influence of estrogen at puberty, the vaginal epithelium shifts from cuboidal to a glycogen-containing stratified squamous epithelium, and there is an associated increased growth of lactobacilli that produce lactic acid and hydrogen peroxide.6,7,63 This results in a decrease in vaginal fluid pH from a prepubertal level of about 7.0 to about 4.0. Changes in the epithelium, colonizing flora, and pH render the vaginal environment relatively resistant to infection caused by C. trachomatis and N. gonorrhoeae. In adolescents, these two organisms cause cervicitis rather than vulvovaginitis. Leukorrhea, the normal white mucous vaginal discharge that represents the effect of estrogen on the vaginal mucosa in adolescents, must be distinguished from pathologic discharge. Saline wet mount examination of vaginal secretions reveals sheets of epithelial cells without inflammatory cells, yeast, clue cells, or trichomonads. Leukorrhea sometimes is considered excessive by patients, and they need reassurance.7,63 The major causes of vaginitis in adolescents are BV, candidiasis, and T. vaginalis infection. BV has replaced the term nonspecific vaginitis because the condition usually is not inflammatory but arises from a change in the vaginal flora.7,64 Less common causes of vaginitis in adolescents include ulceration and infection associated with tampons, cervical caps, vaginal contraceptive ring, and other foreign bodies; chemical agents such as those found in douches and spermicides; and toxinproducing Staphylococcus aureus.6,7,65 Bacterial Vaginosis.  BV is the most common cause of vaginitis in postpubertal women, affecting approximately one third of women.63,66–68 BV represents a disruption in the normal vaginal flora, with a decrease in lactobacilli and overgrowth of a variety of primarily anaerobic organisms. BV-associated organisms include G. vaginalis, genital mycoplasmas (M. hominis), U. urealyticum, Bacteroides, Prevotella, Porphyromonas, Peptostreptococcus, Fusobacterium, and Mobiluncus species.63,64,69–71 Although many patients with BV have moderate to heavy concentrations of vaginal Gardnerella species, detection of this organism is not diagnostic because vaginal colonization is common in patients without BV and not specific for the diagnosis.63,64,71 New technologies employing amplification of ribosomal RNA are being used to characterize bacterial species that are not identified by culture 64,70–72 They include three clostridial bacteria, Leptotrichia and Megasphaera species, and Eggerthella-like bacteria.70–72 In one study, detection of these noncultivatable bacteria had excellent sensitivity and specificity for diagnosing BV compared with standard diagnostic criteria.71 In a multivariate analysis of NHANES data from 2001 through 2004, risk factors for BV included a higher number of lifetime sex partners, douching, low educational achievement, and being non-Hispanic black.68 BV has also been associated with poverty, smoking, having a female sex partner, high body mass index, and previous pregnancy.68,73,74 The prevalence of BV among women attending STI clinics is higher (30% to 37%) than among college students (4% to 15%)7 and the prevalence of BV in a nationally representative sample of 14-19 year old women was 18.5%.68 BV is more common among adolescents and young adults who are sexually active and have multiple sexual partners. However, designating BV as an STI has been controversial because some studies have found BV in sexually inexperienced females.64,66,68,75,76 One study of women entering the military found that 19% of subjects denying a history of vaginal intercourse met criteria for BV compared with 28% who had been active sexually.75 Another study questioned the accuracy of sexual histories having failed to find BV in truly sexually inexperienced college students.77 Studies have shown a concordance between the presence of G. vaginalis

