Vulvar Lesions & Genital Ulcers
Genital herpes, syphilis, and, less commonly, chancroid are the most prevalent genital ulcerative lesions in the United States. The diagnosis is difficult to make by physical examination alone. Thus the workup for all genital ulcers should include serologic screening for syphilis, culture/antigen testing for herpes simplex virus (HSV)-1 and HSV-2, and culture for Haemophilus ducreyi in areas where chancroid is prevalent. More than 1 infectious etiology may be present in a single lesion.
- Most commonly caused by HSV-2 but increasingly also caused by HSV-1
- Painful genital ulcers
- Chronic, lifelong, relapsing condition
- Transmissible even in the absence of lesions
- Antivirals improve symptoms, speed healing of lesions, and may decrease asymptomatic viral shedding
Genital herpes simplex virus (HSV) is a chronic viral infection cause by 2 types of virus: HSV-1 and HSV-2. Most cases of recurrent genital herpes are caused by HSV-2, and at least 50 million persons in the United States are infected with this type of genital herpes. However, an increasing proportion of genital herpes infections in some populations (eg, young women and men who have sex with men) have been attributed to infection by HSV-1.
Most patients infected with HSV-2 have not been diagnosed with genital herpes. Many of these patients have mild or unrecognized infections but shed virus intermittently in the genital tract. As a result, the majority of genital herpes infections are transmitted by persons unaware that they have the infection or who are asymptomatic when transmission occurs.
Counseling at the time of diagnosis is essential in order to educate the patient regarding the high probability of recurrence and the prevention of transmission to sexual partners. Sex partners of patients with genital herpes should be evaluated and counseled. Patients should be counseled that viral shedding can occur during asymptomatic periods and that this can lead to transmission. Consistent condom use is associated with a decline in transmission of genital HSV infection. For patients with symptomatic genital HSV-2 infection and an uninfected partner, chronic suppressive therapy to reduce clinical recurrences and viral transmission should be considered. Valacyclovir (500 mg daily) is the best-studied regimen for this specific indication and offers the convenience of once-daily dosing; however, acyclovir may be a reasonable alternative.
For prevention of neonatal herpes, see Genital Herpes in Pregnancy.
The clinical diagnosis of genital herpes is often difficult or inaccurate. Classically, patients present with multiple painful vesicular or ulcerative lesions on the genitals. However, these are absent in many cases, particularly in infections caused by HSV-1. After initial infection, the virus remains dormant, but can be reactivated at a future time, which manifests as a recurrent, symptomatic episode with painful ulceration. Recurrences and subclinical shedding are much less frequent for genital HSV-1 infection than for genital HSV-2 infection.
Patients with a primary HSV infection may, in addition to painful ulceration, have multiple constitutional symptoms such as fever, headaches, and malaise.
Cell culture and polymerase chain reaction (PCR) are the preferred tests for HSV in symptomatic patients. The sensitivity of viral culture is low, especially for recurrent lesions, and declines rapidly as lesions begin to heal. PCR assays for HSV DNA are more sensitive and are increasingly used. PCR is the test of choice for detecting HSV in spinal fluid for diagnosis of HSV infection of the central nervous system (CNS). Viral culture isolates should be typed to determine which type of HSV is causing the infection. Failure to detect HSV by culture or PCR does not indicate an absence of HSV infection, because viral shedding is intermittent.
Both type-specific and non–type-specific antibodies to HSV develop during the first several weeks after infection, persist indefinitely, and can be tested for serologically. Immunoglobulin (Ig)M testing for HSV is not useful, because the IgM tests are not type-specific and might also be positive during recurrent episodes of herpes.
Because nearly all HSV-2 infections are sexually acquired, the presence of type-specific HSV-2 antibody implies anogenital infection and should prompt appropriate counseling. The presence of HSV-1 antibody alone is more difficult to interpret. In most cases, the presence of HSV-1 antibody indicates oral HSV infection acquired during childhood, which might be asymptomatic. However, acquisition of genital HSV-1 is increasing and can be asymptomatic. Lack of symptoms in an HSV-1 seropositive person does not distinguish anogenital from orolabial or cutaneous infection, and regardless of site of infection, these persons remain at risk for acquiring HSV-2.
Type-specific HSV serologic assays may be useful in the evaluation of the following situations: patients with recurrent genital symptoms or atypical symptoms with negative HSV cultures, patients with a clinical diagnosis of genital herpes without laboratory confirmation, and patients who have a partner with genital herpes.
Differential diagnosis includes other causes of genital ulceration such as syphilis and chancroid among infectious causes and drug eruptions and Behçet's disease among noninfectious causes.
Urinary retention can occur due to severe dysuria associated with extensive genital lesions. Rarely patients can develop severe herpes infection manifesting as disseminated infection, pneumonitis, hepatitis, or CNS complications such as meningoencephalitis. These patients should be hospitalized for close monitoring and intravenous antiviral administration.
Systemic antiviral drugs can help to control the symptoms of herpes episodes and may also be used as daily suppressive therapy. However, these drugs neither eradicate latent virus nor affect the risk, frequency, or severity of recurrences after the drug is discontinued.
First Clinical Episode of Genital Herpes
Choose one of the following:
Acyclovir 400 mg orally 3 times a day for 7–10 days
Acyclovir 200 mg orally 5 times a day for 7–10 days
Famciclovir 250 mg orally 3 times a day for 7–10 days
Valacyclovir 1 g orally twice a day for 7–10 days
Treatment can be continued for longer than 10 days if lesions are not resolved.
Suppressive Therapy for Recurrent Genital Herpes
Suppressive therapy reduces the frequency of genital herpes recurrences by 70–80% in patients who have frequent recurrences. Treatment also is effective in patients with less frequent recurrences. Treatment with valacyclovir 500 mg daily decreases the rate of HSV-2 transmission in discordant, heterosexual couples in which the source partner has a history of genital HSV-2 infection. Suppressive antiviral therapy also is likely to reduce transmission when used by persons who have multiple partners and by those who are HSV-2 seropositive without a history of genital herpes.
Choose one of the following:
Acyclovir 200 mg orally twice a day
Famciclovir 250 mg orally twice a day
Valacyclovir 500 mg orally once a day (may be less effective than the other regimens in patients with >10 episodes per year)
Valacyclovir 1g orally once a day
Episodic Therapy for Recurrent Genital Herpes
Effective treatment of recurrences requires initiation of therapy within 1 day of lesion onset or during the prodrome that precedes some outbreaks; therefore, patients should be provided with a supply of drug or a prescription in order to be able to start therapy in a timely fashion should a recurrence occur.
Choose one of the following:
Acyclovir 400 mg orally 3 times a day for 5 days
Acyclovir 800 mg orally twice a day for 5 days
Acyclovir 800 mg orally 3 times a day for 2 days
Famciclovir 125 mg orally twice a day for 5 days
Famciclovir 1 g orally twice a day for 1 day
Famciclovir 500 mg once, followed by 250 mg twice daily for 2 days
Valacyclovir 500 mg orally twice a day for 3 days
Valacyclovir 1 g orally once a day for 5 days
Genital Herpes in Pregnancy
Most mothers of infants who acquire neonatal herpes do not have a history of clinically evident genital herpes. The risk for transmission to the neonate from an infected mother is dependent on when in pregnancy they acquire the infection. In women who acquire genital herpes near the time of delivery, transmission is high (30–50%); conversely, in women with a history of recurrent herpes at term or who acquire genital HSV during the first half of pregnancy, the risk of transmission is low (<1%). However, because recurrent genital herpes is much more common than initial HSV infection during pregnancy, the proportion of neonatal HSV infections acquired from mothers with recurrent herpes is significant.
Prevention of neonatal herpes depends both on preventing acquisition of genital HSV infection during late pregnancy and avoiding exposure of the infant to herpetic lesions during delivery. Women without known genital herpes should be counseled to abstain from intercourse during the third trimester with partners known or suspected of having genital herpes. In addition, pregnant women without known orolabial herpes should be advised to abstain from receptive oral sex during the third trimester with partners known or suspected to have orolabial herpes. Type-specific serologic tests may be offered to uninfected women whose sex partner has HSV infection.
All pregnant women should be asked whether they have a history of genital herpes. At the onset of labor, all women should be questioned carefully about symptoms of genital herpes, including prodromal symptoms, and all women should be examined carefully for herpetic lesions. Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally. Although caesarean section does not completely eliminate the risk for HSV transmission to the infant, women with recurrent genital herpetic lesions at the onset of labor should deliver by caesarean section to prevent neonatal HSV infection.
Acyclovir can be administered orally to pregnant women with first-episode genital herpes or severe recurrent herpes. Acyclovir treatment late in pregnancy reduces the frequency of caesarean sections among women who have recurrent genital herpes by diminishing the frequency of recurrences at term and should be offered to patients for suppression from approximately 36 weeks of gestation.
HIV-positive patients can have prolonged or severe episodes of genital, perianal, or oral herpes. HSV shedding is also increased in HIV-infected persons. Suppressive or episodic therapy with oral antiviral agents is effective in decreasing the clinical manifestations of HSV in this population.
