What are the stages, clinical features, diagnosis, and treatment of syphilis?

Syphilis: Stages, Clinical Features, Diagnosis, and Treatment

Stages and Clinical Features

Primary Syphilis

Primary syphilis presents with a painless ulcer (chancre) at the infection site, typically accompanied by regional lymphadenopathy. 1

• The chancre appears as a single painless nodule that rapidly ulcerates at the site of contact 2
• In HIV-infected persons, multiple or atypical chancres may occur, and primary lesions might be absent or missed 2, 1
• Regional lymph node swelling is characteristically indolent and associated with the chancre 3
• The primary stage is highly infectious 4

Secondary Syphilis

Secondary syphilis develops 2-8 weeks after primary inoculation and involves virtually all organ systems. 2

• Most common manifestations include macular, maculopapular, papulosquamous, or pustular skin lesions that begin on the trunk and spread peripherally, characteristically involving palms and soles 2
• Generalized lymphadenopathy accompanies the rash 2
• Constitutional symptoms include fever, malaise, anorexia, arthralgias, and headache 2
• Condylomata lata (moist, flat papular lesions in warm intertriginous regions) may resemble papillomavirus infection 2
• Mucous patches in the oral cavity and specific angina are prominent signs 3
• Secondary syphilis can mimic acute primary HIV infection with constitutional symptoms and CSF abnormalities 2, 1
• This stage is highly infectious 4
• Symptoms persist from days to several weeks before resolving 2

Latent Syphilis

Latent syphilis is characterized by positive serologic tests without clinical manifestations. 1

• Early latent syphilis is defined as infection acquired within the preceding 12 months 2
• Late latent syphilis refers to infection acquired more than 1 year previously 2
• Relapse of secondary manifestations may occur, most commonly during the first 1-4 years following infection 2

Tertiary (Late) Syphilis

Tertiary syphilis occurs in approximately 25% of untreated patients after 3-12 years of latency. 1

• Gummatous syphilis: Granulomatous lesions (gummas) can affect skin, bones, and other organs 2, 3
• Cardiovascular syphilis: Inflammatory lesions of the cardiovascular system 2
• Neurosyphilis: Can occur at any stage but is a hallmark of late disease 2
• Late manifestations typically become clinically apparent 15-30 years after untreated infection 2

Neurosyphilis

Neurosyphilis can occur at any stage of syphilis and requires specific diagnostic evaluation. 2

• Asymptomatic neurosyphilis: CSF abnormalities (elevated protein, lymphocytic pleocytosis, or positive VDRL-CSF) without symptoms 2
• Symptomatic neurosyphilis: Manifestations include meningitis, meningovascular disease, parenchymatous disease, concomitant uveitis, cranial nerve palsies, and optic neuropathies 2, 5
• HIV-infected persons may have more common manifestations such as concomitant uveitis and meningitis 2

Diagnosis

Direct Detection Methods

Darkfield examination and direct fluorescent antibody tests of lesion exudate or tissue are the definitive methods for diagnosing early syphilis. 2, 1

• These methods provide direct visualization of Treponema pallidum 2
• HIV infection does not decrease the sensitivity or specificity of darkfield microscopy 2
• Biopsy with silver stain can also demonstrate organisms 2

Serologic Testing

Diagnosis requires both nontreponemal and treponemal serologic tests; using only one type is insufficient. 2

Nontreponemal Tests

• Include VDRL (Venereal Disease Research Laboratory) and RPR (Rapid Plasma Reagin) 2, 1
• Antibody titers correlate with disease activity and should be reported quantitatively 2
• A fourfold change in titer (equivalent to two dilutions, e.g., 1:16 to 1:4) is necessary to demonstrate clinically significant difference 2, 1
• Expected to become nonreactive after treatment, though some patients remain "serofast" at low titers 2
• False-positive results may occur and must be confirmed with treponemal tests 2

Treponemal Tests

• Include FTA-ABS (Fluorescent Treponemal Antibody Absorbed) and MHA-TP (Microhemagglutination Assay for Antibody to T. pallidum) 2
• Most patients remain reactive for life regardless of treatment 2, 1
• 15-25% of patients treated during primary stage may revert to nonreactive after 2-3 years 2
• Titers correlate poorly with disease activity and should not be used to assess treatment response 2

Testing Algorithm

• Traditional approach: Screen with nontreponemal tests, confirm reactive results with treponemal tests 2
• Some laboratories use reverse algorithm: Screen with treponemal EIA, confirm with nontreponemal testing 2

Neurosyphilis Diagnosis

Neurosyphilis diagnosis requires CSF examination and cannot be made with a single test. 2

• Reactive VDRL-CSF (RPR is not performed on CSF) is diagnostic when combined with reactive serologic tests 2
• CSF abnormalities include elevated protein, lymphocytic pleocytosis 2
• Probable neurosyphilis: Negative VDRL-CSF but elevated CSF protein or leukocyte count with clinical symptoms consistent with neurosyphilis 2

Special Considerations in HIV

• HIV-infected patients may have atypical serologic responses (unusually high, low, or fluctuating titers) 2
• Consider additional tests (biopsy, direct microscopy) in HIV patients with abnormal serologic results 2
• Serologic tests remain accurate and reliable for the vast majority of HIV-infected patients 2
• All patients with syphilis should be tested for HIV 1, 6

Treatment

Primary and Secondary Syphilis

Benzathine penicillin G 2.4 million units IM as a single dose is the recommended treatment for primary and secondary syphilis. 1, 6

Alternative for Penicillin-Allergic Patients

• Doxycycline 100 mg orally twice daily for 14 days 1
• Pregnant women who are penicillin-allergic must be desensitized and treated with penicillin, as it is the only effective option 1

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 at 1-week intervals. 1, 6

• Alternative for penicillin-allergic non-pregnant patients: Doxycycline 100 mg orally twice daily for 28 days 1

Neurosyphilis

Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours) for 10-14 days. 1

• Penicillin-allergic patients with neurosyphilis must be desensitized and treated with penicillin 1
• All patients with ocular syphilis should be evaluated and treated for neurosyphilis 5

Important Treatment Considerations

• Penicillin remains the only proven effective treatment for neurosyphilis and syphilis in pregnancy 1
• Macrolide resistance has emerged, essentially precluding empirical use of azithromycin 4
• Jarisch-Herxheimer reaction (acute febrile reaction with headache and myalgia) may occur within 24 hours after any therapy for syphilis 1

Follow-Up and Treatment Response

Monitoring

Quantitative nontreponemal tests should be repeated at 3,6,12, and 24 months after treatment. 1

• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis 1
• Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 1

Special Populations

• HIV-infected patients may have more apparent clinical lesions and accelerated disease progression 2, 1
• HIV-positive patients require closer follow-up with repeat quantitative nontreponemal tests 6
• Early syphilis in HIV-infected persons may cause transient decrease in CD4+ count and increase in HIV viral load that improves with standard treatment 2

Partner Management

All sexual partners exposed within 90 days before diagnosis should be treated presumptively, even if seronegative. 6

• Partners should be examined, tested, and treated if they had sexual contact during the 30 days preceding onset of symptoms 2

Prevention Strategies

• Screen sexually active people aged 15-44 years at least once, and at least annually for those at increased risk 7
• Screen pregnant individuals 3 times: at first prenatal visit, during third trimester, and at delivery 7
• Counsel about condom use 7
• Offer doxycycline postexposure prophylaxis (200 mg within 72 hours after sex) to men who have sex with men and transgender women with history of STI in past year 7