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in the urethra of male sex partners of women diagnosed with BV but did not find this organism in male controls.64 Sexual activity, multiple sexual partners, receptive oral sex, and vaginal insertion of sex toys that were not cleaned are associated with BV, whereas the use of condoms appears to be protective.64,73,74,77–80 Treatment of sex partners does not appear to prevent recurrence.64 However, a systematic review of randomized, controlled trials of male partner treatment for BV criticized these studies for having methodologic flaws.81 Up to one third of women experience recurrent episodes of BV within 3 months of treatment.66 In one study, factors associated with recurrence over a 12-month period included a history of BV and having a female sex partner or a regular sex partner.82 Recurrence may be related to reinfection from an infected partner or to failure to re-establish lactobacilli dominance with persistence of pathogenic bacteria.63,67,72 Some investigators have postulated that the recurrence of BV is related to persistence of a biofilm containing G. vaginalis and other organisms that adheres to the epithelial cells and provides protection from systemic and topical antibiotics.72,83–85 Candidiasis.  Vulvovaginal candidiasis has an estimated lifetime incidence of up to 75%.86 Candidal colonization of the vagina usually originates from the gastrointestinal tract, and sexual transmission is not an important mode of acquisition.2,63,86 As many as 30% of healthy asymptomatic women are colonized with yeast, and Candida albicans is the organism found in most uncomplicated cases.63,66 Risk factors include pregnancy, poorly controlled diabetes, immunosuppression, receptive oral sex, use of estrogen, and use of various contraceptives, including intrauterine devices, diaphragms, vaginal rings, and possibly spermicides.63,65,66,86 Antibiotic use is mentioned frequently, but it is not a major cause of infection in most women. Rather, colonization by species of Candida may place a subpopulation of women at higher risk for symptomatic infection.66,86–88 For approximately one half of girls and women, no risk factors are identified.63,66 Most women experience uncomplicated vulvovaginal candidiasis, with infrequent mild to moderate episodes caused by C. albicans.86 However, 10% to 20% of women have complicated vulvovaginal candidiasis that is more severe, recurrent, or caused by other Candida species. These women are more likely to have underlying medical risk factors such as diabetes or immunocompromise.2,86 Approximately 5% of women have recurrent disease (i.e., ≥4 episodes in a 12-month period), which is more likely to be associated with C. glabrata and other non-albicans Candida species.2,66,86,89 Most women with recurrent vulvovaginal candidiasis do not have diabetes mellitus or immunosuppression, but these conditions increase the risk. It is postulated that some patients may have a genetic predisposition to recurrent vulvovaginal candidiasis, suppression of local immunity due to virulence factors produced by the Candida species, or an alteration in local innate response leading to an aggressive inflammatory leukocytic response to yeast colonization.63,66,86,90,91 Trichomonas vaginalis.  T. vaginalis is the third most common cause of infectious vaginitis and has a worldwide distribution, with prevalence in community-based studies ranging from 2% to 46% of women.10,63 It is the most prevalent curable STI worldwide, with most cases found in women.27 In the United States, an estimated 3.7 million people are infected.37 Studies using PCR testing of urine or vaginal swabs from girls and women between the ages of 14 and 26 years have shown T. vaginalis prevalence rates of approximately 2% to 3%, which was higher than the rate for gonorrhea among the same people.52 Certain populations may have a higher prevalence, including 26% of symptomatic and 7% of asymptomatic women at STI clinics, up to 18% of patients at adolescent clinics, 10% of women in college health programs, and up to 47% of incarcerated women.2,10,52 Other risk factors include being African American, smoking, using alcohol and drugs, having multiple partners, and adolescents having an older sexual partner.2,10 T. vaginalis facilitates transmission and acquisition of HIV and commonly is associated with other STIs.

Clinical Manifestations and Differential Diagnosis Clinical presentations that help differentiate BV from candidal vulvovaginitis and trichomonal vaginitis are shown in Table 51.4. In the sexually active adolescent, cervicitis also must be excluded because it can occur as a coinfection or as the sole cause of the vaginal discharge.92

Urethritis, Vulvovaginitis, and Cervicitis

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TABLE 51.4  Characteristics and Recommendations for Treatment of Vaginitis in Adolescents Bacterial Vaginosis

Candidal Vaginitis

Trichomonal Vaginitis

Odor of vaginal discharge

Malodorous

Usually not malodorous

May be malodorous

Vulvar itch

Sometimes

Yes or discomfort

Yes

Dysuria

Sometimes

Yes

Yes

Dyspareunia

Sometimes

Yes

Yes

Other symptoms

No

Symptoms often exacerbated before menses

No

Appearance of vaginal discharge

Thin, homogeneous, white, clings to vaginal wall, ± frothy

Thick, curd-like

Heavy, grey or yellow-green, frothy

Other signs

No

Vulvar and vaginal erythema, vulvar edema

Vulvar and vaginal erythema

pH

>4.5

<4.5

>4.5

KOH preparation

Fishy, amine odor when mixed with 10% KOH (positive whiff test)

