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Syphilis in women
SYPHILIS IN WOMEN Rodney K. Edwards, MD
Infection with the spirochete Treponema pallidum causes syphilis. Transmission of syphilis occurs through sexual contact with persons who have infectious mucocutaneous lesions. Before the advent of penicillin, this infection was responsible for a large portion of the debilitated patients residing in mental institutions. Later during this century, the disease became somewhat uncommon, only to see a resurgence during the early part of this decade. Syphilis progresses through stages defined as primary, secondary, latent, and tertiary. Diagnosis of this infection is by clinical examination, darkfield microscopy, and serology. Penicillin is the treatment of choice for all stages of syphilis. Doxycycline and tetracycline are acceptable alternatives in some penicillin-allergic patients. If patients are pregnant or have central nervous system involvement, alternative regimens should not be used because of lack of efficacy and/or fetal toxicity. Therefore, these patients must be desensitized and treated with penicillin. No effective vaccine for this infection is currently available. (Prim Care Update Ob/Gyns 2000;7: 186 –191. © 2000 Elsevier Science Inc. All rights reserved.)
Bacteriology Syphilis is caused by the spirochete Treponema pallidum. The organism is too thin to allow visualization by conventional light microscopy. With dark-field microscopy, it may be identified because of a characterFrom the University of Florida College of Medicine, Gainesville, Florida.
186
istic spiral motion and flexing about the midportion. Cultivation of T. pallidum in vitro has not yet been accomplished, and this deficiency has hampered the study of the organism. The predominant immune mechanism responsible for clearing tissues of the infecting organism in primary lesions is T cell–mediated, delayed-type hypersensitivity. Immunity is conferred by T cells secreting lymphokines that activate macrophages to engulf and kill infecting organisms. Antibody and T killer cells have little effect on T. pallidum organisms in tissue.1
en’s health care. The ratio of total cases of primary and secondary syphilis in men to women is now less than 2 to 1,2 and in the United States, syphilis disproportionately affects minorities.4 Additionally, the incidence of the disease has shown a predilection for particular urban areas in this country. In 1993, almost half of the total reported cases of primary and secondary syphilis in the United States occurred in southeastern states that account for only 19% of the total population.4 The majority of cases occurred in New York, California, Florida, Texas, and Michigan. Since the early 1990s, total cases have started to decline again.
Epidemiology The infecting organisms gain access to the body via microscopic abrasions in skin or mucosal surfaces and begin to replicate locally. The most common sites of initial lesions are those that are likely to sustain frictional trauma during intimate contact—the fourchette, cervix, anus, lips, and nipples.2 Syphilis is usually transmitted by sexual contact via exposure to mucocutaneous syphilitic lesions that contain infectious spirochetes. Infection by transfusion is rare in this country. All blood for transfusion is required to have a nonreactive test for syphilis. Additionally, under the conditions of blood bank storage, T. pallidum will die within 24 hours.3 From the early 1980s until the early 1990s, the overall incidence of syphilis increased, while during the same period, a marked decline in the incidence of this infection among homosexual men was seen. The consequence of this trend was an increase in the significance of this infection for providers of wom-
© 2000 Elsevier Science Inc., all rights reserved. 1068-607X/00/$20.00
●
Clinical Presentation Left untreated, approximately one third of patients will clear the infection spontaneously. Another third will develop latent syphilis with, by definition, no clinical manifestations but lifelong seropositivity. The remaining third will progress to tertiary syphilis.
PRIMARY SYPHILIS The hallmark of primary syphilis is the chancre that develops at the site of inoculation. The chancre is typically a painless, red, round, firm ulcer with a granular base that has well-formed, raised edges.2 Chancres appear, on average, about 3 weeks after sexual contact and heal in 3 to 6 weeks. However, with a small inoculum, this incubation period may be as long as 90 days. Painless, nonsuppurative adenopathy frequently accompanies this presentation. Because these lesions are usually painless and because
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SYPHILIS IN WOMEN
Figure 1. Rash of secondary syphilis on (A) the palms and (B) the soles (Reprinted by permission of the Massachusetts Medical Society; Wirth FA. Images in clinical medicine: Secondary syphilis. N Engl J Med 1997;337:321).
one of the common sites for them is the cervix, the clinical manifestations of primary syphilis may go unnoticed by the patient and her partner.
SECONDARY SYPHILIS Untreated patients will progress to this stage within 4 to 10 weeks after the signs of primary syphilis resolve. Secondary syphilis is well known for its varied manifestations, giving rise to its nickname, the “great imitator.” Patients at this stage of illness may display fever, generalized lymphadenopathy; a diffuse rash of the palms and soles (see Figure 1)5; mucosal lesions, including condyloma lata and mucous patches; and papular lesions in intertriginous areas. Generalized adenopathy, in which the lymph nodes are enlarged but not painful and have a firm, rubbery feel, is one of the most common findings of secondary syphilis.3 Condyloma lata (see Figure 2)6 are coalesced papules that appear reddish brown Volume 7, Number 5, 2000
or grayish and moist. The gray color is a result of edema of the keratin layer of the skin.3 The lesions of secondary syphilis, like those of primary infection, teem with spirochetes. These lesions are therefore infectious, and the physician should wear gloves when examining the affected patient.
