Treponema pallidum

Indications for Testing

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

Laboratory Testing

Cannot be cultured in vitro
Darkfield exam only if chancre (primary) or condylomata lata (secondary) present
Nontreponemal tests – inexpensive and rapid; require treponemal-based confirmation due to modest specificity
- Rapid plasma reagin (RPR) – if reactive, order titers
- Venereal disease research laboratory (VDRL) test may be used first but has higher false-positive rate
Treponemal tests used for confirmation of positive nontreponemal test
- Microhemagglutination or indirect hemagglutination assay for antibodies to T. pallidum (MHA-TP, TP-PA)
- Fluorescent treponemal antibody absorption assay (FTA-Abs) – higher rates of false positives than TP-PA
- IgM antibody detection by enzyme-linked immunosorbent assay (ELISA)
- IgG antibodies by immunoblot
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 non-reactive 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

Genital chancre/ulcer – primary syphilis
- Herpes simplex virus
- Chancroid
- Lymphogranuloma venereum
- Behçet disease
Macular rash – secondary syphilis
- Contact dermatosis
- Lichen planus
- Squamous cell carcinoma
- Eczema
- Psoriasis
Vasculitic syphilis – secondary syphilis
- Connective tissue disease
- Vasculitis
- Chronic hepatitis
  - Hepatitis B
  - Hepatitis C
- Multiple sclerosis
- Brucella spp
Gummatous syphilis – tertiary syphilis
- Malignancy
- Sarcoidosis
- Fungal disease
Congenital syphilis
- TORCH-like illness
  - Toxoplasma gondii
  - Rubella virus
  - Cytomegalovirus
  - Herpes simplex virus
  - Parvovirus
- Inherited syndromes
CNS syphilis
- Infectious meningitis
  - Viral
  - Bacterial
  - Fungal – eg, yeasts
  - Parasitic
- Vasculitis
- Connective tissue disease
- Stroke
- Vitamin deficiency (B12)
- Dementia
- Psychiatric disease
- Antiphospholipid syndrome
- Diabetic neuropathy

All pregnant females should be screened at initial prenatal visit using VDRL or RPR

Follow positive results with FTA-Abs or TP-PA testing (USPSTF, ACOG, CDC, AAFP recommendations)

Screening recommendations for pregnant women

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 vaginosis	Do not screen for low-risk patients; insufficient evidence to recommend screening in patients at high risk for preterm delivery	No specific recommendation	Do not screen for low-risk patients; insufficient evidence to recommend screening in patients at high risk for preterm delivery	No 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 with 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 females at risk

Screening recommendations for sexually active nonpregnant women

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 vaginosis	Do not screen	No recommendation	No specific recommendations	No 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

Screen exposed males
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

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
  - Venereal disease research laboratory (VDRL) for spinal fluid
- In CNS disease – CSF titers with VDRL
  - Titers should decrease with effective treatment

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
- Leptospira species
- Borrelia species, including B. burgdorferi

Risk Factors for Syphilis

Early age at onset of sexual activity
HIV infection
Gonorrhea infection
Multiple sex partners
Non-Caucasian race
Non-use 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 4-6 weeks
Local nontender adenopathy is frequent

Secondary syphilis

Incubation – 6-12 weeks
Two types
- Latent and early latent <1 year infection
- Late latent ≥1 year infection
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
- One-third 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 infection)
  - Involves the brain or spinal cord
  - Symptoms include headache, stiff neck
- Meningovascular syphilis (usually 5-10 years after 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

Treatment

All stages of neurosyphilis require treatment to prevent disease progression and sequelae
Jarisch-Herxheimer reaction sometimes follows initial syphilis treatment
- Fever/chills
- Headache
- Tachypnea
- Tachycardia
- Usually lasts <24 hours
- Supportive care only
Intrauterine treatment <16 weeks into pregnancy prevents fetal damage

Tests generally appear in the order most useful for common clinical situations

Test name: Treponema pallidum (Rapid Plasma Reagin) with Reflex to Titer

ARUP #: 0050471

Methodology: Semi-Quantitative Charcoal Agglutination

Use:

Initial screening test for syphilis

Follow treatment response

Limitations:

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

Test name: Treponema pallidum (VDRL), Serum with Reflex to Titer

ARUP #: 0093093

Methodology: Semi-Quantitative Flocculation

Use:

Alternative initial screening test for syphilis

Limitations:

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

Test name: Treponema pallidum Antibody by TP-PA

ARUP #: 0050777

Methodology: Semi-Quantitative Particle Agglutination

Use:

Confirm reactive screening nontreponemal test in suspected syphilis

Resolve inconclusive FTA-Abs results

Limitations:

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

Do not use assay for blood donor screening or associated re-entry protocols

Test name: Treponema pallidum Antibody (FTA-ABS), Serum, IgG by IFA with Reflex to Treponema pallidum Antibody by TP-PA

ARUP #: 0050477

Methodology: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Particle Agglutination

Use:

Confirm reactive screening nontreponemal test in suspected syphilis

Confirm inconclusive results from Treponema pallidum (VDRL)

Resolve discrepancies between laboratory results and clinical impressions

Limitations:

FTA tests for syphilis may be false positive in autoimmune disease, leprosy, febrile illnesses, advanced age, Lyme disease and endemic treponematoses

May be helpful in late neurosyphilis when RPR is negative but high clinical suspicion for disease

FTA antibody testing will usually remain reactive despite adequate therapy; do not use to monitor therapy

Do not use assay for blood donor screening or associated re-entry protocols

Test name: Treponema pallidum Antibody, IgM by ELISA

ARUP #: 0050921

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use:

Discriminate maternally derived IgG antibodies that cross placenta from IgM antibodies that indicate active infection in the newborn

Confirm congenital syphilis

Highly specific (100%) and sensitive (91%) test

Limitations:

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

Test name: Treponema pallidum Antibody, IgG by Immunoblot

ARUP #: 2003095

Methodology: Qualitative Immunoblot

Use:

Detect IgG antibodies against T. pallidum; useful as supplemental treponemal-based assay in cases where FTA-Abs results are inconclusive

Limitations:

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

Follow-up:

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

Additional Tests Available

Test name: Treponema pallidum (VDRL), Cerebrospinal Fluid with Reflex to Titer

ARUP #: 0050206

Methodology: Semi-Quantitative Flocculation

Comments:

Test name: Treponema pallidum (Rapid Plasma Reagin) with Reflex to Titer, FTA-ABS & TP-PA

ARUP #: 0050011

Methodology: Semi-Quantitative Charcoal Agglutination/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Particle Agglutination (PA)

Comments:

Follow treatment response

Satisfactory first-line test but higher rate of false positives

Panel is for clients in states requiring automatic confirmation via treponemal test for all reactive RPR tests

Test name: Treponema pallidum (Rapid Plasma Reagin) with Reflex to Titer & TP-PA Confirmation

ARUP #: 0050478

Methodology: Semi-Quantitative Charcoal Agglutination/Semi-Quantitative Particle Agglutination (PA)

Comments:

Test name: Treponema pallidum Antibody, IgG by ELISA

ARUP #: 0050920

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments: