Adolescent Health Care: A Practical Guide

Chapter 64

Syphilis

  1. Dennis Fortenberry

Lawrence S. Neinstein

Syphilis is a chronic systemic infection transmitted by sexual contact. Teens are most likely to present with either signs or symptoms of a primary infection, that is, ulcer at the infection site or a secondary infection manifested by symptoms such as skin rash, lymphadenopathy, fever, or mucocutaneous lesions.

Etiology

The agent causing syphilis is Treponema pallidum, a motile, spiral microorganism 6 to 20 µm in length and 0.10 to 0.18 µm in diameter. The organisms do not stain well and are best visualized by dark-field microscopy. T. pallidum does not grow in artificial media.

Most infections are contracted during sexual contact, including kissing and sexual intercourse. Rare cases are caused by direct contact with infectious cutaneous or mucous membrane lesions. Rashes are not infectious if the skin is intact. Other modes of transmission include congenital and transfusion-related transmission. The estimated rate of transmission after sexual exposure to a person with a chancre is 30%. The risk of transmission persists during the first 4 years of untreated syphilis.

Epidemiology

  1. Incidence: Syphilis incidence shows a cyclical waxing and waning, with peaks at intervals of approximately 7 to 10 years. The incidence decreased during most of the 20th century especially after the discovery and use of penicillin in the 1940s. There was an increase in the mid-1980s due to increases in IV drug use, crack cocaine, and multiple sexual partners. The rates peaked in 1990 at 53.8 cases per 100,000 and these were 18 per 100,000 for 15- to 19-year-old males and 42 per 100,000 for teenage females. Rates fell throughout the 1990s, secondary to aggressive screening and use of condoms. However, from 2003 to 2004 there was an increase of 8% in the cases of primary and secondary syphilis to a rate of 2.7 cases per 100,000. There were 8,724 cases reported of primary and secondary syphilis in 2005.
  2. Geographical concentration Syphilis shows substantial geographical concentration, with more than 50% of primary and secondary cases reported from fewer than 1% of U.S. counties. The southeastern part of the United States bears an especially heavy burden of syphilis.
  3. Race: Non-Hispanic blacks are at higher risk for syphilis than non-Hispanic whites. This ratio was 44 times higher in 1997 and declined to 8 times higher in 2002.
  4. Sex: Male-to-female ratios of primary and secondary syphilis have increased in recent years to 3:1 after falling until 1994.
  5. Age: Highest infection rates occur in young adults aged 20 to 29 years. Adolescents participating in commercial sex work, in cocaine and crack cocaine distribution or use, or in other social or sexual networks are important foci in localized outbreaks.

Pathogenesis

  1. pallidumenters the body through minute abrasions in the skin and through exposure to sera of moist, mucocutaneous lesions. The infection is spread through lymphatics and blood vessels. The spirochetes cause cellular infiltrates, granuloma formation, and an obliterative endarteritis. This can lead to necrosis, with resultant ulcerations and erosions. In later stages, tissue hypersensitivity becomes prominent and can lead to gummas. Syphilitic lesions heal by scar formation so that in tertiary lesions scarring is considerable.

Clinical Manifestations

Primary Syphilis

Syphilis should be considered in the differential diagnosis of any ulcerating lesion of the anogenital or oral areas. Less frequently affected areas are breasts and fingers. After an incubation period of 9 to 90 days with an average of 21 days, the primary lesions appear. Syphilis is characterized by a chancre at the point of inoculation. Characteristics of the syphilitic chancre are as follows:

  1. Location
  2. Ninety-five percent are on the external genitalia.
  3. Single lesions are typical but multiple lesions are common.

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  1. Lesions may also appear as “kissing lesions,” chancres that touch each other across a fold of skin.
  2. Other primary sites include the cervix, mouth, anus, lips, face, breast, and fingers.
  3. Size: 1 to 2 cm.
  4. Chancre: Starts as a painless papule eroding to an indurated, painless ulcer. The ulcer typically has a punched out, clean appearance, with slightly elevated, firm margins.
  5. Regional lymphadenopathy accompanies the lesion. The nodes are firm, nonsuppurative, and bilateral and may be painless.
  6. Healing: The chancre heals in 3 to 6 weeks.

The primary infection may manifest with an inconspicuous lesion, particularly in women. Infection may occur with no papule or ulcer at all, particularly in previously infected patients.

