para>In noncongenital cases, consider child abuse. é á
Pregnancy Considerations
All pregnant patients should be screened with VDRL or rapid plasma reagin (RPR) test early in pregnancy. If high exposure risk, repeat at 28 weeks and at delivery (1,2)[A].
The same nontreponemal test used for initial screening should be used for follow-up (1,2)[A].
é á
EPIDEMIOLOGY
Incidence
- Syphilis rate decreased until 2000. Has increased (primarily in men) since then (3)[A]
- In 2013: 5.3/100,000. Highest for men aged 25 to 29 years and women aged 20 to 24 years (3)[A]
- Men: 9.8/100,000
- Women: 0.9/100,000
- Congenital: 8.7 cases/100,000 live births (4)[A]
- Race/ethnicity (3)[A]
- Male (per 100,000 population)
- White, non-Hispanic: 5.4
- Black, non-Hispanic: 27.9
- Hispanic: 11.6
- Asian/Pacific Islander: 4.6
- American Indian/Alaska native: 4.7
- Female (per 100,000 population)
- White, non-Hispanic: 0.3
- Black, non-Hispanic: 4.0
- Hispanic: 0.8
- Asian/Pacific Islander: 0.2
- American Indian/Alaska native: 1.0
Prevalence
- Predominant sex: male (91%) > female (9%) (3)[A]
- Greatest increase in men having sex with men (MSM) (3)[A]
ETIOLOGY AND PATHOPHYSIOLOGY
T. pallidum subspecies pallidum, spirochete: Can enter through intact mucous membranes or breaks in skin. Highly infectious; exposure to as few as 60 spirochetes is associated with ó ł ╝50% chance of infection. é á
RISK FACTORS
MSM, multiple sexual partners, exposure to infected body fluids, IV drug use, transplacental transmission, adult inmates, high-risk sexual behavior, HIV positive é á
GENERAL PREVENTION
Education regarding safe sex; condoms reduce but do not eliminate transmission (5)[A] é á
COMMONLY ASSOCIATED CONDITIONS
HIV infection, hepatitis B, other STIs é á
DIAGNOSIS
HISTORY
- Previous sexual contact with partner with known infection or high-risk sexual behavior
- Genital lesions (chancre " öprimary syphilis)
- Rash, alopecia, malaise, headache, anorexia, nausea, fatigue (secondary syphilis)
- Mental status changes (tertiary syphilis)
PHYSICAL EXAM
Signs/symptoms depend on stage é á
- Primary: single (occasionally multiple), usually painless ulcer (chancre) in groin or at other point of entry. Regional adenopathy.
- Secondary
- Rash: skin/mucous membranes
- Rough, red-brown macules, usually on palms and soles
- May appear with chancre or after it has healed
- Condyloma lata
- Alopecia
- Nonspecific symptoms: fever, adenopathy, malaise, headache, hair loss
- Tertiary
- Focal neurologic findings (hearing loss, visual loss)
- Gummas (skin, mucous membranes, other organ systems)
DIFFERENTIAL DIAGNOSIS
- Primary: chancroid, lymphogranuloma venereum, granuloma inguinale, condyloma acuminata, herpes simplex, Beh â žet syndrome, trauma, carcinoma, mycotic infection, lichen planus, psoriasis, fungal infection
- Secondary: pityriasis rosea, drug eruption, psoriasis, lichen planus, viral exanthema, Stevens-Johnson syndrome
- Positive serology, asymptomatic: previously treated syphilis/other spirochetal disease (yaws, pinta)
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Dark-field microscopy demonstrating T. pallidum spirochetes in lesion exudate/tissue biopsy: gold standard but difficult and not very sensitive (6)[A]
- Nontreponemal tests (VDRL/RPR) (3,6)[A]
- Primary screening test: positive within 7 days of exposure
- Nonspecific, false-positive results common; must confirm diagnosis with treponemal tests
- Positive test should be quantified and titers followed regularly after treatment.
- Titers usually correlate with disease activity; 4-fold change is clinically significant.
- Titers decrease with time/treatment; following adequate treatment for primary/secondary disease, a 4-fold decline is typically seen after 6 to 12 months.
- Absence of a 4-fold decline suggests potential treatment failure.
- ó ł ╝15% of appropriately treated patients do not have a 4-fold decline in titer 12 months after treatment. Management is unclear, repeat HIV testing and/or CSF examination and continue to follow titers.
- With appropriate treatment, titers should become negative (see Serofast reaction).
- Titers of patients treated in latent stages decline more gradually.
- Prozone phenomenon: negative results from high titers of antibody; test with diluted serum
- Serofast reaction: persistently positive results years after successful treatment; new infection diagnosed by 4-fold rise in titer
- Conditions that may alter treponemal testing (all stages of syphilis can have a false-negative RPR result, especially in primary syphilis)
- Pregnancy, autoimmune disease, mononucleosis, malaria, leprosy, viral pneumonia, cardiolipin antigens, injection drug use, acute febrile illness, HIV infection; elderly can have false-positive results.
