Treponema pallidum - Syphilis

Key Points

Treponema pallidum cannot be cultured. Ideally, early syphilis could be diagnosed by direct detection methods, such as darkfield examination, but these methods are often not available and may miss up to 30% of primary cases.  Therefore, syphilis is usually diagnosed with serologic tests.

Traditional serologic screening for syphilis uses nontreponemal testing initially with confirmation of reactive results using a treponemal test.  New “reverse algorithms” are gaining popularity due to the development of point-of-care CIA/EIA tests. Reverse algorithms use treponemal testing initially (usually EIA or CIA) with confirmation of reactive results using a nontreponemal test.

  • Traditional versus reverse algorithm syphilis testing pros and cons (see table below)

Traditional versus Reverse Algorithm Syphilis Testing (Pros and Cons)
 

Traditional testing

Begins with nontreponemal testing (quantitative)

Reverse testing

Begins with treponemal testing (qualitative)

Pros
  • Detects active infection
  • Use of nontreponemal testing followed by treponemal test for confirmation results in a high positive predictive value
  • Inexpensive and rapid
  • Detects early primary and treated infection that might be missed with traditional algorithm
  • Automated with low costs if used in high volume settings
  • No  false negatives as a result of prozone reaction
Cons
  • Reactivity declines over time
  • Often misses early primary or treated infection
  • Moderately high rate of false positives for initial nontreponemal tests
    • Reactive test requires confirmation with treponemal tests
  • Reactivity lasts over a lifetime
    • Cannot detect active versus previously treated infection
    • Follow up nontreponemal test required for all reactive tests to detect active infection
  • Highly sensitive, not highly specific
    • In low risk populations, frequent false positive testing (initial reactive treponemal with negative confirmatory nontreponemal test) – requires confirmation with 2nd treponemal test
Source: http://www.cdc.gov/std/syphilis/Syphilis-Webinar-Slides.pdf
  • Nontreponemal and treponemal tests (see table below)

Nontreponemal and Treponemal Tests
Nontreponemal Tests (Quantitative)ARUP Tests Available
  • Rapid plasma reagin (RPR)
  • Venereal disease research laboratory (VDRL)
  • Toluidine red unheated serum test (TRUST)

Rapid Plasma Reagin (RPR) with Reflex to Titer and TP-PA Confirmation 0050478

Rapid Plasma Reagin (RPR) with Reflex to RPR Titer or T. pallidum Antibody by Particle Agglutination 2007443

Rapid Plasma Reagin (RPR) with Reflex to Titer 0050471

Treponema pallidum (VDRL), Serum with Reflex to Titer 0093093

Treponemal Tests (Qualitative/Semi-Quantitative)ARUP Tests Available
  • Chemiluminescence Immunoassays (CIAs)
  • Enzyme Immunoassays (EIAs)
  • Treponema pallidum Article Agglutination (TP-PA)
  • Fluorescent Treponemal Antibody Absorbed (FTA-ABS)
  • Microbead Immunoassays (MBIAs)

Treponema pallidum Antibody by TP-PA 0050777

Treponema pallidum Antibody, IgM by ELISA 0050921

Treponema pallidum Antibody, IgG by Immunoblot 2003095

Treponema pallidum Antibody, IgG by ELISA 0050920

Diagnosis

Indications for Testing

  • Suspicion of syphilis (classic lesions, known exposure, high-risk behaviors)
    • Concurrent STI testing

Laboratory Testing

  • Traditional and reverse sequence syphilis screening overview (CDC)
  • Darkfield exam only if chancre (primary) or condylomata lata (secondary) present
  • Refer to Key Points section for treponemal and nontreponemal testing comparisons
  • Neurosyphilis
    • In suspected cases, order VDRL on cerebrospinal fluid (CSF) with concurrent RPR serum
    • If RPR is negative and a high index of suspicion for neurosyphilis remains, perform FTA-ABS on serum
      • Some patients have nonreactive nontreponemal tests in late neurosyphilis
    • CNS is usually the affected site in an HIV patient
  • For further testing recommendations, see the Syphilis Testing Algorithm