Choose one of the following:
Acyclovir 400–800 mg orally 2–3 times a day
Famciclovir 500 mg orally twice a day
Valacyclovir 500 mg orally twice a day
Acyclovir 400 mg orally 3 times a day for 5–10 days
Famciclovir 500 mg orally twice a day for 5–10 days
Valacyclovir 1 g orally twice a day for 5–10 days
HSV is a chronic, relapsing condition. Suppressive therapies are effective at reducing the number of outbreaks in patients with recurrent episodes.
- Caused by gram-negative rod Haemophilus ducreyi
- Painful, tender genital ulcer
- Suppurative inguinal adenopathy
Chancroid prevalence has declined in the United States in recent years. Worldwide prevalence has also declined, but it may still be found in areas of Africa and the Caribbean. The causative organism is the highly infectious gram-negative rod Haemophilus ducreyi. Exposure is usually through coitus, but accidentally acquired lesions of the hands have been reported. The incubation period is typically 4–10 days. Chancroid is a reportable disease.
Sexual partners should be treated, regardless of symptoms, if they have had sexual contact in the 10 days preceding the patient's onset of symptoms.
The chancroid lesion begins as an erythematous papule that evolves into a pustule and ultimately degenerates into a saucer-shaped ragged ulcer circumscribed by an inflammatory wheal. Typically, the lesion is very tender and produces a heavy, foul discharge that is contagious. Patients typically have more than 1 ulcer, and these are almost exclusively confined to the genital region.
Painful inguinal adenitis is noted in approximately 50% of cases, although this may occur less often in women. The nodes may undergo liquefaction, producing fluctuant buboes that may become necrotic and drain spontaneously.
Definitive diagnosis is by identification of H ducreyi on specialized culture media that is not widely available from commercial sources and has sensitivity of less than 80%. There is no PCR test available in the United States that has been approved by the US Food and Drug Administration (FDA), although many labs have developed their own PCR test. However, this test may not be available at many centers due to cost. Therefore, in many cases the diagnosis is presumptive, based on symptoms of multiple painful ulcers with inguinal adenopathy and negative testing for other ulcerative diseases such as HSV and syphilis.
Syphilis, herpes simplex, granuloma inguinale, lymphogranuloma venereum, and Behçet's disease.
Inguinal scarring or fistula formation may occur from draining buboes.
Good personal hygiene is important. The early lesions should be cleansed with mild soap solution. Sitz baths are beneficial. Fluctuant lymph nodes should be needle aspirated or incised and drained through normal adjacent skin to prevent fistula formation or secondary ulcers from spontaneous rupture.
The susceptibility of H ducreyi to antimicrobial agents varies regionally.
Choose one of the following. The course may have to be repeated.
Azithromycin 1 g orally in a single dose
Ceftriaxone 250 mg intramuscularly (IM) in a single dose
Ciprofloxacin 500 mg orally twice daily for 3 days (in nonpregnant patients over age 17 years who are not lactating)
Erythromycin base 500 mg orally 3 times daily for 7 days
Chancroid usually responds quickly to antibiotic therapy, with symptom improvement in 3 days and clinical improvement in 7 days. If there has been no improvement after 7 days, the patient should be re-evaluated. Given the difficulty in isolating H ducreyi, consideration should be given to the following possibilities: whether the original diagnosis was correct, existence of STD coinfection, poor compliance to treatment if a multidose regimen was selected, or antibiotic resistance. HIV-positive patients with chancroid may experience a higher rate of treatment failure, slower healing, and the need for prolonged antibiotic therapy. If the ulcers are not adequately treated, deep scarring may occur.
Granuloma Inguinale (Donovanosis)
- Painless, ulcerative vulvitis, chronic or recurrent
- Donovan bodies revealed by Wright's or Giemsa's stain
Granuloma inguinale is a chronic ulcerative granulomatous disease that usually develops in the vulva, perineum, and inguinal regions (Fig. 43–1). The disease is rare in the United States, being most common in India, Papua New Guinea, the Caribbean, central Australia, and southern Africa. The causative organism is Klebsiella granulomatis (formerly known as Calymmatobacterium granulomatis). The incubation period is 8–12 weeks. Granuloma inguinale is a reportable disease.
Personal hygiene is the best method of prevention. Therapy immediately after exposure may abort the infection. Sex partners must be considered for treatment. Partners who had sexual contact during the 60 days preceding the onset of symptoms or are clinically symptomatic should be examined and offered treatment.
Clinically, the disease is characterized as painless, slowly progressive ulcerative lesions on the genitals or perineum without regional lymphadenopathy. Although granuloma inguinale most often involves the skin and subcutaneous tissues of the vulva and inguinal regions, cervical, uterine, orolabial, and ovarian sites have been reported. A malodorous discharge is characteristic. The disorder often begins as a papule, which then ulcerates, with the development of a beefy-red granular zone with clean, sharp edges. The lesions are highly vascular and bleed easily, with poor healing, and are susceptible to secondary bacterial infection. Rarely, granuloma inguinale present as chronic cervical lesions. These lesions usually take the form of redness or ulceration, or they form granulation tissue. They produce a chronic inflammatory exudate characterized histologically by lymphocytes, giant cells, and histiocytes. They may mimic carcinoma of the cervix and must be distinguished from this as well as other neoplastic diseases.
The causative organism is difficult to culture, and diagnosis requires visualization of dark-staining Donovan bodies on tissue crush preparation or biopsy. Donovan bodies are bacteria encapsulated in mononuclear leukocytes and are best seen in Wright-stained smears as small round or rod-shaped particles that stain purple in traditional hematoxylin and eosin preparations. Initial testing may be done with direct smear from beneath the surface of an ulcer, but if these are negative, a biopsy specimen should be taken. Biopsy of the lesion generally shows granulation tissue infiltrated by plasma cells and scattered large macrophages with rod-shaped cytoplasmic inclusion bodies. Pseudoepitheliomatous hyperplasia often is seen at the margin of the ulcer. No FDA-cleared molecular tests for the detection of K granulomatis DNA exist at this time.
Syphilis, herpes simplex, chancroid, lymphogranuloma venereum, and Behçet's disease.
Scarring may cause introital contraction, which may make coitus difficult or impossible; walking or sitting may also become painful.
Several antimicrobial regimens have been effective. Treatment has been shown to slow progression of lesions, and healing typically proceeds inward from the ulcer margins. Prolonged therapy is sometimes necessary to permit adequate granulation and re-epithelialization.
Doxycycline 100 mg twice daily for at least 3 weeks and until all ulcers are completely healed.
Choose one of the following. All regimens are for 3 weeks or until all lesions are healed.
Azithromycin 1 g orally once per week
Ciprofloxacin 750 mg orally twice daily
Erythromycin base 500 mg orally 4 times a day
Trimethoprim-sulfamethoxazole 1 double strength (160 mg/800 mg) tablet orally twice daily
Sulfonamides, doxycycline, and ciprofloxacin are contraindicated in pregnant women. The addition of an aminoglycoside (eg, gentamicin 1 mg/kg intravenously [IV] every 8 hours) to these regimens can be considered if improvement is not evident within the first few days of therapy or for known HIV-positive patients.
Prognosis is good. Prolonged therapy is often required, but in most cases it is ultimately effective.
- Tender inguinal lymphadenopathy
- Genital ulcer is often not evident
- Diagnosis suggested by positive complement fixation test
The causative agent of lymphogranuloma venereum (LGV) is one of the aggressive L serotypes (L1, L2, or L3) of Chlamydia trachomatis. It is encountered more frequently in the tropical and subtropical nations of Africa and Asia but is also seen in the southeastern United States. Transmission is via sexual contact; men are affected more frequently than women (6:1). The incubation period is 7–21 days. Presence of this infection is strongly associated with HIV-positive status in men who have sex with men, with positive HIV found in up to 75% of this population with a diagnosis of LGV. LGV is a reportable disease.
Avoiding infectious contact with a carrier is achieved by use of a condom or by refraining from coitus. Sexual contacts of a patient who has LGV within the 60 days before onset of the patient's symptoms should be examined, tested for urethral or cervical chlamydial infection, and treated with a chlamydia regimen.
In heterosexuals the most common presentation is tender, usually unilateral inguinal and/or femoral lymphadenopathy. A genital ulcer sometimes occurs at the site of inoculation (Fig. 43–2), although this has often disappeared by the time patient seeks care. Rectal exposure can result in proctocolitis, including mucoid and/or hemorrhagic rectal discharge, pain, constipation, fever, or tenesmus. In the late phase, systemic symptoms such as fever, headache, arthralgia, chills, and abdominal cramps may develop.
Lymphogranuloma venereum. Note involvement of perineum and spread over buttocks.
Diagnosis is based on clinical suspicion, epidemiologic information, and the exclusion of other etiologies for proctocolitis, inguinal lymphadenopathy, or genital or rectal ulcers.
The diagnosis can be proved only by isolating C trachomatis from genital or lymph node specimens and confirming the immunotype. These procedures are seldom available, so less specific tests are used.