Secondary Syphilis

Approximately 6 to 8 weeks (maximum, 6 months) after exposure and 4 to 10 weeks after the onset of the chancre, the manifestations of secondary syphilis appear. During this stage,T. pallidum can be identified in lesions and body fluids. The signs and symptoms of secondary syphilis usually disappear after weeks or months. Up to 25% of patients with untreated secondary syphilis develop relapses of secondary disease, with approximately one fourth of these having multiple relapses. Secondary syphilis lesions are infectious if the lesions are open (e.g., on mucous membranes, in intertriginous areas). Signs and symptoms of secondary syphilis include the following:

  1. General skin eruption: Most common manifestation, affecting 90% of individuals with secondary syphilis
  2. Eruption involves the trunk and extremities with a predilection for palms and soles. The lesions on the palms and soles may be scaly and hyperkeratotic, and they may be the last to clear.
  3. Eruption involves skin as well as mucous membranes.
  4. Eruption tends to follow the lines of cleavage.
  5. Eruption is bilateral and symmetrical.
  6. Individual lesions are sharply demarcated, 0.5 to 2.0 cm in diameter with a reddish-brown hue.
  7. Eruption is most commonly macular, papular, or papulosquamous. Less common are follicular rashes. Vesicular and pustular rashes are rare.
  8. Lesions are typically nonpruritic, but pruritus is not infrequent.
  9. Eruption may last a few weeks to 12 months.
  10. Variety: Almost any type of rash can occur with syphilis, including acneform lesions, herpetiform lesions, and lesions similar to psoriasis. Lesions in intertriginous areas may erode and fissure, especially in the nasolabial folds and near the corners of the mouth. In warm, moist areas, hypertrophic granulomatous lesions (condylomata lata) may occur. These lesions usually occur near the area of the original chancre and have a broad, flat appearance.
  11. General or regional lymphadenopathy (~70%)
  12. Nonpainful nodes
  13. Rubbery, hard feeling; discrete; with no suppuration
  14. Occasional hepatosplenomegaly
  15. Flu-like syndrome (~50%)
  16. Sore throat and malaise most common
  17. Headaches
  18. Lacrimation
  19. Nasal discharge
  20. Arthralgias and myalgias
  21. Weight loss
  22. Fever
  23. Syphilis alopecia (uncommon): Moth-eaten—appearing alopecia of the scalp and eyebrows
  24. Other rare manifestations
  25. Arthritis or bursitis
  26. Hepatitis
  27. Iritis and anterior uveitis
  28. Glomerulonephritis

Latent Syphilis

Latent syphilis, neurosyphilis, and tertiary syphilis are unusual in adolescents. Readers should consult with more detailed references if these entities are suspected.

The early latent period is defined as the first year of infection. Early syphilis includes primary, secondary, and early latent syphilis. The late latent stage refers to the period after this first year unless late (tertiary) syphilis occurs. Latent syphilis is characterized by the following:

  1. Absence of clinical signs and symptoms of syphilis
  2. Repeated positive serological test results (Venereal Disease Research Laboratory [VDRL] and fluorescent treponemal antibody absorption [FTA-ABS]) for syphilis
  3. Negative results from serological tests of the spinal fluid

Neurosyphilis

Neurosyphilis develops in 10% to 20% of patients with untreated syphilis but is uncommon in adolescents. Neurological involvement may become evident within 2 years of the initial infection. Most cases of neurosyphilis in adolescents are asymptomatic or manifest as acute syphilitic meningitis. Meningovascular syphilis is rare.

  1. Asymptomatic neurosyphilis: Characterized by abnormal cerebrospinal fluid (CSF), including pleocytosis, elevated protein, and positive CSF-VDRL
  2. Acute syphilitic meningitis
  3. Usually occurs during secondary syphilis or the early latent period
  4. Common symptoms: Fever, headache, photophobia, and meningismus
  5. Cranial nerve palsies (40%)
  6. Less frequent symptoms: Confusion, delirium, and seizures
  7. CSF: Increased protein, lymphocytic pleocytosis, and sometimes lowered glucose
  8. Meningovascular syphilis
  9. Rare in adolescents (occurs 5 to 12 years after initial infection)
  10. Symptoms and signs from a syphilitic endarteritis producing local areas of infarction
  11. Symptoms: Headache, dizziness, mood changes, and memory loss
  12. Signs: Hemiparesis, hemiplegia, aphasia
  13. Other signs of parenchymal nervous system damage: Argyll-Robertson pupils (accommodation, but no response to light); injury to the posterior column of the spinal cord, causing tabes dorsalis

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Late Syphilis

Signs and symptoms of late syphilis may occur 2 to 10 years after initial exposure in untreated or inadequately treated patients. This includes individuals with gummas and cardiovascular syphilis but not neurosyphilis. Late syphilis has not been reported in adolescents.

Cardiovascular syphilis usually occurs 10 to 30 years after exposure.

Gummas are granulomatous lesions of late syphilis that involve skin, soft tissue, viscera, or bones. They are usually few in number, asymmetrical, indolent, and not contagious.

Congenital Syphilis

The fetus becomes susceptible to infection after the fourth month of gestation. Therefore, adequate treatment of the mother before the 16th week of gestation prevents infection of the fetus. The risk of infection of the fetus during untreated early maternal syphilis is approximately 80% to 95%. Approximately 25% of infants infected in utero die before birth, and 25% die shortly after birth, if untreated. The remainder develop either early or late lesions.

