Epidemiology
Pelvic inflammatory disease (PID) encompasses infections of the upper female genital tract that including salpingitis, endometritis, tubo-ovarian abscess and/or pelvic peritonitis. The downstream sequelae of PID include ectopic pregnancy and tubal infertility. Neisseria gonorrhea and Chlamydia trachomatis are the “classic” organisms responsible for PID and are present in about 65%–75% of cases of PID; however, PID infections are commonly polymicrobial. Anaerobic vaginal bacteria, gardnerella vaginalis, enteric gram-negative rods, mycoplasma hominus, and ureaplasma urealyticum have all been implicated as causal organisms. The PEACH Trial demonstrated that women with PID associated with chlamydia or mycoplasma had symptoms for a week longer prior to seeking medical evaluation than women with N. gonorrhea associated PID. This suggests that gonorrheal PID has a more acute and severe presentation.[17]
Prevention
Two approaches to prevent the sequelae of PID are to screen and treat chlamydia and gonorrhea at the stage of asymptomatic cervicitis and to treat sexually active women with mild symptoms when these are suspicious for PID. The British POPI study demonstrated that 9.5% of 74 women with untreated asymptomatic chlamydia cervicitis developed PID within 12 months.[18] Although most women with tubal infertility do not have a known history of PID, a World Health Organization (WHO) study demonstrated serological evidence of prior chlamydia or gonorrhea infection in 93% of women with bilateral tubal infertility compared to 40% of fertile controls subjects.[19]
Clinical presentation and diagnosis
The presentation of PID may include pelvic or abdominal pain, fever, leukocytosis, elevated ESR or c-reactive protein, mucopurulent cervical or vaginal discharge, and white blood cells (WBCs) on wet mount; however even when several of these findings are present, specificity and sensitivity remain low. A classic study of Swedish women showed that even when using the most specific findings (fever >38.3°C/100.9°F, elevated ESR, and adnexal tenderness), PID confirmed by laparoscopic salpingitis was only present in 65% of the women studied.[20] Additionally, if all three findings were required for diagnosis, sensitivity was low, and failed to detect 35% of cases of laparoscopic-confirmed salpingitis.
Many cases of PID have mild nonspecific symptoms resulting in delayed diagnosis. Laparoscopic diagnosis of Salpingitis may be considered definitive, but the test is expensive and its invasive nature limits its use to women with mild symptoms. Increased rates of tubal infertility and ectopic pregnancy have led to concerns about under treatment; therefore, in 2002 the CDC expanded recommendations for empiric treatment. All sexually active young women or other women at risk for STDs should receive antibiotic treatment if they have pelvic or abdominal pain not explained by another etiology along with the presence of cervical motion, uterine or adnexal tenderness.[14]
Treatment
Most women with suspected PID can be treated in the outpatient setting with outcomes equivalent to inpatient parenteral antibiotic treatment. Exceptions may include women with severe symptomatic illness including those with high fever, tubo-ovarian abscess, pregnancy, inability to tolerate oral medications, or peritoneal signs in whom another form of acute abdomen cannot be ruled out. Failure to respond to oral antibiotics within three days is another indication for inpatient treatment with parenteral antibiotics. The three recommended outpatient regimens include 14 days of doxycycline 100 mg PO BID along with any one of the following: one dose of ceftriaxone 250 mg IM, cefoxitin 2 g IM with probenicid 1 g oral, or other third-generation parenteral cephalosporin.[15] Metronidazole 500 mg orally twice a day (BID) for 14 days may be used as part of the initial treatment, although this is optional based on 2010 CDC recommendations. Oral quinolones and oral cefixime are no longer recommended as first-line treatment for outpatient PID treatment due to resistant Neisseria gonorrhea.[21] All women with PID should be reevaluated in three days. Women with tubo-ovarian abscess need a minimum of 24 hours of inpatient parenteral antibiotics. CDC recommended parenteral regimens include IV cefotetan or cefoxitin with IV or oral doxycycline, or intravenous clindamycin and gentamicin.[15] Women with an intrauterine device (IUD) in place should not have routine removal; removal has not shown improved outcomes. If no improvement occurs after 72 hours of treatment, removal should be considered.[22] Male partners within 60 days of diagnosis should be treated, and if there have been no partners within the last 60 days, then the last partner should be treated.
