Syphillis diagnosis

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Here is a comprehensive breakdown of syphilis diagnosis, drawn from multiple authoritative textbooks.

Syphilis: Diagnosis

Overview

Diagnosis of syphilis rests on three pillars: clinical recognition by stage, direct detection of the organism, and serologic testing. No single test is sufficient on its own - accurate diagnosis requires combining laboratory results with clinical history and signs.

All patients diagnosed with syphilis should also be tested for HIV infection. - Washington Manual of Medical Therapeutics

1. Clinical Diagnosis by Stage

Recognizing the stage guides which tests to prioritize:

Stage	Timing	Key Features
Primary	Weeks after exposure	Painless, indurated, superficial ulcer (chancre); usually single; regional lymphadenopathy
Secondary	2-10 weeks after chancre resolves	Copper-red maculopapular rash (classically involves palms and soles), condylomata lata, mucous patches, constitutional symptoms, diffuse lymphadenopathy
Latent (early)	Serologically positive < 1 year, no symptoms	No clinical signs; purely serologic diagnosis
Latent (late/unknown duration)	Serologically positive > 1 year	No clinical signs; serologic diagnosis
Tertiary	1-20 years after infection	Gummas, cardiovascular syphilis (aortitis, aortic aneurysm), neurosyphilis
Neurosyphilis	Any stage	General paresis, tabes dorsalis, meningovascular disease, ocular syphilis, otosyphilis
Congenital	Vertical transmission	Stillbirth, rash, hepatomegaly, "snuffles," saber shins, Hutchinson teeth, 8th nerve deafness

Secondary syphilis rashes are characteristically non-pruritic and symmetrically distributed. - Symptom to Diagnosis, 4th Edition

2. Direct Detection Methods

Darkfield Microscopy

Permits definitive diagnosis in primary and secondary syphilis by visual identification of motile spirochetes from lesion exudate (serous fluid, free of red blood cells)
Spirochetes show characteristic corkscrew morphology and episodic movements
Limited utility for oral lesions due to presence of saprophytic spirochetes; indirect fluorescent antibody (IFA) test with fluorescein-labeled anti-T. pallidum antibodies is preferred for oral sites
A negative result warrants repeat testing - Dermatology 2-Volume Set 5e

Polymerase Chain Reaction (PCR)

Detects T. pallidum DNA; increasingly being employed even for classic presentations
Particularly useful in: neurosyphilis, congenital syphilis, extra-genital primary syphilis
In neonates, detection of spirochetemia by PCR can improve sensitivity of congenital syphilis diagnosis
T. pallidum cannot be routinely cultured in vitro

Histopathology

Gummas: granulomas with central acellular necrosis + endarteritis obliterans + plasma cell infiltrates
Warthin-Starry silver stain or immunohistochemistry can identify organisms in tissue

3. Serologic Testing (Most Important in Practice)

Serologic diagnosis requires both non-treponemal AND treponemal tests.

Non-Treponemal Tests (NTTs)

Detect IgG and IgM antibodies against cardiolipin-cholesterol-lecithin antigen (lipoidal material released from damaged host cells and T. pallidum).

Test	Notes
RPR (Rapid Plasma Reagin)	Most common; flocculation test; used for screening and monitoring
VDRL (Venereal Disease Research Laboratory)	Standard; used for CSF testing in neurosyphilis
USR, RST, TRUST	Less commonly used variants

Key properties of NTTs:

Become reactive ~4-5 weeks after infection; 100% sensitivity by ~12 weeks
Results reported as titers (1:2, 1:4, 1:8...); RPR and VDRL titers cannot be directly compared
Revert to non-reactive in 25-30% of untreated late latent syphilis cases
A fourfold (two-dilution) decline in titer = successful treatment
A fourfold increase in titer = relapse or reinfection
A day-of-treatment titer must be obtained before starting therapy to allow future comparison
False positives occur (see below)

Treponemal Tests (TTs)

Detect antibodies specific to T. pallidum antigens.