  1. Early congenital syphilis lesions (lesions occurring during the first 2 years of life and usually by 3 months of age)
  2. Vesicular and vesiculobullous eruptions
  3. Superficial desquamation
  4. Rhinitis
  5. Hepatosplenomegaly
  6. Hemolytic anemia, thrombocytopenia
  7. Skeletal involvement: Osteochondritis with periarticular swelling
  8. Neurosyphilis
  9. Ocular: Glaucoma, uveitis, and chorioretinitis
  10. Nephropathy: Uncommon
  11. Late congenital syphilis: This type of syphilis corresponds to tertiary syphilis in adults. In 60% of cases the infection remains latent, and in the rest the lesions can be divided into the following categories:
  12. Inflammatory or hypersensitivity lesions
  13. Gummas
  14. Neurosyphilis
  15. Interstitial keratitis
  16. Clutton joints: Symmetrical, painless swelling of knees
  17. Palatal deformations
  18. Paroxysmal cold hemoglobinuria
  19. Unique stigmata
  20. Hutchinson incisors: Centrally notched, screwdriver-shaped upper incisors
  21. Abnormal facies: Saddlenose, frontal bossing
  22. Eighth nerve deafness
  23. Scaphoid scapulas
  24. Hutchinson triad: Malformed incisors, eighth nerve deafness, and interstitial keratitis

Differential Diagnosis

Primary Syphilis

Sexually Transmitted Causes of Genital Ulcers

The most common sexually transmitted genital ulcers in the United States are herpes, syphilis, and chancroid, in that order. Lymphogranuloma venereum and donovanosis (granuloma inguinale) are rare in the United States.

  1. Herpes simplex: Usually painful, multiple lesions beginning as vesicles on an erythematous base. Primary lesions are usually bilateral, extensive, and associated with tender adenopathy, and recurrent lesions are usually unilateral without significant adenopathy. The vesicles break down into ulcers with nonindurated borders.
  2. Chancroid: Usually painful lesions with a deep purulent base and often erythematous borders. Local lymph nodes are often fluctuant and tender.
  3. Lymphogranuloma venereum: The primary lesion may be a nonindurated, herpetiform ulcer that heals rapidly. Many patients present with advanced disease including fever and massive regional adenopathy.
  4. Granuloma inguinale (donovanosis): Nontender, fleshy, beefy-red ulcers that bleed easily.

Nonsexually Transmitted Causes of Genital Ulcers

The most common nonsexually transmitted cause is trauma.

  1. Traumatic lesions: There should be a history of appearance of the lesion at the time of the trauma. However, many patients attribute genital ulcers to trauma without a specific history of injury.
  2. Fixed drug reaction: There may be history of a similar lesion after prior drug exposure. Lesions may start as reddish plaque and become hyperpigmented, edematous, or eroded.
  3. Candida balanitis.
  4. Behçet syndrome: Not limited to genital area.
  5. Psoriasis, if excoriated.
  6. Lichen planus, if excoriated.
  7. Erythema multiforme, if excoriated.
  8. Cancer: Extremely rare in adolescents.

Secondary Syphilis

  1. Psoriasis
  2. Pityriasis rosea
  3. Drug eruptions
  4. Tinea versicolor
  5. Alopecia areata
  6. Lichen planus
  7. Viremia
  8. Lupus erythematosus
  9. Scabies
  10. Pediculosis
  11. Rosacea
  12. Infectious mononucleosis
  13. Keratoderma blennorrhagica
  14. Condyloma acuminatum

Although the clinical history and appearance of these conditions can often separate them from secondary syphilis, a VDRL or rapid plasma reagin (RPR) test should be performed whenever doubt exists.

Diagnosis

Syphilis screening is an important element of routine health care for sexually experienced adolescents. Adolescents should also be screened during pregnancy or when

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diagnosed with other sexually transmitted infections. However, as the prevalence falls in certain lower-risk groups, such as college students, the criteria for screening syphilis serology will have to be reevaluated.

Laboratory Findings

Dark-Field Examination

The dark-field examination is essential in evaluating moist ulcers and lesions such as a chancre or condyloma lata. Technique is as follows:

  1. Clean lesion with saline and gauze.
  2. Abrade gently with dry gauze. Avoid inducing bleeding, which makes dark-field examination more difficult.
  3. Squeeze lesion (with gloves) to express serous transudate.
  4. Place a drop of transudate on a slide.
  5. Place a drop of saline on transudate and cover with a cover slip.
  6. Examine under dark-field microscope.
  7. For internal lesions, a bacteriological loop can be used to transfer the fluid to a slide.
  8. For lymph node aspirations: Clean the skin, inject 0.2 mL or less of sterile saline, and aspirate the node. Place the fluid on a slide.

Direct Fluorescent Antibody

Specimens from primary lesions can also be sent to reference laboratories or some state health departments for direct fluorescent antibody (DFA) staining. These specimens can be collected as described previously; however, saline should not be added to the slides, and they should be allowed to air-dry.

Both dark-field microscopy and DFA staining are very specific except for oral specimens, but sensitivity depends on many factors, including collection technique, age of lesions, and experience of laboratory personnel.

Serological Tests

  1. Nontreponemal antibody tests: Tests for a nonspecific anticardiolipin antibody that forms in response to surface lipids on the treponeme
  2. Types
  • Agglutination: RPR
  • Flocculation: VDRL
  1. Use: Nontreponemal tests should be used for screening and to monitor treatment success. Nontreponemal test titers correlate with disease activity and fall after treatment. Positive nontreponemal tests should be titered out to the highest point, and monitored over time. A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:8 to 1:32 or 1:16 to 1:4), demonstrates a substantial change if the same serological test is used.
  2. Specific treponemal antibody tests
  3. Types
  • Immunofluorescence: FTA-ABS is used to confirm a positive result from RPR or VDRL.
  • Microhemagglutination: The T. pallidumparticle agglutination Particle Agglutination (TP-PA) test has replaced the FTA-ABS test in many laboratories as the specific treponemal test to confirm a positive result from VDRL.
  • Enzyme-linked immunosorbent assay (ELISA)—used by some blood banks for donor screening.
  1. Use: Treponemal tests are specific and sensitive, but because of their expense and more difficult technical requirement, they are typically used to confirm positive results from a screening test. Once an individual tests positive on treponemal tests, he or she usually remains positive for life. Titers are unrelated to disease activity or treatment. Treponemal antibody titers therefore should not be quantitated but recorded as reactive, nonreactive, or minimally reactive. A minimally reactive test result may represent a false-positive finding, and the test should be repeated.
  2. Sensitivity
  3. The sensitivity of nontreponemal tests (RPR and VDRL) in primary syphilis ranges from 60% to 90% depending on the duration of infection and the population under study. Results are positive at the following times:

Onset of primary chancre

Approximately 25% of individuals are positive

2 wk after chancre appearance

50% are positive

3 wk after chancre appearance

75% are positive

4 wk after chancre appearance

100% are positive

  1. Treponemal tests (TP-PA and FTA-ABS) are positive in 80% to 100% of primary syphilis. Sensitivity of nontreponemal and treponemal tests approaches 100% in secondary syphilis.
  2. False-positive serology test results: Approximately 20% to 40% of all positive nontreponemal test results are false-positive, as shown by a nonreactive treponemal test. Most false-positive nontreponemal test results show a low titer (dilution <1:8), and the probability of a false-positive finding decreases with increasing titer. The causes of false-positive test results include the following:
  3. Acute infection: Viral infections, chlamydial infections, Lyme disease, Mycoplasmainfections, nonsyphilitic spirochetal infections, and various bacterial, fungal, and protozoal infections
  4. Autoimmune diseases
  5. Narcotic addiction
  6. Aging
  7. Hashimoto thyroiditis
  8. Sarcoidosis
  9. Lymphoma
  10. Leprosy
  11. Cirrhosis of the liver
  12. Human immunodeficiency virus (HIV) infection: Can lead to unusually high, unusually low, or fluctuating titers
  13. False-positive findings can occasionally arise in treponemal tests. However, most of these are reported as borderline and not positive.
  14. Tests most commonly used
  15. RPR (screening and quantitative measurement of clinical activity)
  16. VDRL (quantitative measurement to assess clinical activity and response to therapy or qualitative test for screening)
  17. TP-PA or FTA-ABS (to confirm diagnosis in a patient with a positive result from VDRL or RPR)

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  1. Other tests under development are based on polymerase chain reaction (PCR), or enzyme-linked immunospot testing for treponeme-specific antibody–secreting cells. Clinical experience with these tests is limited, and they have not replaced existing modes of screening and confirmation.

Diagnosis by Stage

Primary Syphilis

  1. Definitive diagnosis of early syphilis requires a positive result on dark-field examination or DFA test of lesion transudate or tissue.
  2. Presumptive diagnosis relies on a positive nontreponemal test result (VDRL or RPR) with a high titer (1:8 or higher) or rising titer (two or more than two dilutions) anda positive treponemal test result (e.g., FTA-ABS or TP-PA).

Adolescents with a positive dark-field examination should be treated, as should those with a typical lesion and a positive serological test result. Sexual partners (within the previous 90 days, even if asymptomatic and seronegative) of persons with documented infection should also be treated. If the initial serological test result is negative, it should be repeated 1 week, 1 month, and 3 months later in suspected cases. An FTA-ABS or TP-PA test should be used to confirm a positive nontreponemal test result.

Lumbar puncture is not recommended for routine evaluation of primary syphilis unless clinical signs and symptoms of neurological involvement are present. The role of lumbar puncture in the care of HIV-infected persons with primary syphilis is controversial. Most experts would reserve lumbar puncture for the evaluation of apparent treatment failures.