Differential Diagnosis

Screening

  • All pregnant females should be screened at initial prenatal visit using VDRL or RPR (traditional testing algorithm)
    • Follow positive results with FTA-ABS or TP-PA testing (USPSTF, ACOG, CDC, AAFP recommendations)
    • STI screening recommendations for pregnant women

      STI Screening Recommendations for Pregnant Women

      STI

      USPSTF

      CDC

      AAFP

      ACOG

      Chlamydia

      Screen women <25 years and others at increased risk*

      Screen all sexually active females ≤25 years and those >25 who are at risk**

      Screen women ≤25 years and others at increased risk*

      Screen women at increased risk***

      Gonorrhea

      Screen women <25 years and others at increased risk*

      Screen women at increased risk**

      Screen women at increased risk*

      Screen women at increased risk***

      Syphilis

      Screen all

      Screen all

      Screen all

      Screen all

      HIV

      Screen all

      Screen all

      Screen all

      Screen all

      Hepatitis B

      Screen all

      Screen all

      Screen all

      Screen all

      Hepatitis C

      No specific recommendation

      Screen women at increased risk**

      No specific recommendation

      Screen women at increased risk***

      HSV

      Do not screen asymptomatic patients

      No specific recommendation

      Do not screen general population

      No specific recommendation

      HPV

      No specific recommendation

      No specific recommendation

      No specific recommendation

      No specific recommendation

      Bacterial vaginosisDo not screen for low-risk patients; insufficient evidence to recommend screening in patients at high risk for preterm deliveryNo specific recommendationDo not screen for low-risk patients; insufficient evidence to recommend screening in patients at high risk for preterm deliveryNo specific recommendation

      STI = sexually transmitted infection; USPSTF = U.S. Preventive Services Task Force; CDC = Centers for Disease Control and Prevention; AAFP = American Academy of Family Physicians; ACOG = American College of Obstetricians and Gynecologists; HIV = human immunodeficiency virus; HSV = herpes simplex virus; HPV = human papillomavirus; Pap = Papanicolaou

      * At risk = new or multiple partners; diagnosis of gonorrhea or chlamydia within the last 12 months; those not consistently using barrier methods; those having sex under the influence of drugs

      ** Increased risk = defined as <25 years with inconsistent condom use; history of other STIs; multiple sex partners or drug use

      *** High-risk factors = history of multiple sexual partners or a sexual partner with multiple contacts; sexual contact with individuals with a culture-proven STI; history of repeated episodes of STIs; attendance at clinics for STIs

  • Screen all females at increased risk
    • STI screening recommendations for sexually active nonpregnant women

      STI Screening Recommendations for Sexually Active Nonpregnant Women

      STI

      USPSTF

      CDC

      AAFP

      ACOG

      Chlamydia

      Yearly screening – screen women <25 years and others at increased risk*

      Do not screen women >25 years and not at high risk

      Screen women ≤25 years and others at increased risk***

      Screen women ≤25 years and others at increased risk*

      Screen women ≤25 years and others at increased risk****

      Gonorrhea

      Screen women <25 years and others at increased risk*

      No recommendation for or against screening women not at risk and >25 years

      Screen women at increased risk***

      Do not screen general population

      Screen women <25 years and others at increased risk*

      Screen adolescents and others at increased risk****

      Syphilis

      Screen women at increased risk**

      Screen women exposed to syphilis

      Screen women at increased risk*

      Screen women at increased risk****

      HIV

      Screen women at increased risk*

      Screen all patients 13-64 years regardless of risk factors

      Screen women at increased risk*

      Screen women at increased risk****

      Hepatitis B

      Do not screen general population

      Provide prevaccination screening for women at increased risk***

      Do not screen general population

      No specific recommendation

      Hepatitis C

      Do not screen general population; insufficient evidence to recommend for or against screening women at increased risk