Hyphae or pseudohyphae

Occasionally positive whiff test

Saline preparation

Clue cells, few neutrophils

Neutrophils and epithelial cells in equal numbers

Motile trichomonads, neutrophils

Gram stain

Few gram-positive bacilli; abundant mixed flora

Hyphae or pseudohyphae or blastospores

Trichomonads visualized rarely

Culture

Not useful

Can be useful if KOH negative

Culture more sensitive than wet mount

Oral Metronidazole (500 mg bid for 7 days) or clindamycin (300 mg bid for 7 days) or tinidazole (2 g qd for 2 days) or tinidazole (1 g qd for 5 days) Topical intravaginal Clindamycin cream 2% (one full applicator amount per vagina at bedtime for 7 days) or clindamycin ovules (100 mg per vagina at bedtime for 3 days) Metronidazole 0.75% gel (one full applicator amount per vagina qd for 5 days)

Topical intravaginala Butoconazole cream Clotrimazole cream Miconazole cream or vaginal suppository Terconazole cream or vagina suppository Tioconazole ointment Oral Fluconazole (150 mg once)

Oral Metronidazole (2 g for 1 dose or 500 mg bid for 7 days) or tinidazole (2 g in a single dose)

SYMPTOMS

SIGNS

LABORATORY FINDINGS

TREATMENT

a Intravaginal therapies are available in 1- to 14-day regimens. KOH, potassium hydroxide.

Symptomatic BV manifests with a thin, white-grey, homogeneous vaginal discharge that adheres to the vaginal walls and has a fishy odor.64,66 Women with symptomatic candidal infection commonly complain of vaginal pruritus and burning, dysuria, and dyspareunia. Discharge can be thick and white with a cottage cheese appearance or can be watery and homogeneous. Discharge usually is not malodorous, and in many cases, women do not notice a change in vaginal discharge.66,86 Patients with symptomatic trichomoniasis often have pruritus and a malodorous, frothy, yellow or greenish discharge and can have dysuria, abdominal pain, vulvar erythema and edema, and bloody vaginal discharge. Cervicitis can occur, with punctuate hemorrhages (i.e., strawberry cervix) and friability. Asymptomatic T. vaginalis infection occurs commonly.10

Laboratory Findings and Diagnosis Laboratory features that help distinguish BV from candidal vulvovaginitis and trichomonal vaginitis are shown in Table 51.4. Bacterial Vaginosis.  The diagnosis of BV is commonly established in the clinical setting by the finding of three or more of the following Amsel criteria: (1) thin, homogeneous vaginal discharge; (2) vaginal pH >4.5; (3) characteristic fishy or amine odor released when 10% KOH is added to the vaginal fluid specimen (i.e., positive whiff test); and (4) 20% or more of epithelial cells having the appearance of clue cells, which are

stippled epithelial cells whose borders are obscured by adherent bacteria (see Fig. 51.1).64 Diagnostic accuracy increases with use of the Amsel criteria.25 Alternative tests include the use of Gram stain to group bacteria into morphologic types (i.e., Nugent scoring). Amsel criteria and Nugent scores show good correlation.2,93 Alternative testing includes nonmicroscopic point-of-care testing. Some tests detect the metabolic products of BV-related organisms such as sialidase and prolineaminopeptidase.2,64 A DNA probe for G. vaginalis ribosomal RNA is available but is not useful if rapid results are needed. This test is most helpful as a supplemental marker to detect high concentrations of G. vaginalis.22,93 Routine aerobic and anaerobic vaginal cultures are not helpful, and molecular diagnostic techniques are primarily a research tool.2,67 BV usually does not produce an inflammatory response, and the finding of WBCs on a vaginal smear indicates concurrent vaginitis or cervicitis due to another cause.92,93 Candida species.  Candida vaginitis is diagnosed by demonstrating budding, hyphae, pseudohyphae, or blastospores on microscopic examination of a saline or 10% KOH preparation.2,63 This technique has a sensitivity of about 50% because organisms such as C. glabrata, which does not form hyphae or pseudohyphae, are easily missed on microscopy.2 If the KOH preparation is negative, culture can confirm the diagnosis in symptomatic people.67,86 Culture may be particularly helpful for patients with ongoing nonspecific symptoms in whom BV and trichomoniasis