Secondary Syphilis

  1. Dark-field examination of material from lesions or lymph nodes
  2. VDRL or RPR

An adolescent should be treated if the dark-field examination result is positive or if the patient has typical findings of secondary syphilis and a positive result from VDRL or RPR. Positive nontreponemal test results should be confirmed with an FTA-ABS or TP-PA test.

Neurosyphilis

The standard test is the CSF-VDRL. It is a specific but not a sensitive test for active neurosyphilis. On the other hand, the FTA-ABS is sensitive but not specific for neurosyphilis. Serum antibody may diffuse into the CSF and may not be reflective of active central nervous system (CNS) disease. However, a nonreactive FTA-ABS probably indicates the absence of active neurosyphilis. Pleocytosis in the CSF is another good indicator of active disease.

  1. CNS invasion by treponemes occurs in 30% to 40% of patients with primary or secondary syphilis. However, this may not be an accurate predictor of poor neurological outcome. A spinal tap is not indicated in patients with early syphilis.
  2. Indications for CSF examination can include latent syphilis of unknown duration if:
  3. Neurological or ophthalmological signs or symptoms are present
  4. Treatment failure
  5. Serum nontreponemal test titer is greater than or equal to 1:32 unless duration of infection is known to be <1 year
  6. Nonpenicillin therapy is planned unless duration of infection is known to be <1 year
  7. HIV infection

Evaluation of neurosyphilis should be done in consultation with an expert in this area. There are no perfect tests for evaluating neurosyphilis. The cell count is usually elevated in the presence of neurosyphilis and is an excellent marker for assessing treatment. The VDRL is the standard and most specific test on spinal fluid, but it has a sensitivity of only 60% to 70%. Although the FTA-ABS is highly sensitive, the false-positive rate may be 6% or greater because of transfer of antibodies across the blood–brain barrier. Some experts order both tests. If the FTA-ABS result is negative, the likelihood of neurosyphilis is very small.

Syphilis in Pregnancy

All pregnant adolescents should be screened early in pregnancy. Seropositive subjects should be considered infected unless a prior history documents recent treatment and serological titers have appropriately declined. Screening should be repeated in the third trimester and again at delivery in areas or populations with a high prevalence of syphilis. A woman delivering a stillborn infant after 20 weeks' gestation should also be tested for syphilis.

Syphilis and Human Immunodeficiency Virus

Ulcerative lesions such as syphilitic chancres increase the risk of transmission of HIV. There is also evidence that infection with HIV may alter the serological response to syphilis. There have been reports of patients who were coinfected with HIV and syphilis and had unusual serological responses. Many of these reports involved higher than expected serological titers, but false-negative serological test results have also been reported. Most treponemal and nontreponemal serological tests for syphilis are accurate for most individuals with both syphilis and HIV infection. If serological tests are not consistent with clinical findings, alternative tests, such as biopsy and DFA staining of lesion material, should be considered. HIV-infected individuals with neurological symptoms or failure to respond to antibiotic treatment should be evaluated for neurosyphilis.

Latent Syphilis

A RPR/VDRL and a FTA-ABS test should be done. The FTA-ABS is essential in latent and late syphilis because the nontreponemal tests are only approximately 70% sensitive in these states. The adolescent should be treated if the FTA-ABS result is positive and there is no documentation of appropriate prior treatment. A decision about a lumbar puncture in these instances should be done in consultation with an expert in this area.

Therapy

Penicillin is the optimal antibiotic for syphilis treatment and the dosage and length depends on the state of syphilis. For individuals in these categories with a history of penicillin allergy, skin testing and desensitization, if indicated, are recommended.

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Fewer data are available on nonpenicillin regimens. Adolescents treated for gonorrhea or chlamydia with ceftriaxone, doxycycline, and azithromycin are probably covered for incubating syphilis. If a different antibiotic regimen is used to treat gonorrhea or chlamydia, the teen should have a second serological test for syphilis in 3 months.