      Screen women at increased risk***

      Do not screen general population

      Do not screen general population; insufficient evidence to recommend for or against screening women at increased risk*

      Screen women at increased risk****

      HSV

      Do not screen asymptomatic patients

      Do not screen general population

      Do not screen general population

      Screen if sexual partner has HSV

      HPV

      Insufficient evidence to use as primary screening test for cervical cancer

      Do not screen for subclinical infection

      Insufficient evidence to use as primary screening test for cervical cancer

      Testing with a Pap smear is an option for women >30 years

      Bacterial vaginosisDo not screenNo recommendationNo specific recommendationsNo specific recommendations

      STI = sexually transmitted infection; USPSTF = U.S. Preventive Services Task Force; CDC = Centers for Disease Control and Prevention; AAFP = American Academy of Family Physicians; ACOG = American College of Obstetricians and Gynecologists; HIV = human immunodeficiency virus; HSV = herpes simplex virus; HPV = human papillomavirus; Pap = Papanicolaou

      * At risk = new or multiple partners; diagnosis of gonorrhea or chlamydia within the last 12 months; those not consistently using barrier methods; those having sex under the influence of drugs

      ** Commercial sex workers; persons who exchange drugs for sex; incarceration in adult correctional facility; multiple sex partners

      *** Increased risk defined as <25 years with inconsistent condom use; history of other STIs; multiple sex partners or drug use

      **** High-risk factors = history of multiple sexual partners or a sexual partner with multiple contacts; sexual contact with individuals with a culture-proven STI; history of repeated episodes of STIs; attendance at clinics for STIs

  • HIV/syphilis cotesting
    • Patient with newly diagnosed HIV should have syphilis testing, and patient with newly diagnosed syphilis should have HIV testing
    • If patient has a negative test but continues to engage in risk behavior, retest in 3-12 months
  • Syphilis screening recommendations for men
    • USPSTF
      • No screening if not engaging in high-risk behaviors
      • If engaging in high-risk behaviors, screen for syphilis and HIV
    • CDC
      • Screen all men for HIV who seek medical care
      • Men who have sex with men are at risk – test for rectal and urethral gonorrhea and pharyngeal chlamydia annually

Monitoring

  • Treatment follow-up
    • Nontreponemal tests  measure IgM and IgG antibodies; best for monitoring treatment or for testing for reinfection 
      • Positive titers are used to follow response to therapy for infected patients
      • Rapid plasma reagin (RPR) for serum
    • In CNS disease – CSF titers with VDRL 
      • Titers should decrease with effective treatment

Clinical Background

Treponema pallidum subspecies pallidum is the causative agent of syphilis, a sexually transmitted infection (STI).

Epidemiology

  • Incidence
    • 2-5/100,000
    • Varies by region
    • Incidence has increased in last 5-10 years
  • Age – peaks in teens to late 20s
  • Transmission    
    • Sexual contact
    • Maternal vertical transmission

Organism

  • T. pallidum subspecies pallidum is a member of the Spirochaetales family that causes syphilis and is distinct from the subspecies causing yaws (T. pallidum subspecies pertenue), pinta (T. pallidum subspecies carateum), and endemic syphilis (T. pallidum subspecies endemicum)
  • The Spirochaetales family also includes the following

Risk Factors for Syphilis

  • Early age at onset of sexual activity
  • HIV infection
  • Gonorrhea infection
  • Multiple sex partners
  • Non-Caucasian race
  • Nonuse of barrier methods of birth control
  • Previous history of STI

Clinical Presentation

  • Primary syphilis
    • Incubation – 2-3 weeks
    • Painless chancre at site of inoculation – may persist 3-6 weeks
    • Local nontender adenopathy is frequent
    Secondary syphilis
    • Incubation – 6-8 weeks
    • Two types
      • Latent and early latent <1 year infection – patient remains infectious
      • Late latent ≥1 year infection – patient thought to be noninfectious
    • Diffuse lymphadenopathy
    • Mucocutaneous lesions (condyloma lata) – coalescence in genital regions
    • Macular skin rash (frequently involves palms and soles)
    • Widespread syphilitic vasculitis (~10% of cases)
      • Meningitis (rare)
      • Hepatitis
      • Nephritis
      • Iritis
      • Cranial nerve involvement (most commonly, eighth nerve deafness)
    Tertiary (late) syphilis
    • Incubation – 5-15 years
    • 15-40% of untreated patients develop disease
    • Cardiovascular – aortitis, aneurysm, aortic valvular incompetence
    • Gummatous syphilis – granulomatous, nodular lesions in organs (most commonly skin and bones)
    • Neurologic – general paresis, tabes dorsalis
    Congenital syphilis
    • Can occur during all stages of maternal syphilis – usually in first 2 years of infection
      • Two-thirds of babies born without infection
      • One-third born with congenital syphilis
      • One-third result in miscarriage or stillbirth
    • Typed according to age at diagnosis
      • Early (<2 years, untreated)
        • Snuffles
        • Rash
        • Condyloma lata
        • Bone changes
        • Hepatosplenomegaly
        • Jaundice
        • Anemia
      • Late (>2 years, untreated)
        • Eighth-nerve deafness
        • Arthropathy (Clutton joints)
        • Neurosyphilis
        • Keratitis
      • Residual stigmata
        • Hutchinson teeth
        • Mulberry molars
        • Saddle nose
        • Saber shin
        • Rhagades scars
    Central nervous system (CNS) manifestations
    • May occur at any stage
    • Symptomatic forms
      • Meningeal syphilis (usually <1 year after primary infection)
        • Involves the brain or spinal cord
        • Symptoms include headache, stiff neck
      • Meningovascular syphilis (usually 5-10 years after primary infection)
        • Inflammation of pia and arachnoid, with focal arteritis
        • Stroke syndrome involving middle cerebral artery is common in young adults
      • Parenchymatous (late syphilis)
        • General PARESIS (acronym for Personality, Affect; Reflexes, Eye [Argyll Robertson pupil], Sensorium, Intellect, Speech)
        • Tabes dorsalis – demyelination of posterior columns, dorsal roots and dorsal root ganglia
          • Results in weakness, paresthesias, ataxia, dementia, personality changes, decreased reflexes
          • Characterized by wide-based gait and bladder symptoms
          • Optic atrophy (Argyll Robertson pupil) frequently associated with tabes dorsalis
        • Charcot joints – trophic joint degeneration
    • May also be asymptomatic
    Coinfection with HIV
    • Primary syphilis – multiple, large, painful ulcers
    • Secondary syphilis – genital ulcers more common
    • Tertiary syphilis – possibly more rapid progression to neurosyphilis

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Rapid Plasma Reagin (RPR) with Reflex to Titer and TP-PA Confirmation 0050478
Method: Semi-Quantitative Charcoal Agglutination/Semi-Quantitative Particle Agglutination

CDC recommended test for the screening and diagnosis of syphilis

Reactive results reflex to titer and treponemal test (TP-PA) for confirmation

   
Rapid Plasma Reagin (RPR) with Reflex to Titer 0050471
Method: Semi-Quantitative Charcoal Agglutination

Order to screen for syphilis; for initial diagnosis, reactive results should be confirmed with a treponemal test (eg, TP-PA)

Use to confirm reactive treponemal test (eg, CIA, EIA) if using so-called reverse algorithm testing

Preferred test for monitoring treatment response in established syphilis

False positives may be caused by HIV, herpes simplex virus (HSV), malaria, intravenous drug use (IVDU), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), pregnancy, leprosy, endemic treponematoses

 
Treponema pallidum (VDRL), Serum with Reflex to Titer 0093093
Method: Semi-Quantitative Flocculation

Acceptable initial screening test for syphilis

May use to confirm reactive treponemal test (eg, EIA, CIA) if using so-called reverse algorithm testing