Herpes simplex virus
Herpes simplex viruses are double-stranded DNA viruses. During the initial infection, virions travel up the nerve roots to the ganglia where they can remain latent. Reactivation of latent viral infection can occur traveling back down the nerve to cause cutaneous symptoms typically including painful blisters or ulcers. Women may be totally asymptomatic from their HSV infection.[23] HSV-2 is transmitted though sexual contact as well as perinatal transmission. Genital HSV-1 can be transmitted through oral contact as well as vaginal or anal intercourse.[23]
Epidemiology
About two-thirds of the US population are seropositive for HSV-1. Most acquired the oro-labial form nonsexually during childhood. Adults who acquire HSV-1 are much more likely to acquire the virus through sexual activity. HSV-2 is less common; approximately 17% of the adult US population is sero-positive for HSV-2.[24, 25] HSV has a short incubation period of 2–12 days; patients typically can accurately identify the person who infected them.[26] People who share information about infection with their partners are less likely to infect their partners, likely due to protective measures.[27]
Natural history
Previous infection with HSV-1 does not decrease the rate of HSV-2 acquisition; however, patient’s previously infected with HSV-1 who acquire HSV-2 are less likely to be symptomatic.[28] Women who have HSV-2 are more likely to experience recurrences than those with genital HSV-1, and the recurrences tend to be more severe. The duration of the primary infection appears to be positively correlated with increased number of recurrences. 90% of symptomatic persons with genital HSV-2 infection will have a recurrence compared to 57% of patients with primary genital HSV-1.[29, 30] A woman previously infected with the oro-labial form of HSV-1 appears to be protected against genital HSV-1.[31] Additionally, people who are already infected with HSV-2 are unlikely to subsequently acquire HSV-1.[32]
Viral shedding occurs more frequently with HSV-2 than HSV-1. Within the first year of acquisition of the infection, viral shedding occurs on 30% of days and does not seem to be correlated with the presence of a lesion, and often precedes symptoms.[33]
Screening and diagnosis
The USPSTF recommends against routine serological screening for herpes in asymptomatic persons, and IgM testing is not a reliable indicator of recent infection.[34] Serological testing may be useful for women with recurrent genital symptoms or atypical symptoms who had a negative NAAT, or patients who have been told they have HSV based on clinical symptoms, but who do not have a laboratory diagnosis. One can also consider testing HIV+ persons who present for STD testing.[15]
Prevention and treatment of genital HSV
There is no cure for HSV infection. Antiviral therapy can reduce symptoms, morbidity, and duration of viral shedding, but it has no impact on eradicating the disease or on latent HSV. Treatment during a primary or secondary outbreak does not decrease recurrence.[35]
Consistent condom use can reduce the spread to an unaffected partner. Perfect condom use (100% of the time) results in 30% lower risk of spreading HSV to the unaffected partner.[36] Consistent condom use along with suppressive therapy with antiviral medication can reduce transmission rates by 55%.[37]
Primary HSV can be particularly painful and prolonged (19 days vs. 10 days duration on average for a recurrence), so it should be treated with antivirals. Acyclovir, famciclovir, and valacyclovir are all extremely well tolerated with a very low risk of toxicity and appear to have similar efficacy (see Table 17-1).[38, 39]
| Primary infection treatment | Chronic suppressive therapy for recurrent disease | Episodic treatment for recurrent disease | Suppressive therapy in pregnancy (starting @36 w) | |
|---|---|---|---|---|
| Acyclovir | 400 mg TID or 200 mg 5 × /day for 7–10 days | 400 mg BID | 800 mg BID or 200 mg 5 × /day | 400 mg TID |
| Famciclovir | 250 mg TID for 7 days | 250 mg BID | 125 mg BID | Limited data in pregnancy |
| Valacyclovir | 1g BID for 10 days | 1 g daily (or 500 mg daily for pts <9 episodes/yr) | 500 mg BID × 3 days | 500 mg BID |
Perinatal transplacental transmission to the fetus with subsequent neonatal infection occurs in 30%–50% of neonates when vaginal delivery occurs with active genital lesions of a primary infection compared to only 3% in women having a vaginal delivery with active lesions due to a recurrent infection.[40] Pregnant women with a primary infection during pregnancy should be treated with antivirals to decreased duration and severity of symptoms as well as decrease viral shedding.
Confirmation with viral or serological testing should be considered in patients with only a clinical diagnosis. Pregnant women with a history of recurrent active genital herpes should be offered suppressive treatment with antivirals starting at 36 weeks and through the remainder of the pregnancy.[41] Additionally, if active genital lesions are present at the time of delivery, cesarean delivery should be performed; however, lesions on the sacrum or thigh may be covered to facilitate safe vaginal delivery.[41] The routine screening of women for serological evidence of genital herpes infection is not recommended.
Patients with primary HSV infections may have severe dysuria secondary to ulcerations near the urethra, or difficulty urinating because of sacral nerve root involvement. In such cases adjunctive pain medications or catheterization may be needed.
