Treponema pallidum pallidum

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Treponema pallidum pallidum

Background

  • Causes syphilis

Microbiology

  • Small, slow-growing spirochete
  • Not seen on standard microscopy; requires darkfield microscopy

Clinical Manifestations

Overview of Stages

  • Primary syphilis (incubation period 3 weeks [range 3 to 90 days])
  • Secondary syphilis (incubation period 2 weeks to 3 months [range 2 weeks to 6 months])
  • Latent
    • Early latent (<1 year)
    • Late latent (≥1 year)
  • Tertiary syphilis (incubation period years to decades)
    • Cardiovascular (incubation period 10 to 30 years)
    • Gummatous (incubation period 15 years [range 1 to 46 years])
    • Neurosyphilis (incubation period 2 to 20 years)
      • Meningovascular
      • Parenchymatous
      • Tabes dorsalis
  • Congenital
    • Early (< 2 years)
    • Late (≥ 2 years)

Primary Syphilis

  • Incubation period is about 3 weeks
  • Chancre
  • Genital ulcer disease
    • Clean borders
    • Indurated
    • Not painful unless secondarily infected
    • Lasts 2 to 6 weeks
  • May present with regional lymphadenopathy
  • Diagnosis with darkfield microscopy, fluorescent antibody smear, or (most commonly) serology
  • Serology often negative in early syphilis

Secondary Syphilis

Latent Syphilis

  • Defined as asymptomatic and untreated but with positive serology
    • Can be early latent (<1 year) or late latent (≥1 year)
    • If unknown duration, late latent is assumed
  • High rate of relapse of secondary syphilis within the first 1-2 years following infection (but especially within the first year)

Tertiary Syphilis

  • Eventually occurs in about 30% of untreated cases

Neurosyphilis

  • Of the 25-60% of people who have CNS invasion, 95% are asymptomatic during the early stage and 80% of those spontaneously clear it
  • Incubation period is 7-15 years
  • Three major presentations: meningovascular syphilis, parenchymous syphilis, and tabes dorsalis
Meningovascular
  • Possibly the most common neurosyphilis
  • Subdivided into cerebromeningeal (diffuse or focal) and cerebrovascular
  • Stroke-like symptoms, especially MCA or basilar territory
  • Can present as a sudden change, as syphilitic apoplexy
  • Can present following a prodrome of weeks to months of non-specific headaches, vertigo, irritability, insomnia, and personality changes
Parenchymatous
  • Previously known as "generalized paresis of the insane"
  • Occurs in 2-5% of cases of untreated syphilis
  • Commonly found on psychiatric wards
  • Causes psychosis and dementia
  • Later, coarse tremors, Argyll-Robinson pupil, paresis
Tabes Dorsalis
  • Occurs in 2-9% of cases of untreated syphilis
  • Isolated posterior cord degeneration leading to a loss of proprioception in the lower extremities
  • Stomp the ground when walking to use intact pain/pressure sensation
  • Loss of sensation in the Hitzig zones (tip of nose, band including nipple area, medial forearms, and lateral leg)
  • Can present with Charcot foot and, rarely, recurrent abdominal pain
  • Diagnosed by serum CMIA, but RPR may be negative
Others
  • Isolated ocular neurosyphilis
  • Meningitis: can present at any time during the course of disease
  • Others

Cardiovascular Syphilis

  • Occurs in 10% of people with untreated syphilis
  • Incubation period is 20-25 years
  • Aortic root involvement leading to aortitis and dilatation
  • May result in aneurysm, aortic insufficiency, or angina secondary to stenosis at the aortic root
  • Diagnosed by RPR +/- CMIA

Gummatous Syphilis

  • Gummas are necrotizing granulomatous lesions
  • Occurs in 15% of people with untreated syphilis
  • Incubation period 6-8 years
  • Gummas may appear anywhere, in any organ, but most commonly on the skin, on mucosa, and in bones
  • CNS lesions look like toxo, so beware in HIV patients