Primary and Secondary Syphilis

  1. Benzathine penicillin G: The total recommended dose is a single injection of 2.4 million units intramuscularly (IM).
  2. Penicillin-allergic nonpregnant patients:
  3. Doxycycline 100 mg orally two times a day for 14 days, or
  4. Tetracycline 500 mg orally four times a day for 14 days is recommended.
  5. Ceftriaxone is effective for treatment of early syphilis but the optimal dose and duration have not been defined.
  6. Azithromycin 2 g as a single oral dose. However, treatment failure due to acquired azithromycin resistance of T. pallidumhas been reported in several geographical areas. This treatment should be considered only if other options are not available and careful follow-up can be assured.
  7. Use of any of these therapies in HIV-infected persons has not been well studied.
  8. For those who cannot tolerate one of the above therapies referral for desensitization to penicillin is indicated.
  9. Pregnancy: Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin.
  10. Other considerations
  11. All patients with syphilis should be tested for HIV. For high-risk patients or in high-prevalence areas, patients with primary syphilis should be retested for HIV after 3 months.
  12. Those individuals with signs or symptoms that suggest neurological or ophthalmic disease should be evaluated by CSF analysis or slit-lamp examination, respectively. Routine lumbar puncture is not recommended for individuals with primary or secondary syphilis unless clinical signs and symptoms suggest neurological involvement or if patients fail to respond to antibiotic treatment.
  13. Follow-up
  14. Infected individuals should be reexamined clinically, and serological test results should be rechecked at 3 and 6 months. Quantitative nontreponemal tests should be used for follow-up, because the FTA-ABS and TP-PA results usually remain positive throughout the individual's life. If signs or symptoms persist or nontreponemal antibody titers have not decreased fourfold by 6 months, the patient should have a CSF examination and HIV test and be re-treated. Most individuals with primary syphilis are seronegative by 3 to 12 months, and 75% to 95% of individuals with secondary syphilis are seronegative by 1 year. The drop in titers for primary and secondary syphilis applies only to first episodes of primary or secondary syphilis; those with reinfections have less predictable serological drops.
  15. Individuals are at risk for treatment failure if their nontreponemal titers have not declined fourfold by 3 months after treatment for primary or secondary syphilis. HIV testing should be performed at 3 months in these individuals. Re-treatment should probably include three weekly injections of benzathine penicillin G 2.4 million units IM unless neurosyphilis is present.

Latent Syphilis

Latent syphilis is defined as disease characterized by seroreactivity without other evidence of disease. If acquired in the preceding year this is classified as early latent syphilis. These individuals can be classified as early latent, if during the year before evaluation they had:

  • Seroconversion or fourfold or greater increase in titer of a nontreponemal test
  • Unequivocal symptoms of primary or secondary syphilis
  • A sex partner with documented primary, secondary, or early latent syphilis; or
  • Reactive nontreponemal and treponemal tests from possible exposure within the previous 12 months

Late latent syphilis identifies a disease duration of 1 year or longer. The term latent syphilis of unknown duration is used when the timing of the initial infection cannot be established.

There are two regimens for patients who are not allergic to penicillin and who have normal findings on CSF examinations:

  1. Early latent syphilis: Benzathine penicillin G 2.4 million units IM in a single dose
  2. Late latent syphilis or latent syphilis of unknown duration: Benzathine penicillin G 7.2 million units total administered as three doses of 2.4 million units IM each at 1-week intervals
  3. Penicillin-allergic patients: No clinical data exist that adequately document the efficacy of drugs other than penicillin for syphilis of more than 1 year duration. CSF examinations should be performed before therapy with these regimens. Suggested regimens are doxycycline 100 mg orally two times a day, or tetracycline 500 mg orally four times a day. Either is given for 14 days for individuals with early latent syphilis or 28 days for other individuals. If the CSF examination shows any evidence of neurosyphilis, the patient should be treated for neurosyphilis.
  4. Other considerations
  5. All individuals with latent syphilis should be evaluated for tertiary disease including neurosyphilis, aortitis, iritis, and gummas.
  6. All patients with syphilis should be tested for HIV.
  7. Follow-up
  8. Quantitative nontreponemal serological titers should be done at 6, 12, and 24 months after treatment. If titers increase fourfold or initial high titers (1:32 or greater) fail to decrease fourfold (two dilutions) within 12 to 24 months, or if signs or symptoms of syphilis occur, the individual should be evaluated for neurosyphilis and re-treated appropriately.
  9. Approximately 75% of the patients with early latent disease (duration 4 years or less) become seronegative by 5 years; the remaining 25% have positive serology for life.

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Late Syphilis

The term late syphilis describes patients with gumma disease or cardiovascular involvement but not neurosyphilis. Late syphilis should not occur in adolescents and young adults.

Neurosyphilis

Neurosyphilis can occur during any stage of syphilis. Patients with syphilitic eye involvement should be treated with regimens covering neurosyphilis. Individuals with neurological symptoms should have a CSF examination.

  1. Recommended regimen for neurosyphilis or syphilitic eye disease in individuals not allergic to penicillin: Aqueous crystalline penicillin G 18 to 24 million units daily administered as 3 to 4 million units intravenously (IV) every 4 hours for 10 to 14 days.
  2. Alternative regimen if compliance is a problem: Procaine penicillin G IM 2.4 million units daily, plus probenecid 500 mg orally four times a day, both for 10 to 14 days.
  3. Some experts add benzathine penicillin G 2.4 million units IM after completion of either of these two regimens.
  4. Penicillin-allergic patients: Patients should be desensitized to penicillin, if necessary, and treated with penicillin. No alternatives have been adequately evaluated. Some specialists recommend ceftriaxone 2 g daily IM or IV for 10 to 14 days.
  5. Follow-up: If the initial CSF examination showed an increased cell count, the examination should be repeated every 6 months until the cell count is normal. If the count has not decreased at 6 months or is not normal by 2 years, re-treatment should be strongly considered.