Patients with complicated HSV [meningitis or central nervous system (CNS) involvement, disseminated HSV, pneumonitis, or hepatitis] require parenteral administration of antivirals.
Syphilis
Reported primary and secondary syphilis in 2013 was nearly 10 times more common in men than women. This increased rate of infection appears to be primarily among men who have sex with men; nearly 75% of cases are within this cohort.[42]
The highest risk women are those aged 20–24 (3.9/100,000 in 2012).[42] Despite the low incident rates, syphilis is considered a major public health risk among women due to the serious morbidities of congenital and tertiary syphilis. A high coinfection rate with HIV exists as the genital sores make it easier to transmit HIV.[43] Socioeconomic disparities also are associated with higher rates of syphilis.[43] Syphilis reporting is important, as insuring partners of index cases receive testing and treatment.[44]
Pathophysiology
The causative organism for syphilis is the spirochete Treponemal pallidum.[45] Syphilis has three stages: primary, secondary, and tertiary. Transmission occurs during the primary stage from direct contact with a syphilitic sore through vaginal, anal, or oral sex. Transplacental infection can occur. People are infectious in the primary and secondary stages but may be completely asymptomatic during these stages.
Primary syphilis is characterized by a chancre that typically appears on the genitals approximately three weeks after sexual contact with a syphilis infected individual. The chancre may be on the vaginal wall or cervix; it is a raised erythematous appearing lesion that is often painless and lasts for three to six weeks. Dark-field microscopy or immunofluorescent stains of exudate from the chancre would show many spirochetes.
Approximately 75% of patients with untreated primary syphilis will develop secondary syphilis. The secondary stage of the disease is characterized by spread of the spirochetes to mucocutaneous tissues and skin. Clinically it can present as condyloma lata, palmar rash, diffuse rash (Figure 17-1), or lymphadenopathy. Condyloma lata are raised silvery gray plaques that appear typically in moist areas such as the axilla, inner thighs, and anogenital area. Patients can develop additional superficial spirochete-containing lesions in mucous membranes. Patients typically then go on to develop a latent phase that can last several years during which time milder versions of the superficial lesions can periodically recur.
This patient presented with a secondary syphilitic rash covering his back representing the systemic spread of the Treponema pallidum bacteria.
Tertiary syphilis occurs in one-third of untreated patients and most frequently manifests as cardiovascular syphilis, which causes syphilitic aortitis that can lead to aortic aneurysm and aortic valve insufficiency. Less frequently, tertiary syphilis manifests as neurosyphilis. Neurosyphilis presents as tabes dorsalis, meningovascular disease, and general paresis. Late benign syphilis, or gummatous syphilis, is characterized by gummas that can form on the bone, skin, liver, or mucous membranes, particularly of the oropharynx. Tertiary syphilis has become rare since the advent of penicillin.
Screening and testing
Syphilis screening of women should include every pregnant woman at the first prenatal visit, commercial sex workers, persons in correctional facilities, persons infected with HIV, persons who exchange sex for drugs, and patients with genital ulcers consistent with chancres. Routine screening in asymptomatic low-risk individuals is not recommended.[46]
Traditionally, testing for T. pallidum was conducted by initially performing the nonspecific, quantitative, rapid plasma reagin test (RPR). RPR has good sensitivity, however, due to poor specificity a confirmatory treponemal test, is indicated, most commonly the Fluorescent Treponemal Antibody absorption test (FTA-ABS).
Recently more sensitive and specific T. pallidum immunoassays have been developed that are being used as the initial screening test, with the RPR for confirmation.[47] One issue is that T. pallidum IgG will persistently be positive in people who have a history of successfully treated infection. The RPR can help distinguish patients with active infection from patients with treated infection, as quantitative titer should fall after treatment. The documentation of the history of treatment as well as prior and current RPR titers is part of the evaluation of a positive treponemal test.
Condyloma lata lesions (Figure 17-2) are smooth, moist, and flat, while condylomata acuminatum lesions, though similar, are cauliflower-like, dry, and often bulky.[48]
Also known as “condyloma lata,” this photograph depicts the appearance of what was determined to be secondary syphilitic lesions on a patient’s perineum. Condyloma lata lesions are smooth, moist, and flat, whereas condylomata acuminatum lesions, though similar, are cauliflower-like, dry, and bulky, respectively.
