View source for Treponema pallidum pallidum

==Background==

*Causes '''syphilis'''

===Microbiology===

*Small, slow-growing [[Shape::spirochete]]
*Not seen on standard microscopy; requires darkfield microscopy

==Clinical Manifestations==
===Overview of Stages===

*Primary syphilis (incubation period [[Usual incubation period::3 weeks]] [range [[Incubation period range::3 to 90 days]]])
*Secondary syphilis (incubation period 2 weeks to 3 months [range 2 weeks to 6 months])
*Latent
**Early latent (&lt;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 (&lt; 2 years)
**Late (&ge; 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===

*Incubation period 3 weeks to 3 months
*Often no history of chancre
*Diffuse maculopapular rash that involves palms and soles
**Typically begins on trunk
**Start as pinkish-reddish macular lesions that evolve into brownish-reddish papules that may have scaling
**May progress to pustular lesions (pustular syphilids)
**May be itchy
**Can be isolated to [[Rashes involving palms and soles|palms and soles]]
*Generalized [[lymphadenopathy]]
*Fever, chills, arthralgias
*Less common: [[condyloma lata]], [[aseptic meningitis]], [[iritis]], mucosal white patches, [[glomerulonephritis]], [[paroxysmal nocturnal hemoglobinuria]], [[hepatitis]]
*This is the most common time to develop ocular involvement, including:
**[[Anterior uveitis]] (usually unilateral though can become bilateral)
**Posterior involvement with [[vitritis]], [[necrotizing retinitis]], [[chorioretinitis]], [[retinal vasculitis]], and [[optic neuritis]] (usually toward the end of secondary syphilis)
***[[Chorioretinitis]] is the most common
**Acute posterior placoid chorioretinopathy (in secondary or late latent 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 &quot;generalized paresis of the insane&quot;
*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===

*Isolated auditory syphilis
*Isolated optic syphilis
*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:
**Acute biologic false positive: [[malaria]], [[brucellosis]], and [[mononucleosis]]; maybe [[pregnancy]]
**Chronic biologic false positive: [[lupus]] and other autoimmune disorders, [[HIV]], intravenous drug use, and [[leprosy]]
*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 [[Treponema species|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===
{| class="wikitable sortable"
!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

{| class="wikitable"
!Syndrome
!First-Line
!Alternative
|-
|Primary syphilis
| rowspan="3" |[[benzathine penicillin G]] 2.4 MU IM once
| rowspan="3" |[[doxycycline]] 100 mg PO bid for 14 days<br />[[ceftriaxone]] 1 g IV/IM daily for 10 days
|-
|Secondary syphilis
|-
|Early latent syphilis
|-
|Late latent syphilis
| rowspan="2" |[[benzathine penicillin G]] 2.4 MU IM weekly x3
| rowspan="2" |[[doxycycline]] 100 mg PO bid for 30 days<br />[[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 ===
*[[Is treated by::Benzathine penicillin G]] 2.4 million units IM once, divided between two buttocks
*Alternative (penicillin allergy): [[Is treated by::doxycycline]] 100mg BID for 2 weeks
*Alternative (penicillin allergy and pregnancy): [[penicillin desensitization]] or [[Is treated by::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)===

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

===Tertiary Neurosyphilis===

*[[Is treated by::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 noninferior[[CiteRef::girometti2021cl]]
*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===

*Only [[penicillin]] is recommended, including [[Penicillin desensitization|desensitization]] if needed for allergy
*Some expoerts recommend a second dose of [[benzathine penicillin G]] 2.4 MU IM a week after the first dose for primary, secondary, or early latent syphilis

===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 &lt;1 month of age: [[Is treated by::crystalline penicillin G]] 50 kU/kg IV q12h for the first week of life and q8h thereafter, for a total of 10 days
*If &ge;1 month of age: [[Is treated by::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 [[Is treated by::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==

*[https://www.toronto.ca/wp-content/uploads/2018/02/8528-tph-syphilis-lab-interpretation-guideline-Jan-2018.pdf Toronto Public Health Syphilis Laboratory Interpretation and Treatment] (2-page PDF)
*[https://www.canada.ca/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/syphilis.html Canadian Guidelines on Sexually Transmitted Infections: Syphilis]

{{DISPLAYTITLE:''Treponema pallidum pallidum''}}
[[Category:Spirochetes]]
[[Category:Sexually-transmitted infections]]