LATENT SYPHILIS Patients at this stage of disease, by definition, have no clinical evidence of infection. They do, however, demonstrate serologic evidence of infection. Patients who have acquired the infection within the past year have early latent syphilis. This condition is evidenced by documented seroconversion in the past year, unequivocal evidence of primary or secondary syphilis in the past year, or contact with a sex partner in the past year who had primary, secondary, or early latent syphilis.7 Relapses are seen during early latent syphilis in about one fourth of untreated patients, with
most lesions involving the oropharyngeal or anogenital regions.8 All remaining patients who have no clinical evidence of disease but are seroreactive for syphilis have either late latent syphilis or latent syphilis of unknown duration. Differentiation between these two categories is not necessary because the treatment is the same. Nontreponemal serologic test titers (explained under Diagnosis) are usually higher during early than late latent syphilis. However, distinction between these two stages cannot be based on the level of serologic titer. Most untreated patients with late latent syphilis will persist in this stage for life.
TERTIARY SYPHILIS Thirty to 40% of untreated patients with late latent syphilis will progress to tertiary syphilis.8 This stage includes gummatous lesions, cardiovascular disease (aortitis), and neurosyphilis. Gummatous and cardiovascular syphilis are rarely 187
EDWARDS
lowed by focal neurologic deficits that resemble cerebrovascular accidents.10 Though more common than the late manifestations of neurosyphilis, these syndromes are rare but are of concern in patients coinfected with HIV.
Diagnosis
Figure 2. Condyloma lata, a manifestation of secondary syphilis (Reprinted by permission of Wiley-Liss Inc., a subsidiary of John Wiley & Sons, Inc. Soper DE. Images in infectious diseases in obstetrics and gynecology: Secondary syphilis. Infect Dis Obstet Gynecol 1997;5:272).
seen today. The reason for this observation is the success of treatment programs and of antibiotics administered for other indications which simultaneously cure syphilitic infections.9 Neurosyphilis includes a variety of syndromes. The late manifestations (general paresis and tabes dorsalis), which were responsible for a significant proportion of admissions to mental institutions in the early part of this century, are exceedingly uncommon today. If neurosyphilis is encountered today, it is likely to be one of the early forms. These include syphilitic meningitis and meningovascular syphilis. Syphilitic meningitis is characterized by headache, meningeal signs, confusion, and cranial nerve involvement. Meningovascular syphilis presents with a prodrome of headache, psychobehavioral changes, and vertigo, which is fol188
Visualization of treponemes by dark-field microscopy in lesion exudate or tissue or direct fluorescent antibody tests of the same material are the definitive diagnostic tests for early syphilis.7 False-positive results for oral lesions are encountered with dark-field microscopy, owing to the presence of nonpathologic treponemes in the normal oral flora. In addition, neither dark-field microscopy nor direct fluorescent antibody testing are widely available. Therefore, a presumptive diagnosis based on serologic testing is more often made. The diagnosis of patients with latent syphilis is always made by serologic testing; by definition, these patients have no lesions present. All serologic tests for syphilis are based on antibody produced in response to syphilitic infection reacting to provided antigen. These antibody-antigen complexes are then detected with various methods. There are two types of serologic tests for syphilis, treponemal and nontreponemal. Interestingly, the tests used for the diagnosis of syphilis detect antibody produced against the infecting organism, but this antibody does not serve to halt progression of the disease or confer immunity against reinfection. The rapid plasma reagen (RPR) test and the Venereal Disease Research Laboratory (VDRL) test are nontreponemal tests. These tests detect the cross-reaction of antibody to syphilis with cardiolipin. The result is reported as reactive or nonreactive, and a reactive test is
accompanied by a quantitative titer. These titers reflect disease activity and are used to monitor response to treatment.10 It is important to note that the RPR and VDRL are not interchangeable; the same test should be used to follow serial titers in a given patient. A four-fold change in titer, a change of two dilutions, is usually considered a clinically significant difference between two nontreponemal tests using the same method. False-positive nontreponemal tests may occur, especially in patients who are pregnant, are intravenous drug users, have systemic inflammatory diseases such as systemic lupus erythematosus, or have recently had a viral infection.11 A reactive nontreponemal test should be confirmed with a treponemal test such as the fluorescent treponemal antibody-absorption (FTA-ABS) test or microhemagglutination–T pallidum (MHA-TP) test. These tests specifically detect antibodies against T pallidum and are positive for life in the vast majority of infected patients, regardless of stage or treatment history. The FTA-ABS and MHA-TP are reported as positive or negative and are used solely for confirmation of nontreponemal tests, not for following patients known to have syphilis.10 Occasionally, undiluted serum of high titer shows a false-negative result because of saturation of binding sites. This is known as the prozone effect. Because of this possible effect, the clinician should request that the laboratory dilute serum when secondary syphilis is a diagnostic consideration. A “negative” nontreponemal test may subsequently be found to really represent a very high titer.11 The prozone effect occurs when there is such a surplus amount of antibody compared with the amount of antigen provided that no agglutination takes place and, therefore, no antigenantibody complexes are detected. Any patient with syphilis and Prim Care Update Ob/Gyns
SYPHILIS IN WOMEN Table 1. Current Recommendations for the Treatment of Syphilis7 Stage of Disease
Preferred Treatment
Alternative Regimens
Primary, secondary or early latent
Benzathine penicillin G 2.4 million units intramuscularly as a single dose
Late latent, latent of unknown duration, or tertiary
Benzathine penicillin G 2.4 million units intramuscularly once a week for three doses Penicillin G 3–4 million units intravenously every 4 hours for 10–14 days OR procaine penicillin 2.4 million units intramuscularly once daily and probenecid 500 mg orally four times daily, each for 10–14 days
Doxycycline 100 mg orally twice daily or tetracycline 500 mg orally four times daily, each for 2 weeks Doxycycline 100 mg orally twice daily or tetracycline 500 mg orally four times daily, each for 4 weeks None acceptable
Neurologic or ophthalmic
signs or symptoms suggestive of neurologic involvement should have an examination of the cerebrospinal fluid. These manifestations would include ophthalmic symptoms, auditory symptoms, cranial nerve palsies, and signs or symptoms of meningitis. Patients with neurosyphilis demonstrate pleocytosis and an elevated protein level in the cerebrospinal fluid. Even in patients with no neurologic symptoms, T. pallidum has been isolated from cerebrospinal fluid in 30% of patients with primary or secondary syphilis. 12 However, lumbar puncture is not routinely recommended for patients with primary or secondary disease because neurosyphilis is rare after appropriate treatment. All patients with syphilis should undergo a pelvic examination to fully evaluate for clinical stage. Additionally, patients diagnosed with this infection should receive evaluation for other sexually transmitted infections, including HIV.
Treatment Penicillin G is the drug of choice for treating all stages of syphilis and is the only treatment of documented efficacy for neurosyphilis or syphilitic infection during pregnancy (ie, treatment of the fetus).7 The current recommendations of the Centers for Disease Control and Prevention Volume 7, Number 5, 2000
(CDC) for treatment, stratified by clinical stage of the disease, are presented in Table 1. Of note is that erythromycin is no longer recommended as an alternative treatment for any stage of disease because of its decreased efficacy compared with that of other agents. Patients with cardiovascular or central nervous system involvement should be managed in consultation with an infectious-disease expert. The Jarisch-Herxheimer reaction is an acute response that may occur in the hours after treatment of syphilis. This phenomenon is characterized by fever, myalgias, headache, and possibly other symptoms.7 Though of no proven benefit, antipyretics may be given. Some recommend oral steroids before treatment.3 The reaction is believed to represent an allergic response to the breakdown of spirochetes.
MANAGEMENT OF SEXUAL PARTNERS Patients having sexual contact within 90 days preceding diagnosis of primary, secondary, or early latent syphilis in his or her sexual partner should be presumptively treated with the regimen recommended for primary syphilis. Patients should also be treated presumptively if this contact was greater than 90 days preceding diagnosis and either follow-up
care cannot be assured or serologic test results are not immediately available. In addition, presumptive treatment of patients having sexual contact with a person who has latent syphilis of unknown duration is prudent if this contact has a high (at least 1:32) titer on serologic testing. Patients having long-term sexual contact with persons diagnosed with late syphilis should undergo serologic evaluation and receive treatment based on these results.7
FOLLOW-UP OF TREATED PATIENTS Patients treated for primary or secondary syphilis should undergo clinical and serologic reexamination at 6 and 12 months after treatment. If a repeat titer does not decrease four-fold, the patient may either be followed closely or be retreated. For retreatment, benzathine penicillin G, 2.4 million units intramuscularly once a week for three doses, should be administered. Those who demonstrate persistent or recurrent signs or symptoms or who have a four-fold rise in titer are considered to have failed treatment or to have been reinfected. Patients who have treatment failures, as opposed to reinfection, should undergo lumbar puncture to evaluate for subclinical neurosyphilis and should be tested for HIV infection.7 189
EDWARDS
For patients receiving treatment for latent disease, repeat physical examination and serologic testing should be performed at 6, 12, and 24 months after treatment. Retreatment and evaluation for neurosyphilis should be prompted by any of the following: 1) four-fold rise in titer, 2) failure of an initially high (at least 1:32) titer to decrease fourfold 12–24 months after treatment, or 3) development of signs and symptoms of recurrent disease. Patients treated for neurosyphilis should undergo repeat evaluation of the cerebrospinal fluid every 6 months until normal, and consideration should be given to retreating if the cell count does not normalize by 6 months.