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have been excluded.86 In cases of complicated vulvovaginal candidiasis, culture is important in identifying the species of the organism because therapy may be different or longer.63,94 Culture can also demonstrate eradication of the organism, and for patients with persistent symptoms, an alternative cause should be investigated.63,94 It is useful to measure vaginal pH because the vaginal pH remains low (<4.5) in vaginal candidiasis, unlike BV or trichomoniasis.86 Trichomonas vaginalis.  Diagnosis of trichomoniasis can be made by visualizing the motile protozoa on a wet mount preparation; however, the test result is negative in 30% to 50% of cases.2,67 Culture using Diamond media or the InPouch T. vaginalis culture system is more sensitive.2,25,67 Culture can be performed on vaginal specimens, including patient self-collected specimens. Conventional and liquid Papanicolaou (Pap) tests are not considered diagnostic because of high false-positive and false-negative rates.2,95 A DNA probe test has a sensitivity of 63% and specificity of 99% compared with culture and TMA. It usually is best performed in the laboratory rather than the office setting because the test is moderately complex and requires about 45 minutes to complete.2 One point-of-care test that uses an immunochromatographic capillary flow assay with monoclonal antibodies takes 10 minutes to complete and has 82% to 95% sensitivity and 97% to 100% specificity.2 PCR has excellent sensitivity and specificity (85% to 100%) but is not available commercially.10 TMA has 95% to 100% sensitivity and 95% to 100% specificity and is approved for endocervical, urine, and vaginal swab specimens in women.2,47,48 NAAT using SDA is approved for use with female endocervical, vaginal, and urine specimens.2 Because urine or vaginal specimens collected without use of a speculum can be used to detect trichomoniasis, vulvovaginal candidiasis, N. gonorrhoeae, and C. trachomatis, it is possible to avoid the more invasive speculum examination to determine the cause of vaginitis in adolescents.

Management Bacterial Vaginosis.  Metronidazole administered orally for 7 days is the recommended therapy for women with symptomatic BV,2 and it is preferred over single-dose therapy because of superior efficacy.2,25,64,69 Alternative regimens with intravaginal metronidazole or clindamycin, which are outlined in Table 51.4, have fewer gastrointestinal side effects and cure rates similar to those for oral metronidazole at 1 month after treatment.2,25,67,69 Clindamycin cream should not be used when condoms are used because the oil base weakens the latex.2 Alternate therapeutic regimens have included the use of tinidazole, which has fewer side effects than metronidazole but is more expensive, and oral clindamycin.2,66,96 A Cochrane review found insufficient evidence to recommend for or against probiotics. The 2015 STD treatment guidelines do not recommend this therapy or currently available lactobacillus formulations as adjunctive or replacement therapy to restore normal vaginal flora.2,97 There are no current standard recommendations for treatment of recurrent BV infection, which occurs within 3 months in approximately one third of women.69 Treatment may only suppress biofilm-embedded infection and allow organisms to evade host defense responses. Recurrences may be due to relapse rather than reinfection.67,69,85 A large, multicenter study demonstrated the 70% efficacy of twice-weekly maintenance therapy using metronidazole vaginal gel, but it only suppressed BV in many subjects and led to vaginal candidiasis as a complication.98,99 One uncontrolled study showed promising results with nitroimidazole and boric acid used to disrupt the biofilm and allow penetration of the antibiotic.100 Other regimens that have been evaluated include oral nitroimidazole and intravaginal boric acid followed by suppressive metronidazole gel and a combination of monthly oral metronidazole and fluconazole.100,101 The latter regimen was associated with decreased BV episodes and increased colonization with normal flora. Long-term treatment with vaginal metronidazole is well tolerated, unlike oral treatment, which can be associated with neutropenia or peripheral neuropathy. Prolonged treatment with clindamycin increases the risk of C. difficile colitis.69 Resistance to metronidazole and clindamycin has been seen in cases of recurrent BV.68 The 2015 STDs treatment guidelines do not recommend treating asymptomatic nonpregnant women.2

