Syphilis

Syphilis Overview

Causative Agent:

• Infection caused by the bacterium Treponema pallidum.

Transmission:

• Most new cases are sexually acquired.
• Transmission usually occurs via direct contact with an infectious lesion during sex.
• Highly infectious stages: primary chancre and secondary syphilis (mucous patches, condyloma lata).
• Contact with infected secretions can lead to primary syphilis lesions at almost any site.
• Syphilis can be spread by kissing or touching a person with active lesions on the lips, oral cavity, breasts, or genitals.
• Less infectious via cutaneous lesions through intact skin.
• Early latent syphilis patients are considered infectious due to recently active or missed lesions.
• Can cross the placenta, resulting in fetal infection.
• Rarely transmitted through transfused blood due to thorough donor screening.
• T. pallidum cannot survive longer than 24-48 hours under blood bank storage conditions.

Pathogenesis:

• Early Local Infection:
  • T. pallidum initiates infection by accessing subcutaneous tissues, evading early host immune responses, and establishing the initial ulcerative lesion, the chancre.
  • During early local replication, some organisms establish infection in regional draining lymph nodes, leading to subsequent dissemination.
  • Immune responses during early infection coincide with the resolution of the primary chancre, even in the absence of therapy.
  • Despite apparent immune control, widespread dissemination of spirochetes can occur, leading to secondary or tertiary syphilis in untreated patients.
• Late Infection:
  • Waning immunity with aging may facilitate recrudescence of a small number of treponemes that survived in sequestered sites.
  • A partially immune hypersensitive host may react to the presence of treponemes, causing a chronic inflammatory response.
  • Gummas (late benign syphilis) often involve the skin, viscera, or other tissues (e.g., bone, brain, abdominal viscera) and are characterized by granulomas, indicating a cellular hypersensitivity reaction.

Stages of Disease

General Note: Syphilis can present with central nervous system manifestations (neurosyphilis) at any time during the course of infection.

Primary Syphilis (Chancre Stage):

• Presentation: Typically involves a localized skin lesion at the inoculation site, such as the posterior pharynx, anus, or vagina.
• Incubation Period: Median of 21 days, ranging from 3 to 90 days.
• Lesion Characteristics: A solitary, small, firm, red, painless papule on the genital area that rapidly evolves into a painless ulcer with a well-defined, indurated, non-exudative base. Multiple lesions can also occur.
• Prognosis: The ulcer usually resolves spontaneously within 3-6 weeks, but its painless nature often delays medical attention, increasing the risk of disease transmission.

Secondary Syphilis:

• Systemic Illness: Affects around 25% of untreated individuals, typically developing within weeks to a few months after chancre resolution. Incubation averages 6 weeks (range: 2-24 weeks).
• Infectivity: Highly contagious to sexual partners and fetuses.
• Symptoms:
  • General Symptoms:
    • Fever
    • headache
    • malaise
    • sore throat
    • weight loss
    • myalgias
    • anorexia.
  • Lymphadenopathy:
    • Enlarged, minimally tender, firm lymph nodes (posterior cervical, axillary, inguinal, femoral).
  • Dermatologic Findings:
    • Diffuse, symmetric macular or papular rash often involving palms and soles
    • pustular syphilis
    • condyloma lata (raised gray or white lesions in moist areas)
    • alopecia with a “moth-eaten” scalp appearance.
  • Gastrointestinal Symptoms: Hepatitis and possible gastrointestinal tract infiltration.
  • Musculoskeletal Manifestations:
    • Synovitis
    • osteitis
    • periostitis.
  • Renal Involvement:
    • Transient albuminuria
    • nephrotic syndrome
    • acute renal failure.
  • Neurological and Ocular Symptoms:
    • Headache
    • meningeal inflammation
    • uveitis (anterior, posterior, panuveitis).

Tertiary Syphilis

Overview: Tertiary syphilis describes patients with late syphilis who have symptomatic manifestations involving the cardiovascular system or gummatous disease.

• Cardiovascular Syphilis:
  • Involves the ascending thoracic aorta, resulting in a dilated aorta and aortic valve regurgitation.
  • Thought to be a consequence of vasculitis in the vasa vasorum, leading to a weakening of the aortic root wall.
  • Typically occurs 15 to 30 years after initial infection in untreated patients.
• Gummatous Syphilis: Characterized by granulomatous lesions (gummas) affecting skin, bones, or other organs.

Latent Syphilis (Asymptomatic Phase):

Definition: Positive serologic evidence of infection without symptoms.

