Sexually transmitted diseases in women
Chlamydia trachomatis and herpes simplex infections
Jeffrey T. Kirchner, DO; David H. Emmert, MD
VOL 107 / NO 1 / JANUARY 2000 / POSTGRADUATE MEDICINE
CME learning objectives
This is the first in a series of articles on women's health coordinated by Jeffrey T. Kirchner, DO, associate director, family practice residency program, department of family and community medicine, Lancaster General Hospital, Lancaster, Pennsylvania. Part 2 of this article, which focuses on diagnosis and treatment of gonorrhea and syphilis, will appear in the February issue.
Preview: The spread and sequelae of sexually transmitted diseases pose a serious public health threat. Chlamydia trachomatis infection, which is often asymptomatic, has surpassed syphilis and gonorrhea in prevalence. Herpes simplex virus types 1 and 2 affect an estimated one third of the world's population. In part 1 of this two-part article, Drs Kirchner and Emmert discuss diagnosis, treatment, and prevention of chlamydial and herpes simplex infections, stressing the importance of discussing sexual issues with patients. Part 2, which focuses on diagnosis and treatment of gonorrhea and syphilis, will appear in the February issue.
Sexually transmitted diseases (STDs) continue to be a significant public health problem in the United States. An estimated 12 million new cases occur yearly at a cost to the healthcare system of $10 billion (1). This does not include monies spent for the care of patients infected with HIV, which total about $7 billion. Although Chlamydia trachomatis infection has surpassed syphilis and gonorrhea in prevalence, viral STDs such as genital herpes, human papillomavirus, and hepatitis B infection are a more burdensome problem in terms of number of individuals infected (1). Moreover, the spread of HIV is closely linked to STD transmission.
For a variety of reasons, including the fact that several STDs are more easily transmissible from male to female, women tend to have more serious complications. Because there may be no symptoms, women are more often victims of the "hidden epidemic," as STDs are referred to in a recent report from the Institute of Medicine (2). According to the report, reasons for the ongoing epidemic include a lack of adequate public health measures and a scarcity of effective systems for prevention and treatment of STDs. In addition, many practicing physicians do not question patients about their sexual behavior. Even among those who do, many physicians may not be diagnosing and treating STDs properly. A recent study by Hessol and colleagues (3) found that 50% of primary care physicians who were managing patients with pelvic inflammatory disease were either unsure of or did not follow the guidelines for treatment of STDs from the Centers for Disease Control and Prevention (CDC) (4). In an era in which the heterosexual transmission of HIV is increasing, it is remarkable that more public health emphasis is not being placed on prevention, as well as on diagnosis and prompt treatment, of all STDs.
In this two-part article, we discuss diagnosis and treatment of four major STDs: chlamydial infection, herpes simplex virus infection, gonorrhea, and syphilis. However, the underlying theme of both parts is the important role of primary care physicians in screening for and diagnosing and treating all STDs (table 1). If we are to make an impact on the long-term sequelae of STDs, which include infertility and the increased spread of HIV, physicians need to become comfortable questioning and counseling all patients about sexual issues and their risks for STDs. Clinicians should also keep up to date as newer diagnostic and treatment regimens become available.
C trachomatis infection is the most commonly reported STD in the United States. The incidence of chlamydial infection has increased from 182 cases per 100,000 in 1995 to 197 cases per 100,000 in 1997 (5). This translates to more than 4 million cases annually. Of concern for women are the sequelae of C trachomatis infections, which include pelvic inflammatory disease, tubal infertility, and ectopic pregnancy.
Seventy percent to 90% of women with endocervical infections caused by C trachomatis are asymptomatic and may harbor the organism for months to years (6,7). Chlamydial upper genital tract infection that is asymptomatic is believed to occur three times more often than that which is accompanied by symptoms (6).
Chlamydial infection appears to have the highest prevalence in women under 20 years of age who live in urban areas (8). Among women screened at prenatal clinics, the incidence ranges from 5% to 7%, but rates as high as 20% have been reported, depending on the population studied (7). Other risk factors for chlamydial disease include age 15 to 21 years, single marital status, a new sexual partner, and multiple sexual partners.
The immune response to C trachomatis is variable and not well understood. Certain chlamydial strains may be more pathogenic in causing pelvic inflammatory disease (6). In addition, reinfection is the norm rather than the exception for many patients, despite a measurable antibody response.
Although a variety of laboratory techniques have been developed for the diagnosis of C trachomatis infection, cell culture remains the "gold standard." It has a specificity of nearly 100% but a sensitivity of only 70% to 85% (9). Because C trachomatis is an intracellular pathogen, the organism needs a cell culture system to propagate. Specimens must be collected with use of a cotton-tipped swab or cytological brush and include columnar epithelial cells from the endocervix. Swabs with wooden shafts should not be used because of their toxic effects on cell cultures. For optimal results, meticulous specimen collection and transport and a turnaround time of 3 to 7 days are needed. These requirements have decreased the use of culture, although it is still the standard test for cases of sexual assault or child abuse (9).