Syphilis in Pregnancy

All pregnant women should receive penicillin doses appropriate for their stage of syphilis. Although penicillin is effective in preventing transmission to the fetus and in treating infections in the fetus, the exact optimal penicillin regimens have not been adequately studied. Treatment in pregnancy should be the penicillin regimen appropriate for the stage of syphilis. Some experts recommend additional therapy, such as a second dose of benzathine penicillin G 2.4 million units IM given 1 week after the first dose for women who have primary, secondary, or early latent syphilis. During the second half of pregnancy, syphilis treatment may be adjusted by sonographic fetal evaluation for congenital syphilis. Tetracycline should not be used, because it is contraindicated in pregnancy. Erythromycin has a high risk of failure to cure the fetus. Therefore, pregnant women with a history of an allergy to penicillin should be skin tested and either treated or desensitized. A Jarisch-Herxheimer reaction during the second half of pregnancy can induce premature labor or fetal distress.

Treatment of Sex Partners

  1. Persons exposed to an individual with primary, secondary, or early latent syphilis within the preceding 90 days should be treated presumptively. These individuals might be infected even if they are seronegative. If exposure occurred more than 90 days before examination, the individual should be treated presumptively if serological test results are not immediately available and follow-up is uncertain.
  2. Partners should be notified and treated if the affected patient has syphilis of unknown duration and high nontreponemal serological test titers (1 : 32 or greater).
  3. Sex partners of patients with late syphilis should be evaluated both clinically and serologically for syphilis.
  4. Identification of at-risk sex partners: Time periods used to determine partners at risk are as follows:
  5. Three months plus duration of symptoms for primary syphilis
  6. Six months plus duration of symptoms for secondary syphilis
  7. One year for early latent syphilis

Human Immunodeficiency Virus-Infected Individuals

Among HIV-positive individuals, there have been reports of higher rates of neurological complications and treatment failures with traditional regimens for syphilis. There have also been cases of rapid progress of syphilis into secondary and tertiary stages in HIV-positive patients. However, no treatment regimens have yet been demonstrated to be more effective in treating HIV-infected individuals than those used in patients without HIV infection. HIV-positive patients with syphilis require careful evaluation for late and unusual manifestations of syphilis, including CSF evaluation. These patients require careful follow-up after therapy.

  1. Penicillin regimens should be used whenever possible. Skin testing and desensitization can be used as appropriate.
  2. Primary and secondary syphilis in HIV-infected patients: The Centers for Disease Control and Prevention (CDC) recommends no change in therapy for early syphilis in HIV-infected patients. Some experts recommend adding multiple doses of benzathine penicillin G, similar to the dosages used to treat late syphilis.
  3. Because of the confusing CSF findings and difficulty in definitively diagnosing neurosyphilis, some authorities recommend CSF examination of all individuals who are HIV infected, with treatment altered accordingly.
  4. Follow-up: HIV-infected adolescents should have follow-up serological testing at 3, 6, 9, 12, and 24 months. Those individuals with treatment failure should have a CSF examination and be re-treated similarly to those who are not HIV infected. If the CSF is normal, most experts would re-treat with benzathine penicillin G 7.2 million units as three weekly doses of 2.4 million units each.
  5. Latent syphilis
  6. Patients with HIV and latent syphilis should have a CSF examination before treatment begins.
  7. Treatment in those individuals with normal CSF should include benzathine penicillin G 7.2 million units (as three weekly doses of 2.4 million units each). Those with abnormal findings on CSF examination should be treated and managed as patients with neurosyphilis.

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Jarisch-Herxheimer Reaction

A remarkable reaction occurs within 2 hours of treatment in 50% of patients with primary syphilis, in 90% of those with secondary syphilis, and in 25% of those with early latent syphilis. The reaction consists of the following:

  1. Fever and chills
  2. Myalgias
  3. Headache
  4. Elevated neutrophil count
  5. Tachycardia

The duration of symptoms is 12 to 24 hours, and treatment is reassurance, bed rest, and aspirin. The reaction can induce transient uterine contractions in pregnant women.

Web Sites

For Teenagers and Parents

http://www.cdc.gov/std/Syphilis/STDFact-Syphilis.htm. CDC site on syphilis.

http://www.drkoop.com/ency/93/001327.html. Dr. Koop's site on syphilis.

http://www.iwannaknow.org. The American Social Health Association Web site designed specifically for teens. Sexuality and STD prevention are directly and explicitly addressed on general STD topics.

http://kidshealth.org/parent/infections/bacterial_viral/syphilis.html. Kids health site on syphilis.

For Health Professionals

http://www.cdc.gov/STD/treatment/. The CDC Web site with recent statistics and treatment guidelines.

http://www.ashastd.org. The American Social Health Association home page—lots of information and hotline access.

http://www.niaid.nih.gov/factsheets/stdsyph.htm. National Institute of Allergy and Infectious Diseases fact sheet from National Institutes of Health.

http://emedicine.com/ped/topic2193.htm. E-medicine site on syphilis.