- Treponemal tests (confirmatory test after positive nontreponemal screening test): FTA-ABS, TP-PA (T. pallidum particle agglutination) (6)[A]:
- Confirmatory test; not used for screening
- Usually positive for life after treatment
- Titers of no benefit
- 15 " ô25% of patients treated during primary stage revert to serologic nonreactivity after 2 to 3 years.
- Lumbar puncture indicated for (6)[A]:
- Neurologic, ocular, or auditory manifestations
- Some experts advise in all secondary and early latent cases " öeven without neurologic symptoms
- HIV-positive patients with late latent/latent of unknown duration
- In patients with late latent/latent of unknown duration if nonpenicillin therapy planned
- In treatment failures
- If other evidence of active tertiary syphilis is present (e.g., aortitis, gumma, iritis)
- In children to rule out neurosyphilis
- VDRL, not RPR, used on CSF; may be negative in neurosyphilis; highly specific but insensitive
- Send CSF for protein, glucose, and cell count.
- Monitor resolution by cell count at 6 months along with serologies (see "Patient Monitoring " Ł).
- Negative FTA-ABS or microhemagglutination (MHA)-TP on CSF excludes neurosyphilis (highly sensitive).
- Positive FTA-ABS or MHA-TP on CSF is not diagnostic because of high false-positive rate.
- Traumatic tap, tuberculosis (TB), pyogenic/aseptic meningitis can all result in false-positive VDRL.
TREATMENT
GENERAL MEASURES
- Advise patients to avoid intercourse until treatment is complete, and notify partners (6)[A].
- Test for HIV (3,6)[A].
- Management of sexual contacts (6)[A]
- Presumptively treat partners exposed within 90 days of diagnosis.
- Treat those exposed >90 days before diagnosis presumptively if serologic results are not available immediately and follow-up is uncertain.
- Presumptively treat those exposed to a patient diagnosed with syphilis of unknown duration who have high treponemal titers (>1:32).
- Long-term sex partners of patients with latent infection should be evaluated clinically and serologically and treated accordingly.
MEDICATION
ALERT
Bicillin L-A should be used instead of Bicillin C-R (combination benzathine " ôprocaine penicillin) when penicillin G benzathine is indicated.
é á
First Line
Parenteral penicillin G is the drug of choice. The particular formulation is determined by the disease stage and clinical presentation. é á
- Primary, secondary, and early latent <1 year (6)[A]
- Benzathine penicillin G 2.4 million U IM â Ś 1 dose
- Penicillin-allergic patients: doxycycline 100 mg PO BID for 2 weeks, or tetracycline 500 mg PO QID for 2 weeks, or ceftriaxone 1 to 2 g IM or IV daily for 10 to 14 days
- Azithromycin 2 g PO â Ś 1 dose (early syphilis only; should not be used in HIV, MSM, or pregnancy)
- Resistance and treatment failures have been noted in several U.S. regions.
- Late latent/latent of unknown duration and tertiary without evidence of neurosyphilis (6)[A]
- Benzathine penicillin G 2.4 million U IM weekly â Ś 3 doses
- Penicillin-allergic patients: Attempt desensitization and treatment with penicillin or doxycycline 100 mg PO 2 BID for 28 days, or tetracycline 500 mg PO QID for 28 days; compliance may be an issue.
- Ocular or neurosyphilis (6)[A]
- Aqueous crystalline penicillin G 3 to 4 million U IV q4h as continuous infusion for 10 to 14 days
- Alternative: Procaine penicillin G 2.4 million U IM daily in conjunction with probenecid 500 mg PO QID â Ś 10 to 14 days (if compliance can be ensured)
- Penicillin-allergic patients: Attempt desensitization and treat with penicillin; ceftriaxone 2 g/day IM or IV for 10 to 14 days.
- If late latent, latent of unknown duration, or tertiary in addition to neurosyphilis, consider also treating as recommended for late latent after completion of neurosyphilis treatment.
- Congenital (6)[A]
- Aqueous crystalline penicillin G 50,000 U/kg/dose IV q12h for the first 7 days of life and q8h thereafter for a total of 10 days, or procaine penicillin G 50,000 U/kg/dose IM daily for 10 days
- If negative CSF serologies, normal physical exam, and titer: Maternal titer, then 50,000 U/kg benzathine penicillin G IM in single dose is also an alternative.
- If >1 day of drug is missed, restart course.
- Children (after newborn period): aqueous crystalline penicillin G 50,000 U/kg/dose IV q4 " ô6h for 10 days; late latent, 50,000 U/kg IM as 3 doses at 1-week intervals
- For contacts without symptoms: Treat as primary after serologies are obtained.
- HIV-infected and pregnant patients may show poor response to recommended IM doses. Use IV therapy for all treatment failures in these patients.
- Do not give benzathine or procaine penicillins IV.
- Children (after newborn period) (6)[A]: aqueous crystalline penicillin G 50,000 U/kg/dose IV q4 " ô6h â Ś 10 days; late latent, 50,000 U/kg IM as three doses at 1-week intervals
- Pregnancy (6)[A]
- Treatment is the same as for nonpregnant patients
- Some recommend 2nd dose of 2.4 million units benzathine penicillin G 1 week after initial dose in 3rd trimester or with primary, secondary, or early latent syphilis.