A complement fixation test using a heat-stable antigen that is group-specific for all Chlamydia species is available. A titer of >1:64 is considered positive, whereas a titer of <1:32 is considered negative. If acute or convalescent sera are available, a rise in titer is particularly helpful in making the diagnosis. Application of a microimmunofluorescent test may also be useful.
As with any disseminated disease, the systemic symptoms of LGV may resemble meningitis, arthritis, pleurisy, or peritonitis. The cutaneous lesions must be differentiated from those of granuloma inguinale, tuberculosis, early syphilis, and chancroid. In the case of colonic lesions, proctoscopic examination and mucosal biopsy are needed to rule out carcinoma, schistosomiasis, and granuloma inguinale.
LGV is an invasive, systemic infection, and if it is not treated early, LGV proctocolitis can lead to chronic, colorectal fistulas and strictures, which can involve the entire sigmoid. Vulvar elephantiasis can cause marked distortion of the external genitalia. Vaginal narrowing and distortion may result in severe dyspareunia.
Doxycycline 100 mg twice daily orally for 21 days. If disease persists, the course should be repeated.
Erythromycin 500 mg orally 4 times daily for 21 days.
Local & Surgical Treatment
Anal strictures should be dilated manually at weekly intervals. Severe stricture may require diversionary colostomy. If the disease is arrested, complete vulvectomy may be done for cosmetic reasons. Abscesses should be aspirated.
Treatment cures infection and prevents ongoing tissue damage, although tissue reaction to the infection can result in scarring.
- Painless genital sore (chancre) on labia, vulva, vagina, cervix, anus, lips, or nipples
- Painless, rubbery, regional lymphadenopathy followed by generalized lymphadenopathy in the third to sixth weeks
- Dark-field microscopic findings
- Positive serologic test in 70% of cases
- Bilaterally symmetric extragenital papulosquamous eruption
- Condyloma latum, mucous patches
- Dark-field findings positive in moist lesions
- Positive serologic test for syphilis
- Cardiac, neurologic, ophthalmic, and auditory lesions
- History or serologic evidence of previous infection
- Absence of lesions
- Serologic test usually reactive; titer may be low
Syphilis is a chronic, systemic disease caused by the spirochete Treponema pallidum, which is transmitted by direct contact with an infectious moist lesion. In the majority of cases it is sexually acquired, although it can also be vertically transmitted from mother to fetus. The disease has been divided into several stages based on clinical presentation in order to guide best treatment. It is transmissible in the primary or secondary stages. Treponemes pass through intact mucous membranes or abraded skin, and 10–90 days later, a primary lesion, or chancre, develops (median incubation period is 21 days). Two weeks to 6 months (average of 6 weeks) after the primary lesion appears, the generalized cutaneous eruption of secondary syphilis may appear. Latent syphilis may follow the secondary stage and may last a lifetime, or tertiary syphilis may develop. The latter usually becomes manifest 4–20 or more years after disappearance of the primary lesion. Syphilis is a reportable disease.
If a patient is known to have been exposed to syphilis, preventative treatment should not be delayed by waiting for symptoms to develop, although every effort should be made to reach a diagnosis, including a complete physical examination. Any patient who has been exposed and becomes symptomatic within 90 days of sexual contact should be treated regardless of negative serologies, and similarly, if it has been >90 days since exposure with positive titers, treatment should be initiated. If the duration since exposure is unknown and the treponemal antibody titer is greater than 1:32, treatment is indicated.
All pregnant women should undergo routine serologic testing for syphilis at the first prenatal visit, and this should be repeated at 28–32 weeks' gestation in high-risk regions. If the test result is positive, attention must be given to the patient's prior serologic test and therapy (if any) for syphilis. If doubt exists regarding whether the patient has active syphilis, repeat therapy is far better than the risk of congenital syphilis.
Syphilis is still a serious public health problem, and education is still the best method of control. Use of a condom, together with soap and water decontamination after coitus, would prevent most cases. Screening people at high risk for acquiring syphilis (men who have sex with men, who engage in high-risk behaviors, commercial sex workers, persons who exchange sex for drugs, and those in adult correctional facilities) is a recommended strategy.
The chancre (Fig. 43–3) is an indurated, firm, painless papule or ulcer with raised borders. Groin lymph nodes may be enlarged, firm, and painless. Genital lesions are not usually seen in women unless they occur on the external genitalia; however, careful examination may reveal a cervical or vaginal lesion. Primary lesions may occur on any mucous membrane or skin area of the body (nose, breast, perineum), and dark-field examination is required for all suspect lesions. Serologic tests should be done every week for 6 weeks or until positive.
Chancre of primary syphilis (arrow).
Signs of diffuse systemic infection become evident as the spirochetes spread hematogenously. A “viral syndrome” presentation, often with diffuse lymphadenopathy, is not uncommon. The characteristic dermatitis appears as diffuse, bilateral, symmetric, papulosquamous lesions that often involve the palms and soles. Lesions may also cover the trunk and be macular, maculopapular, papular, or pustular. Other systemic manifestations include patchy alopecia, hepatitis, and nephritis. Moist papules can be seen in the perineal area (condyloma lata). Mucous patches may also be seen; like condyloma lata, they are dark-field–positive, infectious lesions. Serologic tests for syphilis are invariably reactive in this stage.
With resolution of the lesions of primary and secondary infection or the finding of a reactive serologic test without a history of therapy, a patient passes into latency. Persons are infectious in the first 1–2 years of latency, with clinical relapses resembling the secondary stage occurring in approximately 25% of cases in the first year. Latent syphilis acquired within the preceding year is referred to as early latent syphilis. All other cases of latent syphilis are referred to as either late latent syphilis or latent syphilis of unknown duration.
Although the CNS is always vulnerable to T pallidum, it is most commonly infected during latent syphilis. Neurologic involvement of ophthalmic and auditory systems can be detected. Cranial nerve palsy and meningeal signs should be evaluated on physical examination.
Syphilis during Pregnancy
The course of syphilis is unaltered by pregnancy, but misdiagnoses are common. The chancre is often unnoticed or internal and not brought to medical attention. Chancres, mucous patches, and condyloma lata are often thought to be herpes genitalis.
The effect of syphilis on pregnancy outcome can be profound. The risk of fetal infection depends on the degree of maternal spirochetemia (greater in the secondary stage than in the primary or latent stages) and the gestational age of the fetus. Treponemes may cross the placenta at all stages of pregnancy, but fetal involvement is rare before 18 weeks. After 18 weeks, the fetus is able to mount an immunologic response, and tissue damage may result. The earlier in pregnancy the fetus is exposed, the more severe the fetal infection and the greater the risk of premature delivery or stillbirth. Antepartum infection in late pregnancy does not necessarily result in congenital infection; only 40–50% of such infants will have congenital infection. Placental infection can occur, with resultant endarteritis, stromal hyperplasia, and immature villi. Grossly, the placenta looks hydropic (pale yellow, waxy, and enlarged). Because polyhydramnios is frequently associated with symptomatic congenital infection, fetuses are ultrasonographically followed throughout pregnancy.
Most infants with congenital syphilis are born to women of low socioeconomic status with inadequate or no prenatal care. Either these neonates may be affected at birth from intrauterine infection (hepatosplenomegaly, osteochondritis, jaundice, anemia, skin lesions, rhinitis, lymphadenopathy, nervous system involvement), or symptoms may develop weeks or months later. The clinical spectrum of congenital infection is analogous to adult secondary disease, as the disease is systemic from onset due to transplacental hematogenous inoculation. The specifics of congenital syphilis are beyond the scope of this text.
Identification of the Organism
Definitive diagnosis of T pallidum is by identification of spirochetes by dark-field examination of specimens from cutaneous lesions. When this specimen is not available, diagnosis depends on the history and serologic tests. An immunofluorescent technique is now available for dried smears. Silver staining for T pallidum of biopsy specimens, placental sections, or autopsy material may confirm the diagnosis in difficult cases. Motile spirochetes can be identified in amniotic fluid obtained transabdominally in women with syphilis and fetal death. PCR is extremely specific for detection of T pallidum in amniotic fluid and neonatal serum and spinal fluid. Newer techniques involving molecular methods are now being used to diagnosis early syphilis.
Diagnostic tests after the primary or secondary moist lesion has disappeared are confined largely to serologic testing. Serologic tests become positive several weeks after the primary lesion appears.
These tests measure reaginic antibody detected by highly purified cardiolipin-lecithin antigen. They can be performed rapidly, easily, and inexpensively. Nontreponemal tests are used principally for syphilis screening, but due to their nonspecific nature, false positives can occur. Nontreponemal tests currently in use are the Venereal Disease Research Laboratory (VDRL), the Rapid Plasma Reagin test (RPR) and the Toluidine Red Unheated Serum Test (TRUST).
These antibody titers may correlate with disease activity, and results should be reported quantitatively. A 4-fold change in titer (equivalent to a change of 2 dilutions: eg, from 1:16 to 1:4 or from 1:8 to 1:32) is considered necessary to demonstrate a clinically significant difference between 2 nontreponemal test results that were obtained using the same serologic test. Sequential serologic tests in individual patients should be performed using the same testing method (eg, VDRL or RPR), preferably by the same laboratory. Nontreponemal test titers usually decline after treatment and might become nonreactive with time; however, in some persons, nontreponemal antibodies can persist for a long period of time.
The VDRL test generally becomes positive 3–6 weeks after infection, or 2–3 weeks after the appearance of the primary lesion, and is invariably positive in the secondary stage. False-positive serologic reactions are frequently encountered in a wide variety of situations, including collagen diseases, infectious mononucleosis, malaria, many febrile diseases, leprosy, drug addiction, old age, and possibly pregnancy. False-positive reactions are usually of low titer and transient and may be distinguished from true-positive results by specific treponemal antibody tests.
B. Treponemal Antibody Tests—
The fluorescent treponemal antibody absorbed test (FTA-ABS) and microhemagglutination assay for Treponema pallidum (MHA-TP) detect antibody against Treponemaspirochetes. Both tests are generally more sensitive and specific than nontreponemal tests. These tests remain positive despite therapy, so they are not given in titers or used to follow serologic response to treatment (Table 43–1).
Table 43–1. Percent Sensitivity of Serologic Tests in Untreated Syphilis. ||Download (.pdf)
Table 43–1. Percent Sensitivity of Serologic Tests in Untreated Syphilis.
Stage of Disease
Type of Test
Syphilis has often been called “the great imitator” because so many of the signs and symptoms are indistinguishable from those of other diseases. Amongst others, primary syphilis must be differentiated from chancroid, granuloma inguinale, lymphogranuloma venereum, herpes genitalis, carcinoma, scabies, trauma, lichen planus, psoriasis, drug eruption, aphthosis, mycotic infections, Reiter's syndrome, and Bowen's disease. Secondary syphilis must be differentiated from pityriasis rosea, psoriasis, lichen planus, tinea versicolor, drug eruption, perlèche, parasitic infections, iritis, neuroretinitis, condyloma acuminatum, acute exanthems, infectious mononucleosis, alopecia, and sarcoidosis.
In one-third of untreated cases, the destructive lesions of tertiary syphilis develop. These may involve skin or bone (gummas), the cardiovascular system (aortic aneurysm or insufficiency), and the nervous system (meningitis, tabes dorsalis, paresis). The complications of tertiary syphilis are fatal in almost one-fourth of cases. However, another one-fourth never show any ill effects.
Penicillin G, administered parenterally, is the preferred drug for treating all stages of syphilis. The preparation, dosage, and length of treatment depend on the stage and clinical manifestations of the disease. Selection of the appropriate penicillin preparation is important, because T pallidum can reside in sequestered sites that are poorly accessed by some forms of penicillin.
Early Syphilis & Contacts
Includes primary, secondary, and early latent syphilis (<1 year's duration):
Benzathine penicillin G 2.4 million units IM in a single dose.
Includes latent syphilis of indeterminate duration or more than 1 year's duration, gumma, and cardiovascular syphilis, but not neurosyphilis.
Benzathine penicillin G 2.4 million units IM weekly for 3 successive weeks (7.2 million units total).
Aqueous crystalline penicillin G 18–24 million units per day, administered as 3–4 million units IV every 4 hours or continuous infusion, for 10–14 days.
Procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally 4 times a day, both for 10–14 days.
Data to support the use of alternatives to penicillin in the treatment of early syphilis are limited. However, several therapies might be effective in nonpregnant, penicillin-allergic patients who have primary or secondary syphilis:
Choose one of the following:
Doxycycline 100 mg orally twice daily for 14 days
Tetracycline 500 mg orally 4 times daily for 14 days
Some limited studies suggest that ceftriaxone 1 g daily either IM or IV for 10–14 days is effective for treating early syphilis. However, the optimal dose and duration of ceftriaxone therapy have not been defined.
Azithromycin as a single 2-g oral dose is effective for treating early syphilis; however, azithromycin resistance and treatment failures have been documented in several geographical areas in the United States. Therefore, the use of azithromycin should be used with caution only when treatment with penicillin or doxycycline is not feasible. Close follow-up of persons receiving any alternative therapies is essential. Patients with a penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin.
Parenteral penicillin G is the only therapy with documented efficacy for syphilis during pregnancy. Pregnant women with syphilis in any stage who report penicillin allergy should be desensitized and treated with penicillin. If serologic tests are equivocal (eg, possible biologic false-positive result), it is better to err on the side of early treatment. Because of an increased risk for treatment failure, a second dose of 2.4 million units of penicillin IM is often recommended in pregnancy.
Adequate maternal treatment before 16–18 weeks' gestation prevents congenital syphilis. Treatment thereafter may arrest fetal syphilitic infection, but some stigmata may remain. Penicillin treatment with varying regimens and preparations is recommended for most cases depending on clinical presentation of the infant and results of serologic, laboratory, and radiologic testing. The details of the management of congenital syphilis are beyond the scope of this text.
The Jarisch-Herxheimer reaction occurs in 50–75% of patients with early syphilis treated with penicillin. It is a febrile reaction accompanied by myalgias and headaches that occurs 4–12 hours after injection and is completed by 24 hours. The cause is uncertain but likely involves a release of treponemal toxic products upon organism lysis. The reaction is generally benign but may trigger labor or fetal distress in pregnancy. Prophylaxis with antipyretics or corticosteroids is of unknown value.
Coexisting Infection with HIV
Syphilis and HIV coinfection is alarmingly common; therefore, all patients with syphilis should be tested for HIV and vice versa. No specific changes in management for HIV-positive patients is recommended, but closer follow-up is necessary to ensure adequate treatment.
Untreated syphilis may progress to tertiary or neurosyphilis with resultant sequelae. Treatment with penicillin is highly effective at curing this infection.
- White homogenous vaginal discharge with fishy odor
- Presence of clue cells on wet preparation microscopy
- Vaginal pH >4.5
Bacterial vaginosis is the most prevalent vaginal infection, although almost 50% of affected women are asymptomatic. The term bacterial vaginosis refers to the changes of vaginal bacterial flora with a loss of lactobacilli, an increase in vaginal pH, and an increase in multiple anaerobic and aerobic bacteria. It is a polymicrobial infection, and commonly involved organisms include Gardnerella vaginalis, Ureaplasma, Mycoplasma, Prevotella spp., and Mobiluncus spp. G vaginalis, the predominant organism involved, is a small, nonmotile, nonencapsulated, pleomorphic rod. The characteristic fishy odor of bacterial vaginosis is due to anaerobic bacteria.
Bacterial vaginosis is associated with multiple sex partners, new sex partner, douching, lack of condom use, and lack of vaginal lactobacilli.
Condom use and avoidance of douching will help to prevent bacterial vaginosis. It is not necessary to treat male sexual partners of affected women. Women with bacterial vaginosis who have sex with women should have their partners screened and, if positive, treated.
Patients usually complain of a vaginal discharge with an odor. Clinical criteria for diagnoses include (1) homogeneous white, noninflammatory discharge, (2) microscopic presence of clue cells, (3) vaginal discharge with pH >4.5, and (4) fishy odor with or without addition of 10% potassium hydroxide. Three of these 4 criteria are required to make a clinical diagnosis of bacterial vaginosis. Clue cells are the unstained vaginal cells in a wet preparation that appear to be dusted with many small dark particles, which are the G vaginalis organisms.
Gram stain is the gold standard for diagnosis, which shows a relative lack of lactobacilli and presence of gram-negative and gram variable rods and cocci.
Trichomoniasis, atrophic vaginitis, and desquamative inflammatory vaginitis should be considered in the differential diagnosis of bacterial vaginosis.
Observational studies have consistently shown an association between bacterial vaginosis and adverse pregnancy outcomes, including preterm delivery, preterm premature rupture of membranes, spontaneous abortion, and preterm labor. However, 2 large randomized, placebo-controlled trials demonstrated that treatment of bacterial vaginosis in asymptomatic pregnant women with metronidazole does not prevent preterm deliveries. Nevertheless, the CDC recommends that pregnant women with a history of preterm delivery and asymptomatic bacterial vaginosis be evaluated for treatment.
Therapy should be initiated for symptomatic relief. Pregnant women who are at high risk for preterm labor may benefit from treatment. Treatment is recommended for low-risk groups during pregnancy if patients are infected and symptomatic. Lastly, patients who may also benefit from therapy are asymptomatic carriers before scheduled pelvic/abdominal surgery.
Choose 1 of the following:
Metronidazole 500 mg orally twice daily for 7 days
Metronidazole gel 0.75%, 1 full applicator (5 g) intravaginally once daily for 5 days
Clindamycin cream 2%, 1 full applicator (5 g) intravaginally at night for 7 days
Choose 1 of the following:
Tinidazole 2 g orally once a day for 2 days
Tinidazole 1 g orally once a day for 5 days
Clindamycin 300 mg orally twice daily for 7 days
Clindamycin ovules 100 mg intravaginally once at night for 3 days
During pregnancy, oral treatment is preferred to local agents due to the possibility of subclinical upper genital tract infection.
Recommended Regimens in Pregnancy
Choose 1 of the following:
Metronidazole 500 mg orally twice daily for 7 days
Metronidazole 250 mg orally 3 times a day for 7 days
Clindamycin 300 mg orally twice daily for 7 days
Thirty percent of patients with an initial response to therapy will have recurrent symptoms within 3 months, and greater than 50% will have recurrence within 12 months. If a patient has had multiple recurrences, suppressive therapy may be beneficial.
- Common infection caused by the flagellated protozoan Trichomonas vaginalis
- Purulent, malodorous, thin vaginal discharge
- Diagnosis by wet-prep, point-of-care tests or culture
- High rate of reinfection
Trichomoniasis is caused by the flagellated protozoan Trichomonas vaginalis. It is common, accounting for up to 35% of vaginitis in symptomatic patients, and should be considered in all women presenting with vaginal discharge. It is virtually always sexually transmitted, although it is usually transient and self-limited in male partners. The incubation period is thought to be 4–28 days.
Use of condoms, limiting the number of sexual partners, and possibly good vulvar hygiene reduce the risk of acquiring trichomoniasis. Sex partners of patients with T vaginalis should be treated, and patients should abstain from sexual intercourse until both partners are treated and asymptomatic.
Symptoms include a purulent, malodorous, thin discharge (70%) with associated burning, pruritus, dysuria, frequency, and dyspareunia. Postcoital bleeding can occur. The urethra is also infected in the majority of women. The classically described green, frothy, foul-smelling discharge is found in fewer than 10% of symptomatic women. Many women, however, will be asymptomatic.
Physical examination often reveals erythema of the vulva and vaginal mucosa with observation of yellow-green discharge. Punctate hemorrhages may be visible on the cervix (“strawberry cervix”) in 2% of cases.
Diagnosis of vaginal trichomoniasis is usually performed by immediate wet preparation microscopy of vaginal secretions. However, this has a sensitivity of only 60–70%.
FDA-cleared point-of-care tests for trichomoniasis exist and include OSOM Trichomonas Rapid Test, an immunochromatographic capillary flow dipstick technology, and the Affirm VP III, a nucleic acid probe test that evaluates for T vaginalis, G vaginalis, and Candida albicans.
Culture on Diamond's medium is another sensitive and highly specific method of diagnosis. Among women in whom trichomoniasis is suspected but not confirmed by microscopy, vaginal secretions can be cultured for T vaginalis.
Bacterial vaginosis, atrophic vaginitis, and desquamative inflammatory vaginitis should be considered in the differential diagnosis of trichomoniasis.
Trichomoniasis is a risk factor for development of posthysterectomy cellulitis, tubal infertility, and cervical neoplasia. In pregnancy it is associated with preterm premature rupture of membranes and preterm delivery.
Choose 1 of the following:
Metronidazole 2 g orally in a single dose
Tinidazole 2 g orally in a single dose
Metronidazole 500 mg orally twice a day for 7 days.
The recommended metronidazole regimens result in cure in 90–95% of cases. However, there is a high reinfection rate (approximately 17% in the first 3 months); therefore, rescreening of patients 3 months after treatment may be considered.
- May be asymptomatic
- Purulent vaginal discharge
- Urinary frequency and dysuria
- Diagnosis by Gram's stain, culture on selective media, or nucleic acid amplification tests
- May progress to pelvic infection or disseminated infection
Neisseria gonorrhoeae is a gram-negative diplococcus that may be recovered from the urethra, cervix, anal canal, or pharynx. The columnar and transitional epithelium of the genitourinary tract is the principal site of invasion. The organism may enter the upper reproductive tract (Fig. 43–4), causing salpingitis with its associated complications. Approximately 700,000 new infections occur each year. After exposure to an infected partner, 20–50% of men and 60–90% of women become infected. Without therapy, 10–17% of women with gonorrhea develop pelvic infection. The incubation period is 3–5 days. Gonorrhea is a reportable disease.
Intra-abdominal spread of gonorrhea and other pathogenic bacteria.
Gonorrhea is a reportable disease that can be controlled only by the detection and treatment of asymptomatic carriers and their sexual partners. All high-risk populations should be screened by routine cultures, including all sexually active women age 25 years or less. Use of condoms will protect against gonorrhea. Sex partners of patients with N gonorrhoeae infection whose last sexual contact with the patient was within 60 days of the onset of symptoms or of diagnosis of the infection should be evaluated and treated for N gonorrhoeae and C trachomatis infections. If a patient's last sexual intercourse was >60 days before onset of symptoms or diagnosis, the patient's most recent sexual partner should be treated. Patients should be instructed to abstain from sexual intercourse until therapy is completed and until they and their sex partners no longer have symptoms.
For prevention of ophthalmia neonatorum, all newborns should receive erythromycin ophthalmic ointment 0.5% to each eye in a single application shortly after delivery.
Many women with gonorrhea are asymptomatic. When symptoms occur, they are generally localized to the lower genitourinary tract and include vaginal discharge, urinary frequency or dysuria, and rectal discomfort. The vulva, vagina, cervix, and urethra may be inflamed and may itch or burn. Unilateral swelling in the inferior lateral portion of the introitus suggests involvement of Bartholin's duct and gland. Anal itching, pain, discharge, or bleeding occurs rarely. Acute pharyngitis and tonsillitis rarely occur. Conjunctivitis can occur; in adults this is usually due to autoinoculation. Ophthalmia neonatorum may result from delivery through an infected birth canal.
Some asymptomatic carriers can develop systemic infection. A triad of polyarthralgia, tenosynovitis, and dermatitis may be present, or purulent arthritis without dermatitis. Septicemia can occur in the former clinical setting and N gonorrhoeae cultured from joint aspirates in the latter. Endocarditis and meningitis have been described.
Gonococcal invasion of nonkeratinized membranes in prepubertal girls produces severe vulvovaginitis. The typical sign is a purulent vaginal discharge with dysuria. The genital mucous membranes are red and swollen. Infection is commonly introduced by adults, and in such cases the physician must consider the possibility of sexual abuse.
A presumptive diagnosis of gonorrhea can be made based on examination of the stained smear; however, confirmation requires positive identification on selective media. Secretions are examined under oil immersion for presumptive identification. Gram-negative diplococci that are oxidase-positive and obtained from selective media (Thayer-Martin) usually signify N gonorrhoeae. However, this test is not completely sensitive so cannot completely rule out infection if negative. Specific diagnosis of infection with N gonorrhoeae can be performed by testing endocervical, vaginal, or urine specimens. Culture, nucleic acid hybridization tests, and nucleic acid amplification testing (NAATs) are also available for the detection of genitourinary infection with N gonorrhoeae.
Because nonculture tests cannot provide antimicrobial susceptibility results, in cases of suspected or documented treatment failure, clinicians should perform both culture and antimicrobial susceptibility testing.
Chlamydia, urinary tract infection, and pelvic inflammatory disease should be considered in the differential diagnosis.
The major complication is salpingitis, which may result in tubal scarring, infertility, and increased risk for ectopic gestations. N gonorrhoeae can be recovered from the cervix in approximately 50% of women with salpingitis. Asymptomatic carriers can also develop these complications. Resistant strains of N gonorrhoeae have emerged in some geographic areas; therefore, follow-up cultures are essential in these settings.
Patients diagnosed with uncomplicated gonorrhea who are treated with any of the recommended or alternative regimens do not need a test-of-cure. It is crucial to instruct patients to abstain from sexual relations for the 7 days after therapy is initiated.
Dual therapy to cover for chlamydia infection has contributed greatly to the declining prevalence of chlamydial infections. Therefore, if chlamydial infection is not ruled out, the following regimens should be given with doxycycline (for nonpregnant patients) or azithromycin.
Quinolone-resistant gonorrhea is now widespread in the United States as well as many other regions. For this reason, quinolones are no longer recommended for treatment of gonorrhea.
Pelvic Inflammatory Disease
See Pelvic Inflammatory Disease.
Patients with disseminated gonococcal infection should be hospitalized. Evidence of endocarditis or meningitis should be sought, and the patient should be closely monitored.
Ceftriaxone 1 g IM or IV every 24 hours.
Choose 1 of the following:
Cefotaxime 1 g IV every 8 hours
Ceftizoxime 1 g IV every 8 hours
All of these regimens should be continued for 24–48 hours after improvement begins, at which time therapy can be switched to cefixime 400 mg orally twice daily to complete at least 1 week of antimicrobial therapy. No treatment failures have been reported with these recommended regimens.
Reactions to first-generation cephalosporins occur in only 5–10% of patients with a history of penicillin allergy and occur less frequently with third-generation cephalosporins. In patients with a history of penicillin allergy, the use of cephalosporins is contraindicated only in those with a history of a severe reaction to penicillin (eg, anaphylaxis, Stevens-Johnson syndrome, or toxic epidermal necrolysis).
Because data are limited regarding alternative regimens for treating gonorrhea among persons who have severe cephalosporin allergy, treatment of these individuals should be undertaken in consultation with an infectious disease specialists. Azithromycin 2 g orally is effective against uncomplicated gonococcal infection, but due to emerging antimicrobial resistance to macrolides, its use should be limited. Cephalosporin desensitization is possible but impractical in most clinical settings.