A number of nonculture alternatives have been developed over the past 10 years. The first of these involved antigen detection using a swabbed specimen from the urethra or cervix. The most common techniques are direct fluorescent antibody testing and enzyme-linked immunosorbent assay. Compared with cell culture, these tests are easier to perform, yield very specific results, and have a quicker turnaround time. However, an important drawback is the variable sensitivity, which ranges from 50% to 90% (6,9).
Nucleic acid identification and hybridization represent important advances in diagnosis of chlamydial infection. The DNA probe test is a useful technique that can detect both C trachomatis and Neisseria gonorrhoeae with use of a single endocervical specimen. As with antigen detection, the specificity is excellent. Thorough endocervical specimen collection is needed to ensure adequate sensitivity.
Ligase chain reaction (LCR) and polymerase chain reaction (PCR) are techniques that use DNA or RNA amplification. The sensitivity and specificity of PCR and LCR approach 100% (9). A significant advantage of these techniques is that they can be performed on urine specimens or on swabbed vaginal specimens collected by the patient. This obviously facilitates screening for disease in a larger number of patients. Results of multiple studies support the use of urine-based screening for chlamydial infection (10,11). Although the nucleic acid-based tests are more expensive than routine culture, there are data to suggest that the money saved by not doing routine pelvic examinations to screen for chlamydial infection outweighs the added cost of the test (12,13). Moreover, screening with this test would allow for earlier treatment of infection and avoidance of pelvic inflammatory disease and future infertility. Once they become more widely available, PCR, LCR, and comparable nucleic acid amplification tests should become the studies of choice for diagnosing chlamydial infection.
Other antimicrobial agents acceptable for treatment of chlamydialcycline, these medications must be given for 7 days, because the organism can reside safely within the confines of epithelial cells for 2 to 3 days. To date, there have been no reports of antimicrobial resistance (6). There are no alternative treatment recommendations for chlamydial infection in patients who also have HIV infection.
Ideally, all women with chlamydial infection should notify their sexual partners and encourage them to be tested and treated. Notification should include anyone who had sexual contact with the patient within 60 days of onset of symptoms or diagnosis of chlamydial infection (4). Some physicians may consider empirical treatment of the partners if there is concern about adequate follow-up, although this approach is controversial. Sexual abstinence is recommended until both persons have been appropriately treated. Testing for HIV is also strongly encouraged.
Herpes simplex virus
Herpes simplex virus (HSV) exists as two separate types, HSV-1 and HSV-2, which together infect more than one third of the world's population (17). HSV-2 is responsible for the majority of cases of genital herpes, although HSV-1 can also cause genital infections. HSV is a double-stranded DNA virus that first targets epithelial cells and then is transported via neural tissue to sensory ganglia, where lifelong latent infection is established (17). Local or systemic stimuli such as immunodeficiency, trauma, fever, menstruation, ultraviolet light, and sexual intercourse can trigger viral reactivation (18). While most sources also attribute a causative role to emotional stress, a recent review (19) found no convincing evidence that stress causes recurrences.
More than 20% of all Americans 12 years of age or over have serologic evidence of HSV-2 infection (20), and this number is growing. Most infected patients are not aware of their disease (4). Genital infection with HSV usually occurs through sexual contact, and independent risk factors include lifetime number of sexual partners, age under 30, African American race, female sex, low socioeconomic status, and HIV-positive status (17,18,20).
Transmission of HSV-2 may occur whenever visible lesions or symptoms are present, but it is well documented that shedding of viral particles also takes place during asymptomatic periods. Immunocompetent patients with HSV shed virus up to 5% of the time they are asymptomatic, and recently infected patients and those with HIV infection shed even more often (17,21,22).
The "gold standard" for laboratory diagnosis of HSV is viral isolation by tissue culture (17), although this can take up to 5 days and sensitivity is only 70% to 80%. Despite these limitations, viral culture is still the diagnostic test of choice for HSV skin infections. Antigen detection and Tzanck tests, while helpful if results are abnormal, have lower sensitivities (17,18). Serologic studies are not helpful during primary illness because of the delay in development of antibodies (17). PCR is sensitive (96%) and specific (99%), but its high cost and limited availability have relegated current use to diagnosis of HSV infections of the central nervous system. However, it may later prove to be clinically useful for outpatient management.