- Penicillin sensitivity: No proven alternatives to penicillin available for treatment during pregnancy.
- Penicillin-allergic patients: Desensitize and treat with penicillin.
- HIV-infected pregnant patients may show poor response to recommended IM doses. Use IV therapy for all treatment failures in these patients.
- Treat contacts without symptoms as primary after serologies.
- History of penicillin allergy:
- Confirmed IgE-mediated reaction: desensitization
- Questionable history of IgE-mediated hypersensitivity: penicillin skin testing if major and minor penicillin determinants available
- Precautions (6)[A]
- HIV-infected and pregnant patients may show poor response to recommended IM doses. Use IV therapy for all treatment failures in these patients.
- Do not give benzathine or procaine penicillins IV.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Clinical and serologic evaluation between 6 and 12 months after treatment; if >1 year duration, check at 24 months (6)[A]
- In HIV-infected persons, clinical and serologic evaluation at 3, 6, 9, 12, and 24 months after therapy (6)[A]
Patient Monitoring
- Use VDRL or RPR test to monitor therapy: 4-fold rise (two dilutions) in titer indicates new infection, whereas failure to decrease 4-fold (two dilutions) in 6 to 12 months may indicate treatment failure (although definitive criteria for cure not established); always use same test (preferably same lab) for initial screening (6)[A].
- Strongly consider retreatment for persistent clinical signs or recurrence, 4-fold rise in titers, or failure of initially high titer to decrease 4-fold by 6 to 12 months.
- Neurosyphilis: repeat lumbar puncture every 6 months to check for normalization of CSF cell count ( é ▒ CSF-VDRL and protein evaluation) (6)[A]
PATIENT EDUCATION
No intimate contacts until 4-fold titer drop é á
PROGNOSIS
- Excellent in all cases except patients with late syphilis complications and with HIV infection
- Syphilis in HIV-infected patient
- Treatment same as for HIV-negative patients
- More often false-negative treponemal and nontreponemal tests or unusually high titers
- Response to therapy less predictable
- Early syphilis: increased risk of neurosyphilis and higher rates of treatment failure
- Late neurosyphilis: harder to treat; can occur up to 20+ years after infection
COMPLICATIONS
- Membranous glomerulonephritis
- Paroxysmal cold hemoglobinemia
- Meningitis and tabes dorsalis
- Cardiovascular aneurysms; valvular damage
- Irreversible organ damage
- Jarisch-Herxheimer reaction
- Fever, chills, headache, myalgias, new rash
- Common when starting treatment (of primary/secondary disease; less common with tertiary) owing to lysis of treponemes
- Should not be confused with drug reaction
- Managed with analgesics and antipyretics
REFERENCES
11 Gomez é áGB, Kamb é áML, Newman é áLM, et al. Untreated maternal syphilis and adverse outcomes of pregnancy: a systematic review and meta-analysis. Bull World Health Organ. 2013;91(3):217 " ô226.22 U.S. Preventive Services Task Force. Screening for syphilis infection in pregnancy: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med. 2009;150(10):705 " ô709.33 Patton é áME, Su é áJR, Nelson é áR, et al. Primary and secondary syphilis " öUnited States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2014;63(18):402 " ô406.44 Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2012. Atlanta, GA: U.S. Department of Health and Human Services; 2013.55 Koss é áCA, Dunne é áEF, Warner é áL. A systematic review of epidemiologic studies assessing condom use and risk of syphilis. Sex Transm Dis. 2009;36(7):401 " ô405.66 Workowski é áKA, Berman é áS. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59(RR-12):1 " ô110.
SEE ALSO
Chlamydia Infection (Sexually Transmitted); Gonococcal Infections é á
CODES
ICD10
- A53.9 Syphilis, unspecified
- A51.0 Primary genital syphilis
- A53.0 Latent syphilis, unspecified as early or late
- A51.5 Early syphilis, latent
- A52.9 Late syphilis, unspecified
- A51.49 Other secondary syphilitic conditions
- A52.3 Neurosyphilis, unspecified
ICD9
- 097.9 Syphilis, unspecified
- 091.2 Other primary syphilis
- 097.1 Latent syphilis, unspecified
- 092.9 Early syphilis, latent, unspecified
- 097.0 Late syphilis, unspecified
- 091.9 Unspecified secondary syphilis
- 094.9 Neurosyphilis, unspecified
SNOMED
- 76272004 Syphilis (disorder)
- 266127002 Primary syphilis (disorder)
- 444150000 Latent syphilis (disorder)
- 186867005 Latent early syphilis (disorder)
- 26039008 Neurosyphilis (disorder)
- 240557004 Secondary syphilis (disorder)
- 72083004 Late syphilis (disorder)
CLINICAL PEARLS
- Screen all HIV-positive patients and patients with high-risk sexual behaviors for syphilis.
- Penicillin remains the treatment of choice for syphilis.
- Syphilis rates are rising " öparticularly among MSM.