The prognosis is excellent for patients with gonorrhea who receive prompt treatment, although infertility may result from even a single episode.
- Mucopurulent cervicitis
- Urethral syndrome
- May progress to pelvic inflammatory disease
- May cause infection in neonates born to infected mothers
Chlamydia trachomatis is the most commonly reported infectious disease in the United States, with highest prevalence found in people age ≤25 years. Higher number of sexual partners and lower socioeconomic status are also associated with increased rates of chlamydial infection rates.
Chlamydiae are obligate intracellular organisms that have a cell wall similar to that of gram-negative bacteria. They are classified as bacteria and contain both DNA and RNA. They divide by binary fission, but like viruses they grow intracellularly. With the exception of the L serotypes, chlamydiae attach only to columnar epithelial cells without deep tissue invasion. C trachomatis infections are associated with many adverse sequelae due to chronic inflammatory changes as well as fibrosis. Chlamydia is a reportable disease.
Many patients who have C trachomatis infection are asymptomatic. Therefore, screening with subsequent treatment of infection is the mainstay of prevention, as well as condom use. The CDC recommends annual screening of sexually active women age ≤25 years and older women with risk factors (eg, new or multiple sex partners).
Patients who test positive for chlamydia should be instructed to refer their sex partners for evaluation, testing, and treatment if they had sexual contact with the patient during the 60 days preceding onset of the patient's symptoms or chlamydia diagnosis. In addition, the most recent sex partner should be evaluated and treated, even if the time of the last sexual contact was >60 days before symptom onset or diagnosis.
Women with chlamydial infection are often asymptomatic. Women with cervical infection may have a mucopurulent discharge with hypertrophic cervical inflammation. Salpingitis may cause pelvic pain or be asymptomatic.
C trachomatis infection can be diagnosed either by testing urine or by collecting specimens from the endocervix or vagina. Rectal and oral C trachomatis infections in persons that engage in receptive anal or oral intercourse can be diagnosed by swabbing those areas. NAATs, cell culture, direct immunofluorescence, enzyme immunoassay, and nucleic acid hybridization tests are available for the detection of C trachomatis. NAATs are the most sensitive test for endocervical specimens and are also FDA approved for use on urine. Some NAATs are FDA approved for vaginal swabs. Most tests are not FDA approved for use on oropharyngeal or rectal specimens, although NAATs have been shown to have improved sensitivity and specificity compared with culture.
Mucopurulent cervicitis is frequently caused by N gonorrhoea, and selective cultures for this organism should be performed.
Adverse sequelae of chlamydia result from upper genital tract involvement. Salpingitis and pelvic inflammatory disease may lead to infertility due to tubal obstruction and ectopic pregnancy. Occasionally, patients with chlamydia infection develop perihepatitis (also known as Fitz-Hugh Curtis syndrome), an inflammation of the liver capsule and adjacent peritoneal surfaces. Adhesions may be seen in this area, which resemble “violin strings.” Perihepatitis is more commonly seen in pelvic inflammatory disease. The pathogenesis of this entity is not fully understood but may involve either direct extension of infected material from the cul-de-sac through the peritoneum and/or lymphatics or an immunologically mediated mechanism.
Perihepatitis should be suspected in persons with right-upper quadrant pain or pleuritic pain, in the clinical context of a lower genital tract infection. There are typically no associated liver enzyme abnormalities. Treatment is supportive, usually with nonsteroidal anti-inflammatory agents.
Pregnant women with cervical chlamydial infection can transmit infections to their newborns, and up to 50% of infants born to such mothers will have conjunctivitis. In 10% of infants, an indolent chlamydial pneumonitis develops at 2–3 months of age. This pathogen may also cause otitis media in the neonate.
Chlamydial infection in pregnancy is a risk factor for premature delivery and postpartum infections, particularly when it is acute. It is hypothesized that asymptomatic cervicitis predisposes to mild amnionitis. This event activates phospholipase A2 to release prostaglandins, which cause uterine contractions that may lead to premature labor. Chlamydial infection is associated with higher rates of early postpartum endometritis as well as delayed infection from Chlamydia that may present several weeks postpartum.
Dual therapy to cover for N gonorrhea is appropriate due to high rates of coinfection.
Choose 1 of the following:
Erythromycin base 500 mg orally 4 times a day for 7 days
Erythromycin ethylsuccinate 800 mg orally 4 times a day for 7 days
Levofloxacin 500 mg orally once daily for 7 days
Ofloxacin 300 mg orally twice daily for 7 days
In pregnancy, amoxicillin 500 mg orally 3 times a day for 7 days is the recommended alternative regimen to azithromycin. Levofloxacin and ofloxacin should not be used in pregnant patients.
Except in pregnancy, test-of-cure (repeat testing 3–4 weeks after completing therapy) is not advised for persons treated with the recommended or alterative regimens, unless therapeutic compliance is in question, symptoms persist, or reinfection is suspected. However, patients should be rescreened approximately 3 months after treatment or, if this is not possible, whenever persons next present for medical care in the 12 months after initial treatment.
Treatment of chlamydial infection is usually effective, although reinfection can occur, particularly if sexual partners are inadequately treated. Long-term sequelae are discussed under Complications and are related to postinflammatory scar tissue formation.
- Caused by hepatitis B virus (HBV)
- Acute illness is often asymptomatic
- Can lead to chronic carrier state—more likely if acquired earlier in life
- Treatment of acute illness is supportive
- Vaccination available
- Hepatitis B immunoglobulin indicated for postexposure prophylaxis along with vaccination
Hepatitis B is caused by infection with hepatitis B virus (HBV), an hepadnavirus. The incubation period is 6 weeks to 6 months. Concentration of HBV is highest in blood, with lower concentrations found in other body fluids such as wound exudates, semen, vaginal secretions, and saliva. HBV is more infectious and relatively more stable in the environment than other bloodborne pathogens such as hepatitis C virus (HCV) and HIV.
HBV is transmitted by percutaneous or mucous membrane exposure to blood or body fluids that contain blood. The primary risk factors associated with infection among adolescents and adults are unprotected sex with an infected partner, history of other STDs, and illegal injected-drug use. HBV is a reportable disease.
Two products are available for hepatitis B prevention: hepatitis B immune globulin (HBIG) and hepatitis B vaccine. HBIG provides temporary (3–6 months) protection from HBV infection and is typically used as postexposure prophylaxis, either as an adjunct to hepatitis B vaccination in previously unvaccinated persons or alone in persons who have not responded to vaccination. HBIG is prepared from plasma known to contain high concentrations of anti-HBs. The recommended dose of HBIG is 0.06 mL/kg.
Hepatitis B vaccine contains hepatitis B surface antigen (HBsAg) produced by recombinant DNA technology and provides protection from HBV infection when used for both pre- and postexposure vaccination. There are multiple vaccines available, which have different schedules depending on the specific product. All products require a series of multiple doses over varying time frames, and which regimen is selected depends on local availability and the age of the patient. The vaccine should be administered IM in the deltoid muscle and can be administered simultaneously with other vaccines.
Prevention of perinatal infection can be achieved through routine screening of all pregnant women for HBsAg and immunoprophylaxis (both HBIG and hepatitis B vaccine) of infants born to HBsAg-positive mothers or mothers whose HBsAg status is unknown. Prevention in infancy and childhood can be achieved by routine infant vaccination, and vaccination of previously unvaccinated children and adolescents through age 18 years. Adults who are previously unvaccinated but at increased risk for HBV, such as health care workers, sex workers, men who have sex with men, persons in correctional facilities, intravenous drug users, or household contacts of persons known to carry HBV, should also be vaccinated. Hepatitis B vaccination is recommended for all unvaccinated adolescents, all unvaccinated adults at risk for HBV infection, and all adults seeking protection from HBV infection. Hepatitis B vaccine should be offered to all unvaccinated persons attending STD clinics or seeking treatment for STDs in other settings. This vaccine may be administered in pregnancy if necessary.
Unvaccinated persons or those known not to have responded to a complete hepatitis B vaccine series should receive both HBIG and hepatitis vaccine as soon as possible (preferably ≤24 hours) after a discrete, identifiable exposure to blood or body fluids that contain blood from an HBsAg-positive source. Hepatitis B vaccine should be administered simultaneously with HBIG at a separate injection site, and the vaccine series should be completed by using the age-appropriate vaccine dose and schedule. Exposed persons who are in the process of being vaccinated but who have not completed the vaccine series should receive HBIG and complete the vaccine series. Exposed persons who are known to have responded to vaccination are considered protected.
Patients known to be chronic carriers of HBV should be counseled to have their household contacts and sex partners immunized, use condoms for sexual intercourse, and cover cuts and skin lesions to prevent transmission to others.
Approximately 70% of patients with acute hepatitis B are asymptomatic, with the remainder having jaundice. Rarely patients will present with fulminant hepatic failure.