1. Early Latent Syphilis (< 2 years):
   • Infection in the absence of any symptoms, known to have been acquired within the previous 2 years.
   • Positive syphilis serology with no clinical symptoms or signs and no evidence of adequate past treatment.
   • If there is any doubt about the length of infection, treat as late latent disease.
   • Potentially highly infectious to sexual contacts and to a fetus.
2. Late Latent Syphilis (> 2 years):
   • Infection for more than 2 years in the absence of any symptoms.
   • No longer infectious to sexual partners after 2 years.
   • Able to be transmitted during pregnancy to the fetus.

Neurosyphilis:

Types of Neurosyphilis:

1. Asymptomatic Neurosyphilis:
   • No symptoms or signs of CNS disease, but may have evidence of concomitant primary or secondary syphilis.
   • Can occur within weeks to months after infection, less commonly more than 2 years after infection.
2. Symptomatic Meningitis:
   • Occurs most often within the first year after infection, but can occur years later.
   • Peripheral findings of early syphilis may coexist, particularly the rash of secondary disease.
3. Ocular Syphilis:
   • Symptoms include optic neuropathy, interstitial keratitis, anterior uveitis, and retinal vasculitis.
4. Otosyphilis:
   • Involves the inner ear and may lead to hearing loss.
5. Late Neurosyphilis:
   • General paresis.
   • Tabes dorsalis.

Syphilis in Pregnancy

Maternal Treatment:

• Penicillin treatment is curative for fetal infection in most cases.
• Treatment ≤30 days before delivery is a risk factor for congenital infection.
• Treatment may precipitate the Jarisch-Herxheimer reaction, potentially causing uterine contractions, preterm labor, and/or nonreassuring fetal heart rate tracing in the second half of pregnancy.

Adverse Outcomes:

• Miscarriage.
• Preterm birth.
• Stillbirth.
• Impaired fetal growth.
• Congenital infection:
  • Nonimmune hydrops fetalis.
  • Failure to thrive.
  • Pneumonia/pneumonitis/respiratory distress.
• Neonatal mortality.

Diagnosis

• Diagnosis is by a combination of serology, PCR of lesions, history and clinical assessment.
• If there is a clinical suspicion of primary syphilis but serology is negative
  • PCR swab
  • repeat serology after 2 weeks following presumptive treatment.
• Blood
  • Serology: syphilis antibody
  • will be tested for an initial syphilis specific antibody à  if reactive, the laboratory will perform supplemental testing with TPPA/TPHA and RPR/VDRL

Test type	Treponemal tests detect antibodies that specifically target Treponema pallidum. Treponemal tests are highly specific for syphilis, meaning they are less likely to give false-positive results for conditions other than syphilis.			Non-treponemal tests detect antibodies (reagin antibodies) that are not specifically directed against Treponema pallidum but rather against lipids released by damaged host cells and lipoprotein-like material from the bacterium. Non-treponemal tests are sensitive and useful for screening, but they can sometimes give false-positive results due to other conditions (e.g., autoimmune disorders, other infections).
Examples	EIA (Enzyme immunoassay) TPPA (Treponema pallidum particle agglutination assay)			RPR (Rapid plasma regain) VDRL (Venereal Disease Research Laboratory)
Detects	Syphilis-specific antibodies			Antibodies to cellular components released due to syphilis infection
Reported as	Reactive or nonreactive			Quantitative titre (1:2, 1:4, etc.) with higher titres indicating stronger positive results
Change over time	Remain positive over time in most cases usually positive for life			Decline over time (decline faster with treatment) often reverts to non-reactive.
Uses	New diagnosis of syphilis Sensitive screening test			Monitoring response to treatment Distinguishing re-infection vs. resolved infection in individuals with positive treponemal test
Syphilis serology interpretation
EIA	TPPA/TPHA	RPR/VDRL	Possible interpretations
Reactive	Reactive	Reactive	Syphilis infection If patient has been treated for syphilis and RPR titre is declining, this may be consistent with treated syphilis
Reactive	Nonreactive	Reactive or Nonreactive	Treponemal tests do not agree, which may indicate: – Early infection (TP-PA not yet positive) – Prior syphilis (treated or untreated) – False positive EIA – Repeat testing in 2 weeks
Reactive	Reactive	non-Reactive	Previously treated syphilis – Early syphilis (RPR not yet positive) Not consistent with syphilis; if concern for primary syphilis (chancre), should treat and repeat testing in 2 weeks

• Swab of ulcer using a PCR swab
  • NAAT or PCR: Swab from base of any ulcer where diagnosis suspected clinically
  • In very early infection, the NAAT test may be positive before seroconversion
• Special considerations
  • Positive syphilis results in a child should be urgently discussed with a specialist and child protection services.
  • Include a standard asymptomatic STI check-up in anyone being tested for human immunodeficiency virus (HIV).
  • Include a NAAT swab for herpes, if any anogenital or pharyngeal ulceration present.
  • In remote Australia include a donovanosis PCR for any genital ulcer

Treatment

Management of Syphilis During Bicillin L-A Shortage

Current Situation:

• Shortage of Bicillin L-A (benzathine benzylpenicillin tetrahydrate) prefilled syringes.
• Shortage expected to last into 2024.
• TGA approved importation and supply of Benzylpenicillin Benzathine (Brancaster Pharma, UK).
• Refer to TGA notice and Fact Sheet for more information.