Acceptable test for monitoring treatment response in established syphilis

Use rapid plasma reagin (RPR) preferentially to decrease false-positive rate

False positives may be caused by HIV, HSV, malaria, IVDU, SLE, RA, pregnancy, leprosy, endemic treponematoses

 
Rapid Plasma Reagin (RPR) with Reflex to RPR Titer or T. pallidum Antibody by Particle Agglutination  2007443
Method: Semi-Quantitative Charcoal Agglutination/Semi-Quantitative Particle Agglutination

Order to confirm a reactive treponemal screening test (eg, CIA, EIA) when using the reverse testing algorithm to screen for syphilis

For traditional CDC recommended algorithm, refer to Rapid Plasma Reagin (RPR) with Reflex to Titer and TP-PA Confirmation

   
Treponema pallidum Antibody, IgG by ELISA 0050920
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Recommended syphilis screening test in so-called reverse screening algorithm

Abnormal results require confirmation by a nontreponemal test (ie, RPR or VDRL)

The CDC recommends a nontreponemal test (ie, RPR or VDRL) for initial syphilis screening prior to confirmation with a treponemal test (eg, TP-PA)

   
Treponema pallidum Antibody by TP-PA 0050777
Method: Semi-Quantitative Particle Agglutination

CDC recommended confirmatory test for syphilis

Order to confirm syphilis if initial screening (eg, RPR, VDRL) is reactive

Cannot differentiate between IgG and IgM antibodies

Compares favorably to FTA test but slightly less sensitive in untreated early primary syphilis

Cannot be tested with CSF

 
Treponema pallidum Antibody, IgM by ELISA 0050921
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Aids in workup of suspected congenital syphilis 

Confirm reactive nontreponemal syphilis screening test (ie, RPR or VDRL)

Primary screening for syphilis in so-called reverse screening algorithm

Monitor serological response to treatment in RPR/VDRL negative primary syphilis

Congenital syphilis – sensitivity is ~80%; therefore, negative IgM does not rule out congenital syphilis

 
Treponema pallidum Antibody, IgG by Immunoblot 2003095
Method: Qualitative Immunoblot

Recommended supplementary confirmatory test for syphilis in so-called reverse screening algorithm

Use when a reactive EIA screening test is not confirmed by the TP-PA test or a reactive TP-PA screening test is not confirmed by the EIA test

Do not use to determine relapse or reinfection of syphilis because of the persistence of reactivity, likely for life

Repeat testing in 2-4 weeks is recommended if results are equivocal

Treponema pallidum Antibody (FTA-ABS), Serum, IgG by IFA with Reflex to Treponema pallidum Antibody by TP-PA 0050477
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Particle Agglutination
Not an optimal reflex test; TP-PA is preferred

May be falsely positive in some cases of systemic lupus erythematosus, pregnancy, and leprosy

Cannot be tested with CSF

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Treponema pallidum (VDRL), Cerebrospinal Fluid with Reflex to Titer 0050206
Method: Semi-Quantitative Flocculation

Preferred diagnostic assay for CSF specimens in suspected tertiary syphilis

Treponema pallidum Antibody, IgG by IFA (CSF) 0055273
Method: Semi-Quantitative Indirect Fluorescent Antibody

May aid in the workup of tertiary syphilis

For CSF specimens, VDRL (CSF) with reflex to titer is preferred

Rapid Plasma Reagin (RPR) with Reflex to Titer, FTA-ABS and TP-PA 0050011
Method: Semi-Quantitative Charcoal Agglutination/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Particle Agglutination

Not an optimal reflex test

Preferred test is RPR with Reflex to TP-PA

Treponema pallidum Antibody Panel (FTA-ABS) IgG and IgM 0093067
Method: Qualitative Immunofluorescence Assay

Not recommended

If congenital syphilis is suspected, order IgM antibody

If syphilis is suspected, preferred test is RPR with reflex to titer and TP-PA confirmation