John L. Phillips, MD, FACS
Dawud Lankford, MD, MPH
BASICS
DESCRIPTION
• “Syphilis” coined by Fracastoro in 1500s
• Describes infection by the spirochete Treponema pallidum, 1st discovered in 1905 by Hoffman
• Primary, secondary, and tertiary forms
• Congenital or acquired
• Often there is an asymptomatic, latent period (serology positive without clinical disease) between forms
EPIDEMIOLOGY
Incidence
• 2011 CDC data
– In US, 55,400 new cases (est.) per year
– 1/3 of new cases primary (P) or secondary (S)
– From 2004 to 2008, rates increased most in 15–20-yr-old men and women
– Rates highest in men who have sex with men (MSM), accounting for 2/3 of primary and secondary cases
– Minorities make up majority of new P & S cases
– Congenital syphilis now more common than perinatal HIV infection (3.4–15.0 times higher in blacks/Hispanics than in whites)
Prevalence
• US (NHNE) (1)
– 0.71% seropositive (SP) in 18–49 yr olds
– 4.1% SP in non-Hispanic blacks
– 0.07% SP in non-Hispanic whites
• China (2) SP rates
– Low-risk groups
Antenatal women (0.45%)
Food & service employees (0.3%)
– High-risk groups
Female sex workers 12.49%
Drug users 6.81%
MSM 14.56%
RISK FACTORS
• Unprotected sex
• Sex with infected partner
• History of other STDs
• High-risk behaviors
– Multiple partners
– Prostitution
– Illicit drug use
– MSM
PATHOPHYSIOLOGY
• Contact inoculation through fluids, in utero; rare dissemination through transfusion
• Incubation 10–90 days
• Primary syphilis
– Chancre: A dry, painless, erosion with raised border (not a true ulcer)
Glans, penile shaft, foreskin
Vulva, cervix
– Regional lymphadenopathy: Painless, nonsuppurating
• Secondary syphilis: Develops 4–10 wk later if primary untreated
– Flu-like symptoms (eg, fatigue, fever, headache)
– Generalized lymphadenopathy
– Generalized eruption
Diffuse, pale, red papules, usually <1 cm
Scaling
Plaques, can be >1 cm
Symmetric on palms, soles of feet, and trunk
– Condyloma lata: Highly infectious, hypertrophic intertriginous genital lesions
• Latent period
– Early <1 yr
– Late >1 yr
– Typically precedes tertiary disease but can take years
• Tertiary syphilis may take 10–20 yr
– Central nervous system involvement: 6–10%
Tabes dorsalis (syphilitic myelopathy); demylenation of dorsal/posterior column of the spinal cord; causes problems with proprioception
Dementia
Seizures
Argyll Robertson pupils (constricting with accommodation but not to light)
– Cardiac Involvement: 10% over 10–30 yr
Aortitis
Aortic aneurysms
Fatal hemorrhage
– Gummatous syphilis: 15% over 45 yr where soft, inflammatory gummas destroy local tissues of:
Bone
Face
Skin
Legs
• Congenital Syphilis: Infection occurs in utero or during vaginal delivery. Nearly 2/3 of neonates asymptomatic but can develop as children:
– Hepatosplenomegaly (75%)
– Fever, chills, rash (50%)
– Pneumonitis (20%)
– Late congenital syphilis (40%)
Saddle nose deformity
Hutchinson teeth (peg-shaped incisors)
Frontal bossing
Higoumenakis sign (unilateral enlargement of sternoclavicular joint)
Painless synovitis (Clutton joints)
Neurosyphilis
ASSOCIATED CONDITIONS
• Other sexually transmitted conditions
– HIV
– Gonorrhea
– Hepatitis B and C
– Chlamydia
GENERAL PREVENTION
• Protected sex
• Early Diagnosis and Treatment
DIAGNOSIS
HISTORY
• Genital lesion
• Risk behavior
• Urethritis, urinary symptoms, burning
• Known history of other STDs
• Drug allergies (which may cause fixed eruptions)
• Vision changes, dyspnea, fever/headache, paresis, neurologic impairment
PHYSICAL EXAM
• Primary syphilis
– Classic painless chancre
Small, solid, raised lesion <1 cm across that becomes a red open sore with a scooped-out appearance. It usually does not bleed