GP Recommendations:

• Community pharmacies may not have Benzylpenicillin Benzathine (Brancaster).
• Ensure access for patients through local hospitals and publicly funded sexual health services.
• Early referral or discussion with a specialist is recommended.
• Repeat RPR serology on the day of treatment for baseline monitoring.

Principle Treatment Options

Situation: Early syphilis (primary, secondary, early latent)

• Recommended: Benzathine benzylpenicillin 2.4 MU (1.8 g) IMI, Stat, given as 2 injections containing 1.2 MU (0.9 g).
• Alternative: Discuss with specialist.

Situation: Late syphilis or syphilis of unknown duration (late latent > 2 years)

• Recommended: Benzathine benzylpenicillin 2.4 MU (1.8 g) IMI, given as 2 injections containing 1.2 MU (0.9 g) weekly for 3 weeks.
• Alternative: Discuss with specialist.

*If any doubt about the length of infection, treat as late latent disease.

Treatment Advice

• Use long-acting intramuscular penicillin formulations (short-acting formulations are ineffective).
• Benzathine benzylpenicillin supplied as 1.2 MU pre-filled syringes (listed on PBS).
• Seek specialist advice if unable to obtain the formulation.

Special Considerations

Jarisch-Herxheimer Reaction:

• Common in primary and secondary syphilis treatment.
• Occurs 6-12 hours after starting treatment, with fever, headache, malaise, rigors, and joint pains.
• Symptoms last for several hours, controlled with analgesics and rest.
• Patients should be informed about the reaction and reassured.

Immediate Management:

• Advise no sexual contact for 7 days post-treatment or until symptoms resolve.
• Advise no sex with partners from the last 3 months (primary syphilis), 6 months (secondary syphilis), or 12 months (early latent) until partners are tested and treated.
• Contact tracing and presumptive treatment of partners if last contact was within 3 months.
• Provide patient with a factsheet.
• Notify local health department as per procedures.
• Report to syphilis registers where applicable.

Special Treatment Situations

Complicated Syphilis:

• Refer those with acute neurological symptoms or suspected tertiary disease to a sexual health or infectious diseases clinic.

Pregnant Patients:

• Seek urgent specialist advice.
• Fetal monitoring may be required if more than 20 weeks pregnant.
• Treat according to stage; penicillin is the only effective treatment, desensitize and treat if allergic.
• Ensure partner is tested and treated.
• Repeat testing during pregnancy to confirm response and detect re-infection.
• Arrange birth and post-natal testing of mother and clinical review of baby.

Allergy to Penicillin:

• Non-penicillin regimens (e.g., doxycycline) have less evidence but can be effective; seek specialist advice.
• Early (< 2 years) syphilis: Doxycycline 100 mg orally twice a day for 14 days.
• Late (> 2 years) or unknown duration syphilis: Doxycycline 100 mg orally twice a day for 28 days.

HIV Co-Infection:

• Discuss with a specialist if CD4 count < 350 cells/μL; lumbar puncture for CSF examination may be advised.

Contact Tracing

• Important to prevent re-infection and reduce transmission.
• Highest priority for ongoing sexual contacts of pregnant patients.
• Diagnosing doctor responsible for initiating and documenting contact tracing discussion.
• Trace back according to sexual history and clinical stage of infection.
• Presumptively treat all sexual contacts from the last 3 months with benzathine benzylpenicillin 2.4 MU (1.8 g) IMI, Stat.
• Refer to Australasian Contract Tracing Guideline – Syphilis for more information.

Follow Up

• Confirm patient adherence to treatment.
• Ensure contact tracing procedures are completed or offer support.
• Repeat serology to assess treatment response – seek specialist advice if needed.
• Educate on condom use, contraception, HIV PrEP/PEP, safe injecting practices, consent, and vaccinations (HAV, HBV, HPV) as indicated.
• Test of Cure:
  • Review patients clinically and with repeat RPR testing at 3 months, 6 months, and (if necessary) 12 months post-treatment.
  • A 4-fold drop in RPR titers (e.g., 1:8 to 1:2) indicates an adequate treatment response.
  • Seek specialist advice if RPR is rising or a 4-fold drop is not achieved by 12 months.
  • Consider testing for HIV and other STIs at the 3-month visit if not done earlier, or retesting post window period.