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Candidiasis.  Topical therapy with azoles, such as clotrimazole, terconazole, miconazole, butoconazole, and tioconazole, is effective for vulvovaginal candidiasis in 1- to 7-day regimens. Many of these topical formulations are available over the counter. Single-dose fluconazole (150 mg) therapy has efficacy that is comparable to topical therapy.2,63,66,102 Symptomatic relief and negative fungal cultures are achieved in up to 90% of patients with uncomplicated vulvovaginal candidiasis. Sexual partners usually do not require therapy unless they have candidal balanitis.2 Recurrent or chronic candidal vulvovaginitis merits investigation for predisposing conditions, which includes obtaining cultures to confirm the diagnosis and identify the pathogen.63 These infections may require a longer duration of topical (7 to 14 days) or oral therapy including nonfluconazole imidazole drugs.2,66,67,86 Topical boric acid in the form of suppositories (600 mg in a gelatin capsule) and topical flucytosine have been useful in patients with non-albicans Candida species and imidazoleresistant species. Alternative therapies are useful, especially in cases of non-albicans Candida species.66,86,94 When using fluconazole, patients with recurrent vulvovaginal candidiasis can be treated initially with a single dose every 3 days for a total of three doses, followed by 100 mg, 150 mg, or 200 mg once each week for 6 months.2 For women who cannot take fluconazole, repeated topical imidazole therapy has been effective.2,66,67 Suppressive therapy usually is continued for 6 months, but recurrence is common after therapy is discontinued because organisms are suppressed rather than eradicated. Prophylaxis can be reinstituted.2,63,86 Fluconazole resistance and clinical failure is uncommon but increasing, and although not usually warranted, in patients with breakthrough Candida infection, susceptibility testing may be helpful.2,103 Only topical azole medications are recommended in pregnancy.2 Trichomonas vaginalis.  Systemic therapy with oral metronidazole or tinidazole is indicated for treatment of trichomoniasis.2 Metronidazole has an 84% to 98% cure rate with a 7-day course (500 mg twice daily) or a large single dose (2 g taken orally). Most recurrent infections are from reinfection, and although uncommon, metronidazole resistance has been reported in approximately 4% to 10% of cases.2,49,67,69 Topical therapy with metronidazole gel is not effective because the gel does not penetrate the urethral and perivaginal glands adequately.2,10,49 Single-dose tinidazole (2 g taken orally) has a 92% to 100% cure rate and reports of 1% resistance.2 Studies show tinidazole to be equivalent or superior to single-dose metronidazole for cure and symptom resolution.2 One study found a 92% cure rate using a combination of oral and vaginal tinidazole in patients unresponsive to metronidazole.104 Tinidazole appears to be better tolerated than metronidazole and has fewer gastrointestinal tract and central nervous system side effects. Sexual partners should be evaluated for STIs and treated for trichomoniasis. For treatment failures, susceptibility testing is recommended for metronidazole and tinidazole.2,49 Women with HIV infections should be treated with metronidazole for 7 days rather than single-dose therapy because the latter is less effective in these patients due to concurrent BV, impaired immunity, and concurrent antiretroviral therapy, which may impact clearance and reduce the efficacy of metronidazole.2,105 There are no contraindications to using metronidazole during pregnancy, but tinidazole should not be used because of concerns about moderate adverse risks.2

Complications Bacterial Vaginosis.  BV has been associated with chorioamnionitis, postpartum endometritis, posthysterectomy vaginal cuff cellulitis, post­ abortion PID, premature rupture of membranes, preterm labor and delivery, low birth weight, spontaneous abortion, and intra-amniotic infection.25,64,76,106 The risk of preterm delivery is restricted to a small subset of women; risk may be related to the genetic host response to inflammation and cytokine production.25,64,76 Vaginal microorganisms can ascend to the upper tract, causing infection and inflammation in the decidua, chorioamnion, or amniotic fluid.64 Data are conflicting about whether the treatment of pregnant women for BV prevents complications.2,25,64,76,107–110 Two systematic reviews found little evidence that screening and treating all pregnant women prevents preterm birth.108,109 The evidence for screening asymptomatic women at low risk for preterm delivery were poor, and evidence for women at high