Can be on the genitalia, anus, or mouth
– Painless regional lymph nodes
• Secondary syphilis
– Maculopapular and symmetric rash on trunk, arms, especially soles of feet
– Lymphadenopathy painless
• Tertiary Syphilis
– Hemiparesis
– Tabes dorsalis (ie, decreased proprioception, touch)
– Cardiac murmur
– Pulmonary edema
– Generalized dementia
DIAGNOSTIC TESTS & INTERPRETATION
• Lab: Critical to diagnosis (2,3)
• Indirect tests (ie, measure serologic response to treponemes)
– Non–treponemal-based tests (screening or preliminary)
Rapid, cheap, simple
Can monitor for reinfection
Reduced sensitivity in primary and late disease
False positivity due to cross-reactions
False negatives due to high antibody levels
Examples: Venereal Disease Research Lab (VDRL); rapid plasma reagin (RPR); unheated serum reagin (USR)
– Treponemal-based tests (confirmatory)
Expensive, technically difficult
Fluorescent anti-treponemal antibody absorption (FTA-ABS) (manually read)
Treponema pallidum particle agglutination (TP-PA) (manually read but simpler than FTA-ABS)
Enzyme immunoassay (EIA) (automated, rapid)
Western blot (helps resolve ambiguity)
• Direct tests (ie, measure treponemes or treponemal antigens directly)
– Dark field microscopy of fresh lesion fluid
Simple, reliable
Requires expertise, limited sensitivity
– Fluorescent antibody against T. pallidum
Most specific test when lesions present
False positive for other treponemes (eg, yaws, pinta)
– Nonfluorescent staining (IHC [immunohistochemistry] + H&E)
– PCR amplification (in development)
For congenital and neurosyphilis
Better sensitivity than traditional tests
• Culture: T. pallidum cannot be cultured
Imaging
Chest x-ray (eg, assess cardiac shadow in late syphilis)
Diagnostic Procedures/Surgery
• Serologic indirect testing
• Wound fluid microscopy
• Confirmatory direct testing
• Spinal tap to assess for neurosyphilis
• Biopsy of atypical lesions
Pathologic Findings
• Tertiary syphilis
– Gummas: Nonspecific granulomatous reaction destroying involved tissue
– Cardiac: Endarteritis obliterans of vasa vasorum with consequent aortic aneurysm formation
DIFFERENTIAL DIAGNOSIS
ALERT
Syphilis is often called the “Great Pretender” as it can resemble other diseases.
• Rule out chancroid (painful ulcer and lymphadenopathy)
• Rule out lymphogranuloma venereum (nodes classically suppurate)
• Rule out granuloma inguinale (painless, beefy red raised ulcer, “pseudobubos” without nodes)
• Rule out herpes (usually clusters of vesicles in varying stages, burning pain)
• Annular syphilis can resemble cutaneous sarcoid (especially in African Americans)
• Condyloma lata do not have the digitate elevations seen in viral condyloma acuminata
• Pityriasis rosea may appear like secondary syphilis
• Psoriasis guttate (follow strep infections, drop-like raised plaques)
• Rule out fixed drug reaction (usually itchy)
• Bacterial meningitis
• Stroke
• Multiple sclerosis
TREATMENT
GENERAL MEASURES
• Antibiotic therapy is mainstay
• Serologic monitoring thereafter
• Contact public health service
MEDICATION
First Line
• Penicillin: 2.4 MU Benzathine PCN G IM × 1 (4)
• PCN-allergy: Tetracycline 500 mg PO q6h or doxycycline 100 mg PO q12 × 2 wk
• If pregnant: Ceftriaxone 1 g IM
• Widespread erythromycin resistance noted
Second Line
• Latent cardiovascular syphilis (duration over 1 yr)
– Benzathine PCN G 2.4 MU IM qwk × 3 wk
– If PCN allergic: Tetracycline 500 mg PO QID × 4 wk or doxycycline 100 mg PO bid × 4 wk
SURGERY/OTHER PROCEDURES
Aortic graft replacement has been used for late syphilitic aortic dissection.