Treatment
Penicillin is the antibiotic of choice and has been proven clinically over many decades of experience to be effective. For early primary and secondary infection, the CDC recommends the use of Benzathine penicillin G (Bicillin L-A) due to its long half-life which effectively treats the slowly multiplying spirochete This should not be confused with Bicillin C-R, which has a significantly shorter half-life and has been shown to not be effective. Benzathine penicillin G should be given in one dose of 2.4 million units IM.[49]
For latent syphilis, intramuscular Benzathine penicillin G 2.4 million units should be given weekly for three weeks. There is no evidence of penicillin resistance; however, macrolide resistance has begun to emerge. Therefore penicillin remains the treatment of choice for pregnant penicillin-allergic patients, who should undergo penicillin desensitization.[49]
One possible complication of treatment is the Jarisch-Herxheimer reaction, which includes fever, myalgias, malaise, and typically occurs within the first 24 hours of treatment for early syphilis. It can be managed with antipyretics and should not prevent treatment.
For penicillin-allergic patients with early syphilis who are not pregnant, alternative treatment options include doxycycline 100 mg by mouth twice a day for 14 days or 2 g of oral azithromycin in one dose in patients with medication compliance problems. The doxycycline is preferred as resistance is emerging to azithromycin.
For latent syphilis in the penicillin-allergic patient, a longer course of antibiotics is required; patients should receive doxycycline 100 mg by mouth twice daily for 28 days.[50]
Genital ulcers
Herpes simplex virus and syphilis are the most common causes of genital ulcers; however, the differential diagnosis is broad and includes infectious and noninfectious etiologies. Noninfectious causes include sexual trauma, Behcet syndrome, psoriasis, cancer, fixed drug eruptions, and Wegener’s graulomatosis.[15, 51] Chancroid (Haemophilus ducreyi), granuloma inguinale, and lymphogranuloma venereum are three uncommon STIs that should be considered in evaluation of ulcers that are not clinically consistent and confirmed to be herpetic or syphilitic in origin. Due to the occurrence of ulcers with multiple organisms, all women with genial ulcers should be tested for HSV with PCR test and syphilis with serological testing.
Chancroid presents as a genital or perianal lesion. It is quite uncommon with only 28 cases reported by US state health departments in 2009, although underreporting is suspected.[51] The ulcers are commonly quite painful and are accompanied by unilateral suppurative adenopathy. It is common for chancroid ulcers to be co-infected with HSV. The ulcers should be cultured specifically for H. ducreyi; however, laboratory diagnosis is difficult and a commercial PCR is not available. Only about 80% of women with lesions have a successful culture based diagnosis. A probable diagnosis of chancroid can be made if a painful ulcer accompanied by clinical presentation and adenopathy consistent with chancroid are present in a patient after syphilis and HSV have been ruled out. The treatment can be a single intramuscular injection of ceftriaxone (250 mg) or a 1-g oral dose of azithromycin.[15] Alternatives include ciprofloxacin 500 mg oral twice daily for three days or erythromycin 500 mg orally three times a day for seven days. In general, symptoms should start to improve within three days with ulcer resolution in seven days, although larger ulcers may take two weeks or longer to completely resolve. A trial of cure is not needed; however, sexual partners from the 10-day period prior to the occurrence of the genital ulcer should be seen and treated. The infected patient should be rechecked for HIV and syphilis three months after treatment if initial tests were negative.
Granuloma inguinale is very rare in the United States; however, it is endemic in many tropical areas and should be suspected in individuals presenting with a slowly growing germinal or perineal ulcer after travel to these areas. The ulcers are painless, have a beefy red appearance, commonly bleed, and are without accompanying adenopathy. The causative organism is the intracellular gram-negative bacterium Klebsiella granulomatis, which is hard to identify. Microscopic examination of biopsy specimen or crushed tissue for Donovan bodies is required. The treatment of choice is azithromycin one gram weekly or 50 mg daily for at least three weeks and until all ulcers have resolved.[15] Doxycycline, ciprofloxacin, erythromycin, and trimethoprim-sulfamethoxazole are alternatives. Sexual contacts within the 60-day period prior to the development of symptoms should be offered treatment.[15]
Lymphogranuloma venereum (LGV) commonly presents in women as tender, unusual unilateral inguinal or femoral adenopathy. Although an ulcer may initially be present, it may no longer be visible at the time of diagnosis. The organism is Chlamydia trachomatis serovars L1, L2, and L3 and these may be identified by culture of genital swabs or aspirated suppurative lymph nodes. LGV can be an invasive systemic illness with proctocolitis progressing to fistulas, strictures, and chronic colitis that can be mistaken for inflammatory bowel disease. Treatment is doxycycline by mouth twice daily for 21 days and presumptive treatment after examination should be given to contacts within sixty days of the development of symptoms.[15]
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