Urethritis, Vulvovaginitis, and Cervicitis

risk for preterm delivery were conflicting. The 2015 STD treatment guidelines state that the evidence is insufficient to recommend screening of asymptomatic pregnant women at low or high risk for preterm delivery, but they do recommend treatment for all symptomatic pregnant women using any oral or vaginal regimen.2 BV has been associated with an elevated risk of acquiring T. vaginalis, N. gonorrhoeae, C. trachomatis, and HSV-2.2,109,111 Studies also have shown an association between BV and cervicitis and PID, but a causal relationship remains unproved.64,66 Organisms associated with BV have been found in the upper genital tracts of women with PID. Studies using endometrial biopsies have found an association between BV and endometritis, which may be silent clinically or manifest as intermenstrual or increased bleeding.64 Women with BV are more likely to have PID, and women with PID are more likely to have BV.25,64,76 Treatment of BV has been associated with decreased PID in women undergoing abortion and decreased postoperative cuff cellulitis.64,76 Intravaginal treatment of BV has been associated with improved rates of resolution of cervicitis.64 However, the relationship between BV and PID for women not undergoing abortion or uterine instrumentation is not clear.25,76,112 There is no current recommendation for treatment of nonpregnant, asymptomatic women as a standard clinical practice.2,64 Trichomonas vaginalis.  Trichomoniasis has been associated with premature rupture of membranes, preterm delivery, and low-birth-weight infants,.2,25,113 T. vaginalis has also been associated with an increased risk of PID in women who are HIV positive.2,113 Although treatment of T. vaginalis during pregnancy does not appear to reduce complications, the 2015 CDC STD treatment guidelines recommend that all symptomatic pregnant women should be tested and considered for treatment at any stage of pregnancy.2,107,114 Although a single dose of metronidazole has been demonstrated to be safe at all stages of pregnancy, more studies are needed regarding use of tinidazole, and current recommendations recommend avoiding use in pregnancy.2 Human Immunodeficiency Virus.  BV and T. vaginalis enhance acquisition of HIV and transmission to a partner.2,25,29,64,76,105,115 Vulvovaginal candidiasis has been associated with increased HIV seroconversion in HIV-negative women and higher levels of cervicovaginal HIV shedding in HIV-positive women. Treatment of T. vaginalis reduces HIV viral shedding in vaginal secretions.105 However, no studies have demonstrated similar effects on viral shedding in subjects with BV or vulvovaginal candidiasis.2,25

Vulvitis in Adolescents Inflammation of the vulva in adolescents most commonly is caused by HSV and yeasts (see Table 51.4). HSV often causes painful genital ulcers, along with vulvar inflammation and inguinal lymphadenopathy (see Chapter 50).7 Occasionally, inflammation can be associated with T. vaginalis infection.

Prevention Correct and consistent use of condoms is the most effective means of preventing and reducing transmission of the STIs associated with vulvovaginitis.

CERVICITIS Cervicitis is inflammation of the endocervix or ectocervix. Both are common problems among adolescents, but neither is common in prepubertal girls. Under the influence of estrogens after puberty, the vaginal epithelium and ectocervix become cornified and relatively resistant to infection with a number of pathogens, including N. gonorrhoeae and C. trachomatis.7 In contrast, the endocervix continues to be lined with columnar epithelium and remains susceptible to infection with these organisms. In adolescents and adult women, these organisms usually cause endocervicitis in the absence of vaginitis. A normal developmental finding in adolescents is the ectropion, an erythematous area surrounding the os at the junction between columnar and stratified squamous epithelium. During adolescence, the ectropion recedes as the result of squamous metaplasia. Although some adolescents with a large ectropion may have significant vaginal discharge, this is not

51

a pathologic or infectious process. The ectropion usually is not friable, and edema or friability suggests infection.6