Prevention Currently, there is no clinically available vaccine. Prevention of this infection centers on education regarding safer sexual practices and identification and treatment of infected individuals to prevent transmission to others.
Special Considerations PREGNANCY As stated previously, penicillin is the only treatment with documented efficacy for treatment of the fetus. Pregnant patients with a history of penicillin allergy should undergo skin testing. If skin tests are positive, these patients should be desensitized and treated with penicillin. Desensitization may be achieved orally, and the protocol for this appears in detail in the 1998 Sexually Transmitted Diseases Treatment Guidelines published by the CDC.7 Patients treated for syphilis in pregnancy should undergo repeat serologic testing in the third trimester. 190
During pregnancy, the JarischHerxheimer reaction may cause preterm labor and/or a nonreassuring fetal heart rate tracing. However, concern over this possibility should not prevent or delay treatment of an infected gravida. Vertical transmission of syphilis can occur via multiple mechanisms and throughout gestation. Transplacental infection of the fetus does occur, and spirochetes have been demonstrated in amniotic fluid as early as 17 weeks gestation.13 Contact with cutaneous lesions at the time of delivery may also result in neonatal infection. The frequency of vertical transmission varies primarily according to stage of maternal disease. The approximate incidence of congenital syphilis is 50% in infants born to mothers with primary or secondary syphilis. This incidence falls to 40% with earlylatent and 10% with either latelatent or tertiary syphilis.14 Congenital syphilis as a result of vertical transmission is classified into either early or late congenital syphilis, depending on whether symptoms appear before or after 2 years of life. Clinical manifestations of early congenital syphilis include a maculopapular rash, rhinitis (snuffles), hepatosplenomegaly, osteochondritis, chorioretinitis, and others. Late congenital syphilis may be characterized by abnormal dentition (Hutchinson teeth, mulberry molars), deafness, mental retardation, optic nerve atrophy, or generalized paresis.14
HIV-INFECTED PATIENTS Because the diagnosis of syphilis centers on detection of antibody produced in response to infection, there is concern that diagnosis of syphilis may be hampered in patients also infected with HIV. However, serologic tests are generally still useful in these patients because the serologic response of HIV pa-
tients is fairly well preserved. HIV patients are more likely to fail treatment for syphilis, though, and the rate of neurosyphilis is higher. Nevertheless, the recommended stagefor-stage treatment of syphilis is not altered by coinfection with HIV. Syphilis is common in patients with HIV; the prevalence is 14 –36%.10 HIV-infected patients treated for syphilis should undergo physical examination and serologic testing every 3 months for the first year after treatment and again at 24 months after treatment. Clinicians should have a lower threshold for performing lumbar puncture to evaluate for evidence of central nervous system involvement in these patients.7 References 1. Barbosa-Cesnik CT, Gerbase A, Heymann D. STD vaccines—an overview. Genitourin Med 1997;73: 336 – 42. 2. Wendel GD, Gilstrap LC. Syphilis in the nonpregnant patient. Infection protocols for obstetrics and gynecology. Montvale, NJ: Medical Economics Publishing, 174 – 80. 3. Fiumara NJ. The diagnosis and treatment of infectious syphilis. Comp Ther 1995;21:639 – 44. 4. Nakashima AK, Rolfs RT, Flock ML, et al. Epidemiology of syphilis in the United States 1941–1991. Sex Transm Dis 1996;23:16 –23. 5. Wirth FA. Images in clinical medicine: secondary syphilis. N Engl J Med 1997;337:321. 6. Soper DE. Images in infectious diseases in obstetrics and gynecology: secondary syphilis. Infect Dis Obstet Gynecol 1997;5:272. 7. Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually transmitted diseases. MMWR 1998;47:28 – 49. 8. Clark EG, Danbolt N. The Oslo study of the natural course of untreated syphilis: an epidemiologic investigation based on a re-study of the Boeck-Bruusgaard material. Med Clin North Am 1964;48:613–23. 9. Hook EW, Marra CM. Acquired syphilis in adults. N Engl J Med 1992;326:1060 –9. 10. Flores JL. Syphilis: a tale of twisted treponemes. West J Med 1995;163: 552–9. Prim Care Update Ob/Gyns
SYPHILIS IN WOMEN 11. Zenilman JM. Update on bacterial sexually transmitted disease. Urol Clin North Am 1992;19:25–34. 12. Lukehart SA, Hook EW, BakerZanders SA, Collier AC, Critchlow CW, Handsfield HH. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann Intern Med 1988;109:855– 62.
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13. Nathan L, Bohman VR, Sanchez PJ, et al. In utero infection with Treponema pallidum in early pregnancy. Prenat Diagn 1997;17:119 –23. 14. Duff P. Maternal and perinatal infections. In: Gabbe SG, Niebyl JR, Simpson JL, eds. Obstetrics: normal and problem pregnancies. New York: Churchill Livingstone, 1996: 1193–246.
Address correspondence and reprint requests to Rodney K. Edwards, MD, University of Florida College of Medicine, Department of Obstetrics and Gynecology, P.O. Box 100294, Gainesville, FL 32610-0294.