A serum sickness-like syndrome may develop during the prodromal period, followed by constitutional symptoms, anorexia, nausea, jaundice, and right upper quadrant discomfort. The symptoms and jaundice generally disappear after 1 to 3 months, but some patients have prolonged fatigue even after normalization of serum aminotransferase concentrations.
Patients with chronic hepatitis B are generally asymptomatic, unless they develop significant cirrhosis or have extra hepatic manifestations. Patients may report nonspecific symptoms such as fatigue. Physical examination may be normal, or there may be stigmata of chronic liver disease, or decompensated cirrhosis.
Diagnosis of acute or chronic HBV infection is by serology. Because HBsAg is present in both acute and chronic infection, the presence of IgM antibody to hepatitis B core antigen (IgM anti-HBc) is diagnostic of acute or recently acquired HBV infection. Antibody to HBsAg (anti-HBs) is produced after a resolved infection and is the only HBV antibody marker present after vaccination. The presence of HBsAg and total anti-HBc, with a negative test for IgM anti-HBc, indicates chronic HBV infection. The presence of anti-HBc alone might indicate a false-positive result or acute, resolved, or chronic infection.
The differential diagnosis of hepatitis B is broad and includes any other cause for hepatitis such as other infectious causes, genetic causes of liver disease, alcoholic hepatitis, autoimmune hepatitis, and medications.
The most serious, yet rare complication is acute liver failure and death, which occurs in 1% of reported cases. Becoming a chronic carrier of HBV is also a potential complication of acute infection. Risk for chronic infection is inversely related to age at acquisition; approximately 90% of infected infants and 30% of infected children aged <5 years become chronically infected, compared with 2–6% of persons who become infected as adults. Among persons with chronic HBV infection, the risk for premature death from cirrhosis or hepatocellular carcinoma is 15–25%.
The treatment of acute HBV is supportive care. There are no specific effective antiviral drugs available at this time.
Patients who have chronic HBV infection should be managed by physicians with specific expertise of chronic liver disease. The agents interferon, lamivudine, adefovir, dipivoxil, telbivudine, and entecavir may be used to treat chronic HBV infection.
Acute hepatitis B is usually a self-limited condition, and if the affected patient does not become a chronic carrier, complete recovery is expected in the majority of cases. Chronic carrier status is associated with the potential complications previously described.
- Caused by hepatitis C virus (HCV), an RNA virus
- Primarily transmitted by parenteral route; rarely sexually transmitted
- Up to 85% of affected patients become chronic carriers; of these, up to 70% will develop chronic liver disease
- No effective vaccine
- No effective treatment for acute disease
- Chronic HCV can be treated with combination therapy of pegylated interferon and ribavirin
Hepatitis C is caused by hepatitis C virus (HCV), a small single-stranded RNA virus. HCV RNA can be detected in blood 1–3 weeks after exposure, and antibodies to HCV (anti-HCV) may be detected in the blood as early as 8–9 weeks postexposure. As with hepatitis B, hepatitis C may manifest as an acute or chronic illness and is the most common chronic bloodborne infection in the United States, with approximately 3.2 million people affected.
HCV is transmitted through parenteral exposures to contaminated blood, usually through use of injected drugs and, to a lesser extent, through exposures in health care settings as a consequence of inadequate infection-control practices. Transmission rarely follows receipt of blood, tissues, and organs from HCV-infected donors who were not identified during routine screening activities, which have been mandated in the United States since 1992. Occupational and perinatal exposures can also result in transmission of HCV.
Sexual transmission of HCV had been considered to occur rarely, although it is observed, especially among HIV-infected persons. Ten percent of patients with acute HCV infection report contact with a known HCV-infected sex partner as their only risk for infection. HCV is a reportable disease.
No vaccine for hepatitis C is available, and prophylaxis with immune globulin is not effective in preventing HCV infection after exposure. Therefore, prevention is focused on reducing transmission and reducing chronic liver disease in HCV-infected persons by identifying them and providing medical management and antiviral therapy, as indicated.
Although sexual transmission occurs rarely, condom use is still advisable. Screening of patients who are at risk of HCV is the key to reducing transmission. Patients presenting to STD clinics or in correctional facilities should be offered screening for HCV. All patients with HIV infection should also be screened. Other risk factors for which HCV testing is recommended include prior blood transfusion or solid organ transplant before July 1992, prior transfusion of clotting factor concentrates produced before 1987, long-term dialysis, and signs and symptoms of liver disease.
To reduce the risk for transmission to others, HCV-positive persons should be advised not to donate blood, body organs, or semen; not share any personal items that might have blood on them (eg, toothbrushes and razors); and cover cuts and sores.
HCV-positive women do not need to avoid pregnancy or breastfeeding. However, they should be advised that approximately 6 of every 100 infants born to HCV-infected woman become infected. This infection occurs predominantly during or near delivery, and no treatment or delivery method has been demonstrated to decrease this risk. The risk is increased by the presence of maternal HCV viremia at delivery and also is greater if the woman is coinfected with HIV. HCV has not been shown to be transmitted through breast milk, although HCV-positive mothers should consider abstaining from breastfeeding if their nipples are cracked or bleeding. Infants born to HCV-positive mothers should be tested for HCV infection and, if positive, evaluated for the presence of chronic liver disease.
Patients newly infected with HCV typically are either asymptomatic or have a mild clinical illness. As a result, most infected persons remain unaware of their infection because they feel well and therefore serve as a source of transmission to others as well as being at risk for chronic liver disease and other HCV-related chronic diseases for decades to come.
Testing for antibodies to HCV (anti-HCV) is recommended for screening of asymptomatic persons based on risk factors or a recognized exposure. Multiple FDA-approved tests are commercially available. Nucleic acid PCR testing to detect HCV RNA is necessary to confirm the diagnosis of current HCV infection in a patient with a positive anti-HCV. Elevated ALT levels are suggestive of chronic liver disease.
The differential diagnosis of hepatitis C is broad and includes any other cause for hepatitis such as other infectious causes, genetic causes of liver disease, alcoholic hepatitis, autoimmune hepatitis, and medications.
Chronic HCV infection develops in up to 85% of HCV-infected persons, and of these, up to 70% will develop evidence of active liver disease.
Patients who have been determined to be anti-HCV positive should be evaluated for the presence of active infection, presence or development of chronic liver disease, and possible treatment.
Combination therapy with pegylated interferon and ribavirin is the treatment of choice for patients with chronic hepatitis C. Providers should consult with gastroenterology or infectious disease specialists who are familiar with the most current management options for HCV.
Cirrhosis occurs in up to 50% of chronically infected patients. In patients with cirrhosis, there is a risk of subsequent hepatic decompensation and also of hepatocellular carcinoma, the latter risk being up to 3% per year. Death may occur as a consequence of these complications.
HIV Infection and Acquired Immune Deficiency Syndrome
- HIV antibody, antigen, or ribonucleic acid or culture
- Mononucleosis-like syndrome with weight loss, fever, night sweats
- Erythematous maculopapular rash
- Extragenital lymphadenopathy.
Acquired Immunodeficiency Syndrome (AIDS)
- Opportunistic infections
- Cognitive difficulties or depression
- Kaposi's sarcoma
- CD4 counts below 200
- Cervical neoplasia
HIV infection represents a spectrum of disease that begins with a brief acute viral syndrome that typically transitions to a chronic and clinically latent illness. Without treatment, this illness eventually progresses to a symptomatic, life-threatening immunodeficiency disease known as AIDS. In untreated patients, the time between initial HIV infection and the development of AIDS varies significantly from a few months to many years, with an estimated median time of approximately 11 years.
HIV is a single-stranded RNA retrovirus that attaches to the CD4 receptor of the target cell and integrates into the host genome. Its replication is present during all stages of the infection. This progressively depletes CD4 lymphocytes, which are essential for maintenance of effective immune function. When the CD4 cell count falls below 200 cells/μL, patients are at high risk for life-threatening AIDS-defining opportunistic infections. In the absence of treatment, virtually all HIV-infected persons will die of AIDS.
HIV infection can be acquired by sexual contact, parenteral exposure to blood or body fluids, or transmission from an infected woman to her fetus or infant. Sexual transmission risk is greatest for the female sexual partners of men with AIDS. Other factors that increase the risk for heterosexual acquisition of HIV infection are the number of exposures to high-risk sexual partners, anal-receptive intercourse, and infection with other STDs such as syphilis, genital herpes, chancroid, and condylomata acuminata. The reason for these findings is due to the high concentration of HIV in semen and the fact that coitus causes more breaks in the introital mucosa than in the penile skin. These breaks in the mucosa, similar to those that occur with anal-receptive intercourse, increase the chances for acquiring HIV through sexual contact. The presence of a genital ulcerative disease also increases the risk of infection in a similar fashion.
More than 80% of the female AIDS cases occur in women of reproductive age, making heterosexual and perinatal transmission important concerns. Minorities are disproportionately represented in the reported AIDS cases. In the United States most cases are due to HIV-1, with HIV-2 prevalence being very low. HIV-2 is endemic in parts of West Africa and has been reported increasingly in Angola, Mozambique, Portugal, and France. AIDS is a reportable disease.
Primary prevention is based on condom use for sexual intercourse, avoiding the sharing of needles in persons who use IV drugs, universal precautions in occupations where blood of body fluid exposure is possible (ie, health care workers), and good prenatal care of HIV-infected pregnant women. In the latter group, antiretroviral therapy in pregnancy, in addition to peripartum intravenous antiretroviral therapy, caesarean section in selected cases, and avoidance of breastfeeding, can significantly decrease the risk of vertical transmission. In the third world, breastfeeding is still recommended for these women due to the risks associated with contaminated water for formula.
Secondary prevention guidelines for seropositive patients include refraining from donating blood, plasma, organs, or tissue and maintaining a mutually monogamous sexual relationship with condom use for all sexual activity. Circumcision decreases the transmission of HIV and is recommended in areas with high prevalence of HIV infection such as Africa.
Screening high-risk populations is essential in order to properly practice these prevention strategies. HIV serologic testing should include pre- and post-test counseling about interpretation of test results. HIV testing should be offered to persons that use or have used IV drugs, engaged in prostitution, have sex partners who are HIV-infected or are at risk for HIV infection, have other STDs, have lived in communities or were born in countries where the prevalence of HIV infection is high, have received blood transfusions between 1978 and 1985, have been inmates in correctional systems, or who are pregnant.
As many as 45–90% of patients develop an acute HIV-induced retroviral infection in the first few months after infection. This is similar to mononucleosis, with symptoms of weight loss, fever, night sweats, pharyngitis, lymphadenopathy, erythematous maculopapular rash, and extragenital lymphadenopathy. Critical awareness of this acute syndrome is important because of improved prognoses associated with early antiretroviral treatment. This syndrome usually resolves within several weeks, and the patient becomes asymptomatic. HIV-infected individuals ultimately show evidence of progressive immune dysfunction and the condition progresses to AIDS as immunosuppression continues and systemic involvement becomes more severe and diffuse. Characteristic opportunistic infections may occur, such as Pneumocystis carinii pneumonia, esophageal candidiasis, Kaposi's sarcoma, disseminated Mycobacterium avium infection, tuberculosis, cytomegalovirus, recurrent bacterial pneumonia, toxoplasmosis, chronic cryptosporidiosis, disseminated histoplasmosis, invasive cervical cancer, and chronic HSV.
The CDC definition of AIDS is an HIV-infected person with a specific opportunistic infection (eg, P carinii pneumonia, CNS toxoplasmosis), neoplasia (eg, Kaposi's sarcoma), dementia, encephalopathy, wasting syndrome, rapid progression of cervical dysplasia to cancer, or CD4 lymphocyte count less than 200/μL.
The diagnosis of HIV infection is usually by HIV-1 antibody tests. Routine testing for HIV-2, other than at blood banks, is currently not recommended unless a patient is at risk for HIV-2 infection or has clinical findings of HIV disease and has had a negative HIV-1 antibody test. In general, the enzyme-linked immunosorbent assay (ELISA) functions as a screening test for exposure to HIV. Most patients exposed to HIV develop detectable levels of antibody against the virus by 12 weeks after exposure. The presence of antibody indicates current infection, although the patient may be asymptomatic for years. The sensitivity and specificity of the ELISA test is 99% when it is repeatedly reactive.
The probability of a false-negative test in an uninfected woman is remote unless she is in the “window” before antibody is produced. Individuals in high-risk groups should be retested in 3 months.
Rapid HIV testing can be used to identify HIV infection in women who arrive at labor and delivery with undocumented HIV status and to provide an opportunity to begin prophylaxis of previously undiagnosed infection before delivery. Test results are available within a few hours. Most rapid assays have a sensitivity and specificity comparable to that of ELISA.
Viral load (evaluated by PCR) is useful in determining the activity level of the disease. In the acute infective period the viral load is usually extremely high. The CD4 count will also determine disease activity, as it decreases as the disease progresses.
The differential diagnosis of acute HIV infection includes mononucleosis due to Epstein-Barr virus or cytomegalovirus, toxoplasmosis, rubella, syphilis, viral hepatitis, disseminated gonococcal infection, and other viral infections. Opportunistic infections seen in HIV-infected patients may also present in patients with immunodeficiency of other etiologies.
Complications relate to the opportunistic infections that can occur in patients with HIV infection as well as development of cancers such as Kaposi's sarcoma, lymphoma, and cervical carcinoma.
The specifics of treatment of HIV-infected patients is beyond the scope of this text, and these patients should be managed by specialists in infectious disease medicine. However, the general approach is to use combination highly active antiretroviral therapy (HAART) in order to increase disease-free survival through suppression of HIV replication and improvement in immunologic function. The CD4 count is the main indicator of immune function in HIV-infected patients, and this value is used to determine when to initiate HAART and chemoprophylaxis for opportunistic infections, as well as being a valuable prognostic indicator. Patients with a CD4 count of less than 200/μL should be initiated on HAART. Patients with CD4 counts of 200–500/μL may also benefit from HAART, although the benefit is less pronounced than with more immunosuppressed patients. Patients with a history of an AIDS-defining illness or patients who are pregnant should also be treated with HAART.
For selected patients with a CD4 cell count greater than 500/μL, HAART may be considered. Appropriate patients include those who are motivated to start lifelong therapy, and these patients should be advised that there is less evidence for the potential benefits of treatment at earlier stages of HIV infection. The decision to treat should be balanced against potential toxicities of long-term therapy.
The specifics of the HARRT regimens are outside the scope of this text, but in general, 2 nucleoside reverse transcriptase inhibitors and 1 non-nucleoside reverse transcriptase inhibitor or a protease inhibitor are used in combination.
Antibiotic prophylaxis against various opportunistic infections should be initiated in patients who have CD4 counts of less than 200/μL. The specific coverage depends on how low the CD4 count is, and these decisions should be made by specialists in infectious disease medicine.
Maternal transmission of HIV can occur transplacentally before birth, peripartum by exposure to blood and bodily fluids at delivery, or postpartum through breastfeeding. Therefore, all pregnant women should be offered HIV testing. In the absence of any intervention, an estimated 15–30% of mothers with HIV infection will transmit the infection during pregnancy and delivery, and 10–20% will transmit the infection through breast milk. Vertical transmission of HIV-1 occurs mostly during the intrapartum period (50–70%) but also can occur in the antepartum period (15–30%), especially in untreated women who seroconvert during pregnancy. The mode of delivery may play a role in increasing or decreasing the risks of developing pediatric AIDS. It is recommended that membranes not be ruptured longer than 4 hours. Fetal scalp electrodes and scalp sampling are contraindicated.
Prenatal care must be individualized, with referral to support systems ideally occurring during the pregnancy rather than postpartum. Screening for other STDs is important. HIV-infected patients should undergo shielded chest radiography, a tuberculin skin test with controls, and cytomegalovirus and toxoplasmosis baseline serologic tests. Susceptible patients should receive hepatitis B virus, pneumococcal, and influenza vaccines. CD4 cell counts should be monitored each trimester, as should plasma viral load (HIV-1 RNA).
Zidovudine (ZDV) administered during the second and third trimesters, during labor, and for 6 weeks to the newborn has been shown to decrease vertical transmission from 25–30% to 5–8%. Combination HAART has been shown to reduce the overall transmission to approximately 1.2%.
Caesarean section before onset of labor and rupture of membranes further decreases the risk of vertical transmission; however, the risk of vertical transmission is related to the viral load. When the viral load is less than 1000 copies per milliliter, the perinatal transmission rate approaches zero. Therefore, it is reasonable to offer scheduled caesarean section before onset of labor and rupture of membranes to HIV-infected women with viral loads greater than 1000 copies per milliliter. The American College of Obstetricians and Gynecologists (ACOG) recommends that a scheduled caesarean section be performed at 38 weeks' gestation in order to prevent HIV transmission. ZDV infusion should be started 3 hours preoperatively. The increased maternal morbidity associated with caesarean section must be taken into account, however, when making decisions regarding mode of delivery. Whether caesarean section is beneficial when the mother has received HAART and/or has low to undetectable viral loads is unclear. Also unclear is whether caesarean section after rupture of membranes or onset of labor confers a decrease in HIV transmission.
In resource-rich settings, patients should be counseled against breastfeeding in order to further decrease the risk of transmission.
Although early mortality was nearly certain for most HIV-infected patients in the beginning of the epidemic in the 1980s, the introduction of potent combination therapy has resulted in profound reductions in morbidity and mortality.
American College of Obstetricians and Gynecologists. Scheduled cesarean delivery and the prevention of vertical transmission of HIV infection. ACOG Committee Opinion No. 234. Washington, DC: ACOG; 2000.
Anderson JR (ed). A Guide to the Clinical Care of Women with HIV. Washington, DC: US Department of Health and Human Services, HIV/AIDS Bureau; 2001, pp. 1, 77.
Blattner W, et al. Effectiveness of potent antiretroviral therapies on reducing perinatal transmission of HIV-1. XIII International AIDS Conference, Durban, South Africa, July 9–14, 2000. [Abstract LbOr4]