Ectocervicitis Ectocervicitis represents infection of the stratified squamous epithelium of the ectocervix. Ectocervicitis can occur in conjunction with trichomonal vaginitis and HSV infection. HSV causes ectocervicitis and endocervicitis.6

Endocervicitis Etiologic Agents and Epidemiology Endocervicitis represents infection of the endocervical columnar epithelium and can produce mucopurulent cervicitis. Common pathogens that cause endocervicitis are N. gonorrhoeae, C. trachomatis, M. genitalium, and HSV.6,116–119 Multiple studies have demonstrated an association between M. genitalium and mucopurulent cervicitis.16,33,36,59,116–118,120–123 There also is a possible association with BV because cervicitis is more likely to resolve when patients also are treated for BV.25,116–118,120 Theories about this relationship include proinflammatory vaginal cytokines in patients with BV and the glycosidases and proteinases produced by BV-associated organisms that may degrade cervicovaginal mucus.116,117 The prevalence of cervicitis varies from 22% to 41% depending on the definition used, which is inconsistent among the various studies in the literature.116 A randomized, multicenter study that ruled out C. trachomatis, N. gonorrhoeae, T. vaginalis, and M. genitalium by NAAT found that 61% of subjects had mucopurulent cervicitis of unknown origin.124 Clinically apparent cervicitis is not caused solely by sexually transmitted agents. Other entities include tuberculosis, noninfectious causes such as sarcoidosis and Behçet disease, and local insults due to chemical douches, spermicides, and foreign bodies.116–119

Clinical Manifestations and Differential Diagnosis Endocervicitis often is overlooked and underdiagnosed because signs and symptoms can be mild or absent. PID is one consequence of untreated mucopurulent cervicitis.6 Sexually active adolescents with vaginal discharge, lower abdominal pain, abnormal vaginal bleeding, or deep dyspareunia should be evaluated for endocervicitis.6 Evaluation also is indicated if a sexual partner has an STI. Cervical abnormalities associated with endocervicitis range from subtle changes to a yellow endocervical discharge and an edematous, erythematous, and easily friable appearance to the cervix.6 There is no consensus definition for mucopurulent cervicitis, which makes evaluation of the research literature difficult.116,117 Definitions include inflammation of the endocervix with possible edema, yellow-green endocervical discharge, increased numbers of neutrophils on microscopic examination of cervical secretions, and inducible endocervical bleeding. The 2015 CDC STD treatment guidelines outline the two major diagnostic criteria as purulent or mucopurulent endocervical discharge and sustained endocervical bleeding.2 Mucopurulence is characterized by a yellow or green color on a cotton-tipped applicator obtained from the endocervix. The number of neutrophils considered significant varies in different studies from at least 30 cells per 400× magnified microscopic field to more than 10 cells per 1000× magnified microscopic field. Although the use of a 30-cell cut point provides greater specificity, detection of yellow endocervical mucopus is more accurate than the number of WBCs.2,6,117–119

Laboratory Findings and Diagnosis Specific microbiologic diagnosis informs appropriate treatment. Patients should be tested for N. gonorrhoeae, C. trachomatis, T. vaginalis, and BV. Gram-negative intracellular diplococci are seen on Gram stain in about one half of cases of gonococcal endocervicitis.6 Given the poor sensitivity of the Gram stain and the possibility of infection in the absence of any abnormality, evaluation for gonococcal endocervicitis must include NAAT.2 Inflammatory changes can be even less remarkable with endocervicitis caused by C. trachomatis. NAAT is recommended in all cases of suspected C. trachomatis infection.2 A saline wet mount preparation can

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TABLE 51.5  Treatment of Cervicitis in Adolescents Results

Suggested Treatment

Mucopurulent or purulent endocervical discharge and/ or sustained easily induced endocervical bleeding

Treat for Chlamydia trachomatis or Neisseria gonorrhoeae with positive test results or consider presumptive treatment for C. trachomatis and N. gonorrhoeae if prevalence is high in patient population or community (e.g., known contact, new and/or multiple sex partners, age ≤25, unprotected sex) and testing not possible and/or follow-up cannot be ensured; if at low risk for STIs, treatment can be deferred pending microbial results