191
Infection with the spirochete Treponema pallidum causes syphilis. Transmission of syphilis occurs through sexual contact with persons who have infectious mucocutaneous lesions. Before the advent of penicillin, this infection was responsible for a large portion of the debilitated patients residing in mental institutions. Later during this century, the disease became somewhat uncommon, only to see a resurgence during the early part of this decade. Syphilis progresses through stages defined as primary, secondary, latent, and tertiary. Diagnosis of this infection is by clinical examination, darkfield microscopy, and serology. Penicillin is the treatment of choice for all stages of syphilis. Doxycycline and tetracycline are acceptable alternatives in some penicillin-allergic patients. If patients are pregnant or have central nervous system involvement, alternative regimens should not be used because of lack of efficacy and/or fetal toxicity. Therefore, these patients must be desensitized and treated with penicillin. No effective vaccine for this infection is currently available. (Prim Care Update Ob/Gyns 2000;7: 186 –191. © 2000 Elsevier Science Inc. All rights reserved.)
Bacteriology Syphilis is caused by the spirochete Treponema pallidum. The organism is too thin to allow visualization by conventional light microscopy. With dark-field microscopy, it may be identified because of a characterFrom the University of Florida College of Medicine, Gainesville, Florida.
186
istic spiral motion and flexing about the midportion. Cultivation of T. pallidum in vitro has not yet been accomplished, and this deficiency has hampered the study of the organism. The predominant immune mechanism responsible for clearing tissues of the infecting organism in primary lesions is T cell–mediated, delayed-type hypersensitivity. Immunity is conferred by T cells secreting lymphokines that activate macrophages to engulf and kill infecting organisms. Antibody and T killer cells have little effect on T. pallidum organisms in tissue.1
en’s health care. The ratio of total cases of primary and secondary syphilis in men to women is now less than 2 to 1,2 and in the United States, syphilis disproportionately affects minorities.4 Additionally, the incidence of the disease has shown a predilection for particular urban areas in this country. In 1993, almost half of the total reported cases of primary and secondary syphilis in the United States occurred in southeastern states that account for only 19% of the total population.4 The majority of cases occurred in New York, California, Florida, Texas, and Michigan. Since the early 1990s, total cases have started to decline again.
Epidemiology The infecting organisms gain access to the body via microscopic abrasions in skin or mucosal surfaces and begin to replicate locally. The most common sites of initial lesions are those that are likely to sustain frictional trauma during intimate contact—the fourchette, cervix, anus, lips, and nipples.2 Syphilis is usually transmitted by sexual contact via exposure to mucocutaneous syphilitic lesions that contain infectious spirochetes. Infection by transfusion is rare in this country. All blood for transfusion is required to have a nonreactive test for syphilis. Additionally, under the conditions of blood bank storage, T. pallidum will die within 24 hours.3 From the early 1980s until the early 1990s, the overall incidence of syphilis increased, while during the same period, a marked decline in the incidence of this infection among homosexual men was seen. The consequence of this trend was an increase in the significance of this infection for providers of wom-
© 2000 Elsevier Science Inc., all rights reserved. 1068-607X/00/$20.00
●
Clinical Presentation Left untreated, approximately one third of patients will clear the infection spontaneously. Another third will develop latent syphilis with, by definition, no clinical manifestations but lifelong seropositivity. The remaining third will progress to tertiary syphilis.
PRIMARY SYPHILIS The hallmark of primary syphilis is the chancre that develops at the site of inoculation. The chancre is typically a painless, red, round, firm ulcer with a granular base that has well-formed, raised edges.2 Chancres appear, on average, about 3 weeks after sexual contact and heal in 3 to 6 weeks. However, with a small inoculum, this incubation period may be as long as 90 days. Painless, nonsuppurative adenopathy frequently accompanies this presentation. Because these lesions are usually painless and because
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SYPHILIS IN WOMEN
Figure 1. Rash of secondary syphilis on (A) the palms and (B) the soles (Reprinted by permission of the Massachusetts Medical Society; Wirth FA. Images in clinical medicine: Secondary syphilis. N Engl J Med 1997;337:321).
one of the common sites for them is the cervix, the clinical manifestations of primary syphilis may go unnoticed by the patient and her partner.
SECONDARY SYPHILIS Untreated patients will progress to this stage within 4 to 10 weeks after the signs of primary syphilis resolve. Secondary syphilis is well known for its varied manifestations, giving rise to its nickname, the “great imitator.” Patients at this stage of illness may display fever, generalized lymphadenopathy; a diffuse rash of the palms and soles (see Figure 1)5; mucosal lesions, including condyloma lata and mucous patches; and papular lesions in intertriginous areas. Generalized adenopathy, in which the lymph nodes are enlarged but not painful and have a firm, rubbery feel, is one of the most common findings of secondary syphilis.3 Condyloma lata (see Figure 2)6 are coalesced papules that appear reddish brown Volume 7, Number 5, 2000
or grayish and moist. The gray color is a result of edema of the keratin layer of the skin.3 The lesions of secondary syphilis, like those of primary infection, teem with spirochetes. These lesions are therefore infectious, and the physician should wear gloves when examining the affected patient.