Other Presentations

  • Otosyphilis
  • Ocular syphilis, including uveitis: blurry vision, floaters, light sensitivity, double vision, eye pain, and foreign body sensation
  • Syphilitic osteitis and osteomyelitis, which can present in any stage

Congenital Syphilis

  • May be either early (<2 years old) or late (≥2 years old)
  • Classic Hutchison triad is interstitial keratitis, cranial nerve VIII deafness, and abnormal teeth
  • See Congenital syphilis for more information

Diagnosis

  • Often done as non-treponemal test to screen, followed by treponemal test to confirm
  • In Ontario, we do a treponemal test to screen (CMIA), then repeat it with a more specific treponemal test (TPPA) alongside RPR

Direct Visualization

  • Darkfield microscopy
    • Chancre cleaned and smear obtained
    • Smear must be visualized immediately
    • Sensitivity decreases with duration
  • Smear for fluorescent monoclonal antibody
    • Best to use in primary syphilis, with a swab from the base of the lesion
    • Can be done by Public Health Ontario

Non-Treponemal Tests (VDRL/RPR)

  • Veneral Diseases Research Laboratory (VDRL) has been replaced by the rapid plasma reagin (RPR) test
    • Quantitative tests for a non-specific anti-cardiolipin antibody that is produced in syphilitic (and other) infections
  • False positives:
  • Only 50% sensitive in primary, 100% sensitive in secondary
  • Tests wane over time, and can eventually become nonreactive in late latent or tertiary syphilis

Treponemal Tests

  • More specific and sensitive, but more expensive
  • False positives: lupus and other autoimmune disorders, Lyme disease, and other treponemal infections
  • Remain positive for life
  • Four main tests:
    • Fluorescent treponemal antibody absorption (FTA-Abs): Essentially the gold standard
    • Chemoluminescnence microparticle immunoassay (CMIA or CLIA): the screening test used in Ontario. Often used as a screening test as it is an easily-automated immunoassay and is more sensitive and specific than RPR.
    • Treponema pallidum Particulate Agglutination assay (TPPA): a modification of the TPHA. Used as the confirmatory test (alongside RPR) used in Ontario.
    • T. pallidum hemagglutination assay (TPHA): very old test.
    • T. pallidum enzyme immunassay (TP-EIA)

Interpretation of Serology

CMIA screen RPR TPPA Interpretation
Non-reactive — — Negative result; or early syphilis (consider repeat in 4 weeks)
Reactive Reactive Reactive Recent or prior syphilis infection
Reactive Non-reactive Reactive Early primary syphilis, prior infection, late latent infection, prozone effect
Reactive Non-reactive Non-reactive False positive; or early primary syphilis, previously treated, or late latent (repeat in 4 weeks)
Reactive Non-reactive Indeterminate Inconclusive result; false positive, early syphilis, old treated syphilis, or old untreated syphilis (repeat in 4 weeks)
Reactive Reactive Non-reactive Inconclusive result; false positive, early syphilis, old treated syphilis, or untreated syphilis (repeat in 4 weeks)
Reactive Reactive Indeterminate Recent or prior syphilis infection

Lumbar Puncture for CSF

  • Should be done routinely when:
    • Neurological (including optic and auditory) signs or symptoms
    • Failure of serologic response
    • Tertiary syphilis
    • Congenital syphilis
    • In patients with HIV: CD4 ≤350 and RPR ≥1:32
  • The sample should be sent for cell count and differential, protein, and either VDRL (not RPR) or FTA-Abs
    • RPR is specific but less sensitive; it helps to rule in CNS disease when present
    • FTA-Abs is sensitive but less specific; it help to rule out CNS disease when absent

Management

  • The standard first-line therapy is penicillin
    • It is the only antibiotic with proven efficacy in neurosyphilis and pregnancy
  • In cases of allergy, desensitization is generally preferred to the second-line therapy of doxycycline
  • A distant third-line option is ceftriaxone, only used when the others absolutely cannot given the lack of clinical data
  • Azithromycin should not be used, given high rates of resistance
  • Treatment may be complicated by a Jarisch-Herxheimer reaction
  • Patients should avoid unprotected sexual contact until 1 week after completing treatment
Syndrome First-Line Alternative
Primary syphilis benzathine penicillin G 2.4 MU IM once doxycycline 100 mg PO bid for 14 days
ceftriaxone 1 g IV/IM daily for 10 days
Secondary syphilis
Early latent syphilis
Late latent syphilis benzathine penicillin G 2.4 MU IM weekly x3 doxycycline 100 mg PO bid for 30 days
ceftriaxone 1 g IV/IM daily for 10 days
Tertiary syphilis
Neurosyphilis penicillin G 4 MU IV q4h for 10-14 days desensitization

ceftriaxone 2 g IV/IM q24h for 10-14 days

Primary, Secondary, and Early Latent

  • Benzathine penicillin G 2.4 million units IM once, divided between two buttocks
  • Alternative (penicillin allergy): doxycycline 100mg BID for 2 weeks
  • Alternative (penicillin allergy and pregnancy): penicillin desensitization or azithromycin
  • Monitor serologic response with RPR titres at 3, 6, and 12 months, and until negative or stable low titre
    • Primary should decrease 4-fold at 6 months and 8-fold at 12 months
    • Secondary should decrease 8-fold at 6 months and 16-fold at 12 months
    • Early latent should decrease 4-fold at 12 months

Late Latent and Tertiary (excluding neurosyphilis)

  • Benzathine penicillin G 2.4 million units IM q1week for 3 weeks
  • Alternative (penicillin allergy): doxycycline for 30 days
  • Monitor serologic response with RPR titres at 12 and 24 months, and until negative or stable low titre

Tertiary Neurosyphilis

  • Penicillin G 4 million units IV q4h for 10 to 14 days
  • Often followed by at least one dose of IM benzathine penicillin, sometimes weekly for 2-3 weeks
  • For early neurosyphilis, the alternative of doxycycline 100 mg p.o. BID for 28 days may be noninferior1
  • Monitor serologic response with RPR titres at 6, 12, and 24 months, and until negative or stable low titre
  • Repeat lumbar puncture every 6 months until parameters normalize
    • Pleocytosis normalizes first, within 6 months, followed by protein levels over months to years
    • CSF-VDRL should decrease 4-fold in 12 month if it is high, but can persist for years until negative

Pregnancy

HIV Coinfection

  • Treat as above
  • Regardless of stage, monitor response with RPR titres at 3, 6, 12, and 24 months, then annually
  • CSF parameters normalize more slowly in people with HIV

Congenital Syphilis

  • If <1 month of age: crystalline penicillin G 50 kU/kg IV q12h for the first week of life and q8h thereafter, for a total of 10 days
  • If ≥1 month of age: crystalline penicillin G 50,000 units/kg IV every 6 hours for 10-14 days
    • If there is no neurological involvement, then you can consider benzathine penicillin G 50 kU/kg (max 2.4 MU) IM weekly for 3 weeks

Follow-Up RPR

  • RPR should be trended after treatment to ensure response, and repeated until negative (or stably low titre)
  • It should be remeasured on the day of treatment, as it will often change significantly from diagnosis, even if it has only been a few days

Prevention

Public Health

  • Contact tracing should be performed, identifying contacts within the presumed maximum incubation/latency period
    • Primary syphilis: 3 months
    • Secondary syphilis: 6 months
    • Early latent syphilis: 1 year
    • Late latent or tertiary syphilis: as appropriate
  • Contacts should be tested, and treated if positive
  • Reasonable to empirically/epidemiologically treat contacts from the previous 90 days if loss-to-follow-up is likely

Further Reading

References

  1. ^  Nicolò Girometti, Muhammad H Junejo, Diarmuid Nugent, Alan McOwan, Gary Whitlock, Keerti Gedela, Sheel Patel, Tara Suchak, Victoria Tittle. Clinical and serological outcomes in patients treated with oral doxycycline for early neurosyphilis. Journal of Antimicrobial Chemotherapy. 2021;76(7):1916-1919. doi:10.1093/jac/dkab100.

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