Test	Notes
FTA-ABS (Fluorescent Treponemal Antibody Absorbed)	Highly sensitive; earliest to become reactive
TPPA (T. pallidum Particle Agglutination)	Widely used confirmation test
TPHA / MHA-TP	Detect antibodies to surface proteins of T. pallidum
TP-EIA / Multiplex Flow Immunoassay	Used in reverse sequence screening algorithms

Key properties of TTs:

More specific than NTTs; false positives are rare
IgM and IgG antibodies usually detectable by end of week 4
Remain positive indefinitely after treatment (serofast) - except in very early syphilis
Cannot differentiate active from past treated infection
Sensitivity by stage: 70-100% (primary), 100% (secondary and latent), ~95% (late)
90% of patients are TPHA-positive at the time they present with a chancre

Serologic Reactivity Over Time

Common patterns of serologic reactivity in syphilis patients

Fitzpatrick's Dermatology, Fig. 170-38: FTA-ABS rises earliest, VDRL/RPR peaks during secondary stage and declines with treatment; treponemal tests remain positive indefinitely.

4. Testing Algorithms

Traditional (Forward) Algorithm

Screening: NTT (RPR or VDRL)
Confirmation if positive: Treponemal test (FTA-ABS, TPPA)

Reverse Sequence Algorithm (Increasingly Used)

Screening: Treponemal EIA or multiplex flow immunoassay
If reactive: quantitative RPR/VDRL
If reactive on both: confirms syphilis
If only treponemal reactive: T. pallidum particle agglutination (TPPA) as a second treponemal test to resolve discordance; ~3% of cases fall into this discordant category

Advantage of reverse sequence: May detect early primary syphilis that NTTs would miss (NTTs can be seronegative in very early primary syphilis). - Washington Manual; Fitzpatrick's Dermatology

5. Neurosyphilis Diagnosis

Indication for LP: All patients with neurologic, ophthalmic, or otologic symptoms
CSF VDRL: Highly specific but low sensitivity (a negative VDRL does NOT rule out neurosyphilis)
CSF abnormalities: elevated protein, pleocytosis (WBC > 5/mm³)
Some experts recommend LP in HIV+ patients with tertiary disease, treatment failure, or late latent syphilis, though evidence for improved outcomes is limited

6. Congenital Syphilis Diagnosis

Maternal serology: reactive treponemal and non-treponemal tests
Infant testing: Quantitative NTT on infant serum (not cord blood - cord blood may give false positives from maternal contamination)
Treponemal tests in infants are difficult to interpret due to transplacental transfer of maternal IgG
Additional workup: darkfield/PCR of lesions, CSF VDRL + cell count + protein, long-bone X-rays (periostitis), LFTs, ophthalmologic and auditory brainstem response testing

Stigmata of late congenital syphilis (Hutchinson's triad):

Hutchinson teeth (notched, peg-shaped incisors)
Interstitial keratitis
Eighth-nerve deafness

7. False Positives in Non-Treponemal Tests

Causes of biologic false-positive RPR/VDRL include:

Acute (< 6 months)	Chronic (> 6 months)
Viral infections (EBV, HIV, hepatitis)	SLE and other autoimmune diseases
Bacterial infections	Antiphospholipid syndrome
Malaria	Chronic liver disease
Pregnancy	Aging
Recent immunization	Intravenous drug use

Treponemal tests have very high specificity; biologic false positives rarely occur with them
Concurrent positive NTT and TT confirms syphilis; discordant results require clinical judgment

8. Treatment Monitoring

Repeat nontreponemal tests (RPR) at 3, 6, and 12 months after treatment
In HIV+ patients: every 3 months for 1 year
Inadequate response = failure to achieve fourfold decline in titer by 12 months (primary/secondary/early latent) or 24 months (late latent/unknown duration)
Treponemal tests are not used for monitoring - they remain positive regardless

Sources:

Dermatology 2-Volume Set 5e (Bolognia), pp. 1753-1754
Fitzpatrick's Dermatology, pp. 3191-3192
Washington Manual of Medical Therapeutics, p. 624
Symptom to Diagnosis: An Evidence-Based Guide, 4th ed., p. 527

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