LATENT SYPHILIS Patients at this stage of disease, by definition, have no clinical evidence of infection. They do, however, demonstrate serologic evidence of infection. Patients who have acquired the infection within the past year have early latent syphilis. This condition is evidenced by documented seroconversion in the past year, unequivocal evidence of primary or secondary syphilis in the past year, or contact with a sex partner in the past year who had primary, secondary, or early latent syphilis.7 Relapses are seen during early latent syphilis in about one fourth of untreated patients, with
most lesions involving the oropharyngeal or anogenital regions.8 All remaining patients who have no clinical evidence of disease but are seroreactive for syphilis have either late latent syphilis or latent syphilis of unknown duration. Differentiation between these two categories is not necessary because the treatment is the same. Nontreponemal serologic test titers (explained under Diagnosis) are usually higher during early than late latent syphilis. However, distinction between these two stages cannot be based on the level of serologic titer. Most untreated patients with late latent syphilis will persist in this stage for life.
TERTIARY SYPHILIS Thirty to 40% of untreated patients with late latent syphilis will progress to tertiary syphilis.8 This stage includes gummatous lesions, cardiovascular disease (aortitis), and neurosyphilis. Gummatous and cardiovascular syphilis are rarely 187
EDWARDS
lowed by focal neurologic deficits that resemble cerebrovascular accidents.10 Though more common than the late manifestations of neurosyphilis, these syndromes are rare but are of concern in patients coinfected with HIV.
Diagnosis
Figure 2. Condyloma lata, a manifestation of secondary syphilis (Reprinted by permission of Wiley-Liss Inc., a subsidiary of John Wiley & Sons, Inc. Soper DE. Images in infectious diseases in obstetrics and gynecology: Secondary syphilis. Infect Dis Obstet Gynecol 1997;5:272).
seen today. The reason for this observation is the success of treatment programs and of antibiotics administered for other indications which simultaneously cure syphilitic infections.9 Neurosyphilis includes a variety of syndromes. The late manifestations (general paresis and tabes dorsalis), which were responsible for a significant proportion of admissions to mental institutions in the early part of this century, are exceedingly uncommon today. If neurosyphilis is encountered today, it is likely to be one of the early forms. These include syphilitic meningitis and meningovascular syphilis. Syphilitic meningitis is characterized by headache, meningeal signs, confusion, and cranial nerve involvement. Meningovascular syphilis presents with a prodrome of headache, psychobehavioral changes, and vertigo, which is fol188
Visualization of treponemes by dark-field microscopy in lesion exudate or tissue or direct fluorescent antibody tests of the same material are the definitive diagnostic tests for early syphilis.7 False-positive results for oral lesions are encountered with dark-field microscopy, owing to the presence of nonpathologic treponemes in the normal oral flora. In addition, neither dark-field microscopy nor direct fluorescent antibody testing are widely available. Therefore, a presumptive diagnosis based on serologic testing is more often made. The diagnosis of patients with latent syphilis is always made by serologic testing; by definition, these patients have no lesions present. All serologic tests for syphilis are based on antibody produced in response to syphilitic infection reacting to provided antigen. These antibody-antigen complexes are then detected with various methods. There are two types of serologic tests for syphilis, treponemal and nontreponemal. Interestingly, the tests used for the diagnosis of syphilis detect antibody produced against the infecting organism, but this antibody does not serve to halt progression of the disease or confer immunity against reinfection. The rapid plasma reagen (RPR) test and the Venereal Disease Research Laboratory (VDRL) test are nontreponemal tests. These tests detect the cross-reaction of antibody to syphilis with cardiolipin. The result is reported as reactive or nonreactive, and a reactive test is
accompanied by a quantitative titer. These titers reflect disease activity and are used to monitor response to treatment.10 It is important to note that the RPR and VDRL are not interchangeable; the same test should be used to follow serial titers in a given patient. A four-fold change in titer, a change of two dilutions, is usually considered a clinically significant difference between two nontreponemal tests using the same method. False-positive nontreponemal tests may occur, especially in patients who are pregnant, are intravenous drug users, have systemic inflammatory diseases such as systemic lupus erythematosus, or have recently had a viral infection.11 A reactive nontreponemal test should be confirmed with a treponemal test such as the fluorescent treponemal antibody-absorption (FTA-ABS) test or microhemagglutination–T pallidum (MHA-TP) test. These tests specifically detect antibodies against T pallidum and are positive for life in the vast majority of infected patients, regardless of stage or treatment history. The FTA-ABS and MHA-TP are reported as positive or negative and are used solely for confirmation of nontreponemal tests, not for following patients known to have syphilis.10 Occasionally, undiluted serum of high titer shows a false-negative result because of saturation of binding sites. This is known as the prozone effect. Because of this possible effect, the clinician should request that the laboratory dilute serum when secondary syphilis is a diagnostic consideration. A “negative” nontreponemal test may subsequently be found to really represent a very high titer.11 The prozone effect occurs when there is such a surplus amount of antibody compared with the amount of antigen provided that no agglutination takes place and, therefore, no antigenantibody complexes are detected. Any patient with syphilis and Prim Care Update Ob/Gyns
SYPHILIS IN WOMEN Table 1. Current Recommendations for the Treatment of Syphilis7 Stage of Disease
Preferred Treatment
Alternative Regimens
Primary, secondary or early latent
Benzathine penicillin G 2.4 million units intramuscularly as a single dose
Late latent, latent of unknown duration, or tertiary
Benzathine penicillin G 2.4 million units intramuscularly once a week for three doses Penicillin G 3–4 million units intravenously every 4 hours for 10–14 days OR procaine penicillin 2.4 million units intramuscularly once daily and probenecid 500 mg orally four times daily, each for 10–14 days
Doxycycline 100 mg orally twice daily or tetracycline 500 mg orally four times daily, each for 2 weeks Doxycycline 100 mg orally twice daily or tetracycline 500 mg orally four times daily, each for 4 weeks None acceptable
Neurologic or ophthalmic
signs or symptoms suggestive of neurologic involvement should have an examination of the cerebrospinal fluid. These manifestations would include ophthalmic symptoms, auditory symptoms, cranial nerve palsies, and signs or symptoms of meningitis. Patients with neurosyphilis demonstrate pleocytosis and an elevated protein level in the cerebrospinal fluid. Even in patients with no neurologic symptoms, T. pallidum has been isolated from cerebrospinal fluid in 30% of patients with primary or secondary syphilis. 12 However, lumbar puncture is not routinely recommended for patients with primary or secondary disease because neurosyphilis is rare after appropriate treatment. All patients with syphilis should undergo a pelvic examination to fully evaluate for clinical stage. Additionally, patients diagnosed with this infection should receive evaluation for other sexually transmitted infections, including HIV.
Treatment Penicillin G is the drug of choice for treating all stages of syphilis and is the only treatment of documented efficacy for neurosyphilis or syphilitic infection during pregnancy (ie, treatment of the fetus).7 The current recommendations of the Centers for Disease Control and Prevention Volume 7, Number 5, 2000
(CDC) for treatment, stratified by clinical stage of the disease, are presented in Table 1. Of note is that erythromycin is no longer recommended as an alternative treatment for any stage of disease because of its decreased efficacy compared with that of other agents. Patients with cardiovascular or central nervous system involvement should be managed in consultation with an infectious-disease expert. The Jarisch-Herxheimer reaction is an acute response that may occur in the hours after treatment of syphilis. This phenomenon is characterized by fever, myalgias, headache, and possibly other symptoms.7 Though of no proven benefit, antipyretics may be given. Some recommend oral steroids before treatment.3 The reaction is believed to represent an allergic response to the breakdown of spirochetes.
MANAGEMENT OF SEXUAL PARTNERS Patients having sexual contact within 90 days preceding diagnosis of primary, secondary, or early latent syphilis in his or her sexual partner should be presumptively treated with the regimen recommended for primary syphilis. Patients should also be treated presumptively if this contact was greater than 90 days preceding diagnosis and either follow-up
care cannot be assured or serologic test results are not immediately available. In addition, presumptive treatment of patients having sexual contact with a person who has latent syphilis of unknown duration is prudent if this contact has a high (at least 1:32) titer on serologic testing. Patients having long-term sexual contact with persons diagnosed with late syphilis should undergo serologic evaluation and receive treatment based on these results.7
FOLLOW-UP OF TREATED PATIENTS Patients treated for primary or secondary syphilis should undergo clinical and serologic reexamination at 6 and 12 months after treatment. If a repeat titer does not decrease four-fold, the patient may either be followed closely or be retreated. For retreatment, benzathine penicillin G, 2.4 million units intramuscularly once a week for three doses, should be administered. Those who demonstrate persistent or recurrent signs or symptoms or who have a four-fold rise in titer are considered to have failed treatment or to have been reinfected. Patients who have treatment failures, as opposed to reinfection, should undergo lumbar puncture to evaluate for subclinical neurosyphilis and should be tested for HIV infection.7 189
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For patients receiving treatment for latent disease, repeat physical examination and serologic testing should be performed at 6, 12, and 24 months after treatment. Retreatment and evaluation for neurosyphilis should be prompted by any of the following: 1) four-fold rise in titer, 2) failure of an initially high (at least 1:32) titer to decrease fourfold 12–24 months after treatment, or 3) development of signs and symptoms of recurrent disease. Patients treated for neurosyphilis should undergo repeat evaluation of the cerebrospinal fluid every 6 months until normal, and consideration should be given to retreating if the cell count does not normalize by 6 months.
Prevention Currently, there is no clinically available vaccine. Prevention of this infection centers on education regarding safer sexual practices and identification and treatment of infected individuals to prevent transmission to others.
Special Considerations PREGNANCY As stated previously, penicillin is the only treatment with documented efficacy for treatment of the fetus. Pregnant patients with a history of penicillin allergy should undergo skin testing. If skin tests are positive, these patients should be desensitized and treated with penicillin. Desensitization may be achieved orally, and the protocol for this appears in detail in the 1998 Sexually Transmitted Diseases Treatment Guidelines published by the CDC.7 Patients treated for syphilis in pregnancy should undergo repeat serologic testing in the third trimester. 190
During pregnancy, the JarischHerxheimer reaction may cause preterm labor and/or a nonreassuring fetal heart rate tracing. However, concern over this possibility should not prevent or delay treatment of an infected gravida. Vertical transmission of syphilis can occur via multiple mechanisms and throughout gestation. Transplacental infection of the fetus does occur, and spirochetes have been demonstrated in amniotic fluid as early as 17 weeks gestation.13 Contact with cutaneous lesions at the time of delivery may also result in neonatal infection. The frequency of vertical transmission varies primarily according to stage of maternal disease. The approximate incidence of congenital syphilis is 50% in infants born to mothers with primary or secondary syphilis. This incidence falls to 40% with earlylatent and 10% with either latelatent or tertiary syphilis.14 Congenital syphilis as a result of vertical transmission is classified into either early or late congenital syphilis, depending on whether symptoms appear before or after 2 years of life. Clinical manifestations of early congenital syphilis include a maculopapular rash, rhinitis (snuffles), hepatosplenomegaly, osteochondritis, chorioretinitis, and others. Late congenital syphilis may be characterized by abnormal dentition (Hutchinson teeth, mulberry molars), deafness, mental retardation, optic nerve atrophy, or generalized paresis.14
HIV-INFECTED PATIENTS Because the diagnosis of syphilis centers on detection of antibody produced in response to infection, there is concern that diagnosis of syphilis may be hampered in patients also infected with HIV. However, serologic tests are generally still useful in these patients because the serologic response of HIV pa-
tients is fairly well preserved. HIV patients are more likely to fail treatment for syphilis, though, and the rate of neurosyphilis is higher. Nevertheless, the recommended stagefor-stage treatment of syphilis is not altered by coinfection with HIV. Syphilis is common in patients with HIV; the prevalence is 14 –36%.10 HIV-infected patients treated for syphilis should undergo physical examination and serologic testing every 3 months for the first year after treatment and again at 24 months after treatment. Clinicians should have a lower threshold for performing lumbar puncture to evaluate for evidence of central nervous system involvement in these patients.7 References 1. Barbosa-Cesnik CT, Gerbase A, Heymann D. STD vaccines—an overview. Genitourin Med 1997;73: 336 – 42. 2. Wendel GD, Gilstrap LC. Syphilis in the nonpregnant patient. Infection protocols for obstetrics and gynecology. Montvale, NJ: Medical Economics Publishing, 174 – 80. 3. Fiumara NJ. The diagnosis and treatment of infectious syphilis. Comp Ther 1995;21:639 – 44. 4. Nakashima AK, Rolfs RT, Flock ML, et al. Epidemiology of syphilis in the United States 1941–1991. Sex Transm Dis 1996;23:16 –23. 5. Wirth FA. Images in clinical medicine: secondary syphilis. N Engl J Med 1997;337:321. 6. Soper DE. Images in infectious diseases in obstetrics and gynecology: secondary syphilis. Infect Dis Obstet Gynecol 1997;5:272. 7. Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually transmitted diseases. MMWR 1998;47:28 – 49. 8. Clark EG, Danbolt N. The Oslo study of the natural course of untreated syphilis: an epidemiologic investigation based on a re-study of the Boeck-Bruusgaard material. Med Clin North Am 1964;48:613–23. 9. Hook EW, Marra CM. Acquired syphilis in adults. N Engl J Med 1992;326:1060 –9. 10. Flores JL. Syphilis: a tale of twisted treponemes. West J Med 1995;163: 552–9. Prim Care Update Ob/Gyns
SYPHILIS IN WOMEN 11. Zenilman JM. Update on bacterial sexually transmitted disease. Urol Clin North Am 1992;19:25–34. 12. Lukehart SA, Hook EW, BakerZanders SA, Collier AC, Critchlow CW, Handsfield HH. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann Intern Med 1988;109:855– 62.
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13. Nathan L, Bohman VR, Sanchez PJ, et al. In utero infection with Treponema pallidum in early pregnancy. Prenat Diagn 1997;17:119 –23. 14. Duff P. Maternal and perinatal infections. In: Gabbe SG, Niebyl JR, Simpson JL, eds. Obstetrics: normal and problem pregnancies. New York: Churchill Livingstone, 1996: 1193–246.
Address correspondence and reprint requests to Rodney K. Edwards, MD, University of Florida College of Medicine, Department of Obstetrics and Gynecology, P.O. Box 100294, Gainesville, FL 32610-0294.
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