References and Additional Readings

Alexander JM, Sheffield JS, Sanchez PJ, et al. Efficacy of treatment for syphilis in pregnancy. Obstet Gynecol 1999; 93:5.

Augenbraun M, Rolfs R, Johnson R, et al. Treponemal specific tests for the serodiagnosis of syphilis. Sex Transm Dis 1998; 25:549.

Beltrami JF, Cohen DA, Hamrick JT, et al. Rapid screening and treatment for sexually transmitted diseases in arrestees: a feasible control measure. Am J Public Health 1997;87: 1423.

Birnbaum NR, Goldschmidt RH, Buffett WO. Resolving the common clinical dilemmas of syphilis. Am Fam Physician 1999; 59:2233.

Centers for Disease Control and Prevention. Guidelines for treatment of sexually transmitted diseases. MMWR 2006; 55(RR–11):22.

Colletti JE, Giudice EL. Syphilis screening in a high-risk, inner-city adolescent population. Am J Emerg Med 2005;23: 225.

Doroshenko A Sherrard J Pollard AJ. Syphilis in pregnancy and the neonatal period. Int J STD AIDS 2006;17(4):221–227.

Ellen JM, Langer LM, Zimmerman RS, et al. The link between the use of crack cocaine and the sexually transmitted diseases of a clinic population: a comparison of adolescents with adults. Sex Transm Dis 1996;23:511.

Genç M, Ledger WJ. Syphilis in pregnancy. Sex Transm Infect 2000;76:73.

Ghanem KG, Erbelding EJ, Cheng WW, et al. Doxycycline compared with benzathine penicillin for the treatment of early syphilis. Clin Infect Dis 2006;42(6):e45–e49.

Holmes KK, Levine R, Weaver M. Effectiveness of condoms for prevention of sexually transmitted infections. Bull WHO 2004;82:454.

Joyanes P, Borobio MV, Arquez JM, et al. The association of false-positive rapid plasma reagin results and HIV infection. Sex Transm Dis 1998;25:569.

Kamb ML, Fishbein M, Douglas JM Jr, et al., Project RESPECT Study Group. Efficacy of risk-reduction counseling to prevent human immunodeficiency virus and sexually transmitted diseases: a randomized controlled trial. JAMA 1998;280: 1161.

Klausner JD, Wolf W, Fischer-Ponce L, et al. Tracing a syphilis outbreak through cyberspace. JAMA 2000;284:447.

Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 2004;351:154.

Marra CM. Neurosyphilis. Curr Neurol Neurosci Rep 2004;4:435.

Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: Does HIV status matter? Clin Infect Dis 2004;38: 1001.

Musher DM. Early syphilis in the adult. In: Holmes KK, Sparling PF, Mardh PA, et al., eds. Sexually transmitted diseases, 3rd ed. New York: McGraw-Hill; 1999.

Myles TD, Elam G, Park-Hwang E, et al. The Jarisch-Herxheimer reaction and fetal monitoring changes in pregnant women treated for syphilis. Obstet Gynecol 1998;92:859.

Peeling RW, Hook EW III. The pathogenesis of syphilis: the great mimicker, revisited. J Pathol 2006;208(2):224–232.

Peterman TA, Heffelfinger JD, Swint EB, et al. The changing epidemiology of syphilis. Sex Transm Dis 2005;32 (Suppl 10):S4.

Peterman TA, Zaidi AA, Lieb S, et al. Incubating syphilis in patients treated for gonorrhea: a comparison of treatment regimens. J Infect Dis 1994;170:689.

Radolf JD, Sanchez PJ, Schulz KF, et al. Congenital syphilis. In: Holmes KK, Sparling PF, Mardh PA, et al., eds. Sexually transmitted diseases, 3rd ed. New York: McGraw-Hill; 1999.

Riedner G, Rusizoka M, Todd J, et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med 2005;353(12):1236–1244.

Sparling PE. Natural history of syphilis. In: Holmes KK, Sparling PF, Mardh PA, et al., eds. Sexually transmitted diseases, 3rd ed. New York: McGraw-Hill; 1999.

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Stamm LV. Biology of Treponema pallidum. In: Holmes KK, Sparling PF, Mardh PA, et al., eds. Sexually transmitted diseases, 3rd ed. New York: McGraw-Hill; 1999.

Weiss HA, Thomas SL, Munabi SK, et al. Male circumcision and risk of syphilis, chancroid, and genital herpes: a systematic review and meta-analysis. Sex Transm Infect2005;82(2): 101–109.

Young F. Syphilis: still with us, so watch out! J Fam Health Care 2006;16:77.

Zhou P, Gu Z, Xu J, et al. A study evaluating ceftriaxone as a treatment agent for primary and secondary syphilis in pregnancy. Sex Transm Dis 2005;32(8):495–498.