Valacyclovir hydrochloride (Valtrex), a new antiviral agent, is the l-valine ester prodrug of acyclovir and is easily absorbed and then converted to acyclovir. Famciclovir (Famvir), another recently approved antiviral medication, is the oral form of penciclovir, a purine analog similar to acyclovir. These two drugs boast higher oral bioavailability and less frequent dosing regimens than acyclovir, and they have good safety records in the few years since their release (18). The costs, however, can be significantly higher than the cost of generic acyclovir, and there is no current evidence that proves greater efficacy.
Antiviral therapy is recommended for initial episodes of genital herpes infection, especially for patients who have systemic symptoms or are immunocompromised (4,18). Oral acyclovir is effective in shortening the duration of lesions and making the symptoms less severe and it is the treatment of choice (table 4) (4,18). Intravenous administration may be required for immunocompromised patients and in cases of severe disseminated infection. Topical acyclovir and penciclovir (Denavir) are less effective (4,18). Both drugs purport to shorten the duration of lesions and make the symptoms less severe, although the differences in duration noted in clinical trials have amounted to less than 24 hours.
Treatment with acyclovir does not influence the frequency or number of recurrences. It cannot eradicate latent virus and does not affect the long-term natural history of the infection (17). Fortunately, in immunocompetent patients most recurrences are mild and infrequent and require no treatment. For patients who desire therapy for recurrences because of the severity, frequency, or personal impact of the episodes, two long-term options are available: suppressive therapy and episodic treatment.
Daily antiviral therapy effectively suppresses recurrences, but because of the high cost and inconvenience, it is usually reserved for patients with more than six recurrences per year. Suppressive therapy decreases asymptomatic shedding by 95% but has not yet been shown to decrease the transmission of HSV to sexual partners (25).
Suppressive regimens of antiviral medication decrease the frequency of genital herpes recurrences by up to 80% (23,26,27). Suppression may continue indefinitely without adverse effects (23), but such therapy should be discontinued annually to assess whether it is needed. In addition, cost and compliance should be discussed with the patient. All three drugs appear to have equal efficacy for suppression (table 5). Valacyclovir has the advantage of once-daily dosing (26). Famciclovir and acyclovir must be given twice daily to be effective (27).
Episodic treatment of genital herpes infections is not intended to decrease the frequency of recurrences, but rather to influence the symptoms after onset of a recurrence. Acyclovir, given within minutes to hours after the prodrome begins, exerts a statistical, albeit minimal, effect on recurrent infections (28). Famciclovir and valacyclovir appear to be slightly more effective for recurrences (table 6).
The clinical benefit of episodic therapy is relatively small, and its utility has been questioned (29). Patients who have frequent recurrences overwhelmingly choose suppressive therapy over episodic therapy (27,30). Patients should be encouraged to participate in decisions about such therapy.
Female patients who have genital herpes should be warned that HSV can cause devastating disease in newborns and that if they become pregnant, they need to inform their doctor about their history of genital herpes. Some circumstances warrant treatment during pregnancy; however, cesarean section is indicated only if lesions are active at the time of labor (4). Some clinicians prescribe suppressive therapy for women who are in the last 4 weeks of pregnancy, although there are no data from clinical trials to support this practice. In the future, vaccines based on mucosal immunity may become feasible (31). Currently, however, the best therapy for genital herpes is to avoid becoming infected.
C trachomatis infection is the most commonly reported STD in the United States, and the majority of women infected are asymptomatic. Screening is recommended for those at high risk, including women who are between 15 and 21 years of age, live in urban areas, are single, or have new or multiple sexual partners. The "gold standard" for diagnosis is chlamydial culture; however, techniques that use DNA and RNA amplification are nearly 100% sensitive and specific and may prove cost-effective. Doxycycline is a recommended first-line therapy, but certain other antibiotics may also be effective.
Herpes simplex virus affects more than one third of the world's population. It is diagnosed by observation of shallow, tender ulcerations around the genitalia and by viral isolation using tissue culture. Initial treatment is with antiviral drugs, which may also be necessary episodically or as a suppressive regimen for recurrences.
Patient education about prevention of these and other STDs, as well as the impact of such disease on sexual partners, is critical. Physicians should therefore become comfortable questioning and counseling patients about sexual issues and risks for STDs.
Dr Kirchner, coordinator of this series, is associate director, family practice residency program, department of family and community medicine, Lancaster General Hospital, Lancaster, Pennsylvania. Dr Emmert is a member, department of family and community medicine, and a clinical affiliate faculty member in the residency program, Lancaster General Hospital. Correspondence: Jeffrey T. Kirchner, DO, Department of Family and Community Medicine, Lancaster General Hospital, 555 N Duke St, PO Box 3555, Lancaster, PA 17604-3555. E-mail: firstname.lastname@example.org.
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