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
• Postexposure prophylaxis
– Ceftriaxone 250 mg IM and Doxycycline 100 mg for 14 days
– or Azithromycin (Zithromax) 1 g PO × 1
• Treat partners (chance of infection within 30 days of sex with infected partner is 15–30%)
• Retreatment if titers rise
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Excellent in primary syphilis
• Good in asymptomatic neurosyphilis
• Poor if symptomatic tabes dorsalis
• Syphilic aneuryms can cause death within 6 mo
• 1/3 of patients treated for above have a negative FTA-ABS by 36 mo
COMPLICATIONS
• Jarisch–Herxheimer reaction to treponemolysis after penicillin therapy begun
– In up to 60% with initial therapy; 90% with secondary syphilis
– Minor: Fever, flu-like symptoms, inflammation of affected structures (watch if cardiac involvement)
– Major: Tachycardia, premature labor, transient paralysis (in tertiary syphilis), iritis, aortitis
– Treatment is supportive
Undertreatment and development of late disease
Tabes dorsalis (poor prognosis)
Aortic aneurysm rupture
FOLLOW-UP
Patient Monitoring
• Repeat serologic testing q3mo × 4 then q6mo × 2
• Yearly thereafter
• 4-fold decrease should be seen in 12–24 mo
• Treatment failure: 4-fold increase in titer
– Check CNS/spinal fluid
– Check HIV status
– Retreatment
Patient Resources
• CDC fact sheet. www.cdc.gov/std/syphilis/syphilis-Fact-Sheet.pdf
• NIH fact sheets. www.niaid.nih.gov and type in “syphilis” in search function
REFERENCES
1. Gottlieb SL, Pope V, Sternberg MR, et al. Prevalence of syphilis seroreactivity in the US: Data from the National Health and Nutrition Examination Surveys (NHANES) 2001–2004. Sex Transm Dis. 2008;35:507–511.
2. Lin CC, Gao X, Chen XS, et al. China’s syphilis epidemic: A systematic review of seroprevalence studies. Sex Transm Dis. 2006;33:726–736.
3. Ratnam S. The laboratory diagnosis of syphilis. Can J Infect Dis Med Microbiol. 2005;16(1):45–51.
4. Sexually Transmitted Diseases Treatment Guidelines, 2012 MMWR December 17, 2010/Vol. 59/No. RR-12.
ADDITIONAL READING
James WD, Berger TG, Elston DM. Syphilis, yaws, bejel, and pinta. In: Andrews’ Disease of the Skin: Clinical Dermatology. 11th ed. New York, NY: Elsevier, Inc., 2011.
See Also (Topic, Algorithm, Media)
• Genital ulcers
• Lymphadenopathy, inguinal Sexually Transmitted Infections (STI) (Sexually Transmitted Diseases [STD]), general
• Syphilis Image 
CODES
ICD9
• 091.2 Other primary syphilis
• 091.9 Unspecified secondary syphilis
• 097.9 Syphilis, unspecified
ICD10
• A51.0 Primary genital syphilis
• A51.49 Other secondary syphilitic conditions
• A53.9 Syphilis, unspecified
CLINICAL/SURGICAL PEARLS
• Screen pregnant women for syphilis (USPSTF grade A recommendation).
• Screen people-at-risk for syphilis (USPSTF grade A recommendation).
• Pregnancy is an absolute contraindication for doxycycline or tetracycline.
• Nonpenicillin, Nontetracyline alternatives are inferior to PCN but include ceftriaxone.
• Patients with syphilis, or being screened for syphilis, should be counseled to undergo HIV testing.
• Late syphilis may be asymptomatic.
• Condyloma lata are highly infectious and must be differentiated from HPV-related condyloma acuminate largely on physical exam.