Trichomonas seen on wet mount or identified on rapid test, culture, NAAT

Treat with oral metronidazole or tinidazole

Bacterial vaginosis diagnosed

Treat with oral metronidazole or tinidazole or intravaginal metronidazole or clindamycin

Clinical presentation suggesting herpes simplex virus infection

Consider oral acyclovir or famciclovir or valacyclovir

Persistent or recurrent cervicitis

Rule out re-exposure or treatment failure for N. gonorrhoeae and C. trachomatis or other identified STIs and exclude BV. Testing for Mycoplasma genitalium in settings with validated assays can be conducted. Moxifloxacin can be used if NAAT results are positive and initial treatment with azithromycin (1 g PO once) failed. CDC recommends deferring therapy until further microbial results are availablea

BV, bacterial vaginosis; CDC, Centers for Disease Control and Prevention; NAAT, nucleic acid amplification test, STIs, sexually transmitted infections. a Data from Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015;64(RR-3):1–137.

at lower risk for STIs, treatment can await the results of diagnostic testing.2 More data are needed about the treatment of M. genitalium cervicitis. The antibiotics directed at treating N. gonorrhoeae and C. trachomatis are not adequate to treat cervicitis caused by other organisms, and the standard treatment regimen for PID with cefoxitin and doxycycline is ineffective for women with M. genitalium associated with PID.120,125,126 Testing for M. genitalium is recommended for women with persistent cervicitis or persistent PID for whom re-exposure to an infected partner or nonadherence has been ruled out.2,35,116 If the initial treatment did not include azithromycin, the antibiotic should be given. According to CDC guidelines, moxifloxacin can be given based on having positive M. genitalium test results.2 Other investigators have suggested considering this treatment for recurrent or persistent cervicitis when testing is not available,35 but some have questioned the treatment of cervicitis of unknown origin because the clinical cure described is not related to antibiotic therapy.127 The need to consider M. genitalium in the adolescent population was demonstrated in several studies. One showed a cumulative rate over a 27-month period among 14- to 17-year-old girls to be 14%, which was concordant with their male partners.128 Another study of girls and women 14 to 21 years old found a rate of 22%.129 Follow-up after completion of therapy is recommended for adolescents with persistent symptoms.2 The management of mucopurulent cervicitis also requires evaluation and treatment of all sexual partners for STIs, and it provides an opportunity to reinforce STI prevention measures.2

Complications Complications of untreated mucopurulent cervicitis include PID and the possible long-term sequelae of ectopic pregnancy and infertility. The relationship between N. gonorrhoeae or C. trachomatis and PID is well established, and there is increasing evidence that M. genitalium also is associated with PID.6,59,118,130–132 Cervicitis also increases the risk of transmission and acquisition of HIV infection. Viral shedding of HIV decreases with effective treatment for cervicitis.2,6,118

Prevention Consistent use of condoms can reduce transmission of STI pathogens associated with cervicitis. All references are available online at www.expertconsult.com.

be used to diagnose T. vaginalis and to help establish the diagnosis of BV.2,6,7,117 Because of the poor sensitivity of wet mounts, further testing for T. vaginalis by culture, antigen-based tests, or NAAT should be conducted if the wet mount result is negative. If HSV is suspected, a culture or PCR test should be obtained, although the utility of HSV testing remains unknown.2 NAAT for M. genitalium is not available commercially but may be available in laboratories where validation testing has been completed.2

Treatment The initial management of endocervicitis depends on the clinical findings and risk of the adolescent for certain STIs (Table 51.5). A positive laboratory test result for N. gonorrhoeae, C. trachomatis, T. vaginalis, or HSV defines treatment. However, empiric treatment can be considered if there is a strong suspicion of N. gonorrhoeae or C. trachomatis based on a high prevalence of either microbe in the community or a concern that the patient may be at risk for loss to follow-up.2,120 BV should be treated because some studies have shown higher rates of resolution of endocervicitis with treatment of BV.117 For women

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Urethritis, Vulvovaginitis, and Cervicitis

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