Syphilis

What is syphilis?

Venereal syphilis is a contagious, systemic disease caused by Treponema pallidum. T. pallidum enters via abraded skin or intact mucous membrane and distributes via the bloodstream and lymphatics after an incubation period of around three weeks.

• Early syphilis causes significant morbidity and is an important facilitator of HIV transmission.

• All patients diagnosed with syphilis must be tested for HIV and those having follow-up for HIV must have regular screening for syphilis.

• Congenital syphilis is a major cause of stillbirth, childhood morbidity, and mortality worldwide.¹

• Syphilis is classified as acquired or congenital.

Acquired syphilis

• Primary syphilis: incubation period 2-3 weeks (range 9-90 days): local infection.

• Secondary syphilis: incubation period 6-12 weeks (range 1-6 months): generalised infection.

• Early latent syphilis: asymptomatic syphilis of less than two years' duration.

• Late latent syphilis: asymptomatic syphilis of two years' duration or longer.

• Late symptomatic syphilis (tertiary syphilis): cardiovascular syphilis, neurosyphilis, gummatous syphilis.

Congenital syphilis²

• The term mother-to-child transmission (MTCT) of syphilis should be used so as to highlight all the possible adverse outcomes of the disease, which include spontaneous abortion, stillbirth, prematurity, clinical manifestations of congenital syphilis, infant death, and late sequelae.¹

• Early congenital syphilis occurs within the first two years of life.

• Late congenital syphilis emerges in children older than 2 years.

How common is syphilis? (Epidemiology)³

• There are an estimated 10.6 million incident cases of syphilis worldwide each year.⁴

• Annual diagnoses of infectious syphilis have tripled in the past 10 years in England, increasing from 2,648 diagnoses in 2010 to 7,982 in 2019. This increase was steepest between 2013 and 2017 (110% increase), with a 10% increase between 2018 and 2019.

• Syphilis disproportionally affects gay, bisexual and other men who have sex with men (MSM), who accounted for 78.4% of new diagnoses in 2019.

• People of Black ethnic backgrounds experience the highest rate of diagnosis.

• Although the increase is widespread, new infections are concentrated in large urban centres, with highest rates in 2019 in London, Brighton and Hove, Blackpool, Manchester and Salford.

Symptoms of syphilis⁵

Primary syphilis

• The primary lesion develops at the site of infection, which heals in 2-6 weeks.

• The small, painless papule rapidly forms an ulcer (the chancre). The chancre is usually single, round or oval, painless, surrounded by a bright red margin, indurated with a clean base and discharging clear serum.

• Chancres may be atypical - eg, multiple, painful, purulent, and destructive and may be extragenital.

• They are usually found in heterosexual men on the coronary sulcus, the glans and inner surface of the prepuce but may appear on the shaft and beyond. In MSM, they are usually found in the anal canal and, less frequently, in the mouth and genitalia. In women, they are found on the vulva, labia and, much less frequently, on the cervix.

• Extragenital sites are the lips, mouth, buttocks and fingers.

• There are enlarged regional lymph nodes that are painless, discrete, firm and not fixed to surrounding tissues.

Secondary syphilis

• Secondary syphilis often appears six weeks after the beginning of the primary lesion but may overlap or not appear for several months.

• Untreated, around 25% of patients develop secondary syphilis after the appearance of the initial chancre.⁶

• Multisystem involvement occurs within the first two years of infection.

• Systemic symptoms are mild or absent but include night-time headaches, malaise, slight fever and aches.

• A generalised polymorphic rash often affects the palms, soles and face. The rash is classically non-itchy; however, it may be itchy, especially in dark-skinned patients. It is associated with generalised painless lymphadenopathy.

• Papules enlarge into condylomata lata (pink or grey discs) in moist warm areas. Papule lesions disappear spontaneously.

• There may also be mucocutaneous lesions.

• Less common presentations include patchy alopecia, anterior uveitis, meningitis, cranial nerve palsies, hepatitis, splenomegaly, periostitis and glomerulonephritis.

• In 80% of cases, patients enter the latent asymptomatic stage which for over half of them persists for life. In about 20% of patients, an infectious relapse occurs during the next year.

Early latent syphilis

• Characterised by positive serological tests for syphilis with no clinical evidence of treponemal infection within the first two years of infection.

Late latent syphilis

• Infection of more than two years' duration, diagnosed on serological testing with no symptoms or signs of late manifestations of syphilis.

• Studies of cohorts of untreated patients suggest that symptomatic late syphilis is found in up to 40% of individuals with late T. pallidum infection.

• Late disease is divided into gummatous disease (15% of patients), cardiovascular disease (10%) and late neurological complications (7%).⁶

• The clinical manifestations of late syphilis are highly variable and are now rarely seen due to the use of treponemacidal antibiotics for other indications.

Tertiary syphilis

This consists of three major clinical manifestations, which may co-exist:

Neurological syphilis

• Asymptomatic neurosyphilis: late syphilis with abnormal cerebrospinal fluid (CSF) examination but with no associated neurological symptoms or signs.

• Symptomatic neurosyphilis: the most common presentations are dorsal column loss (tabes dorsalis), dementia (general paralysis of the insane) and meningovascular involvement.

• Tabes dorsalis typically occurs 15-25 years after infection and is characterised by sensory ataxia and lighting pains.

• Approximately half of patients with neurosyphilis are infected with HIV.⁷

• Neurosyphilis is now not always considered to be tertiary disease.

Cardiovascular syphilis

• Characterised by an aortitis, which usually involves the aortic root but may affect other parts of the aorta, usually spreading distally from the aortic root.

• The most frequent clinical manifestations are aortic regurgitation, aortic aneurysm and angina.

Gummata

• Inflammatory fibrous nodules or plaques, which may be locally destructive.

• Can occur in any organ but most commonly affect bone and skin.

Differential diagnosis⁸

Primary syphilis

Differentials of chancre include:

• Herpetic ulcers (especially chronic mucocutaneous anogenital herpes occurring with HIV infection).

• Chancroid.

• Lymphogranuloma venereum.

• Donovanosis.

Secondary syphilis

Differentials of the rash include:

• Pityriasis rosea.

• Viral exanthema.

Tertiary syphilis

As the presentation is variable so the differential diagnoses are extensive but syphilis should be considered in anyone presenting with cardiac or neurological signs or symptoms. The history and examination should help guide the likelihood of tertiary syphilis as a cause.

Investigations⁹

Investigations must include a screen for all sexually transmitted infections (including HIV) as well as investigation for other possible diagnoses. All patients with neurological signs or symptoms and those who fail treatment should have a lumbar puncture. Likewise, neurological imaging may be appropriate. Similarly, cardiac investigations may also be indicated - eg, ECG and echocardiogram.

Specific treponemal diagnostic tests⁶

These include:

• Treponemal enzyme immunoassay (EIA) - can be for immunoglobulin M (IgM) for early infection or immunoglobulin G (IgG) (the latter becomes positive at five weeks) or both. Check both for screening.

• T. pallidum chemiluminescent assay (CLIA).

• T. pallidum haemagglutination assay (TPHA).

• T. pallidum particle agglutination assay (TPPA).

• Fluorescent treponemal antibody absorbed test (FTA-abs).

• T. pallidum recombinant antigen line immunoassay.

All the above tests can be used for screening but the recommendations are to request EIA IgM for primary syphilis. Currently, cases of possible syphilis are commonly investigated using the treponemal serological tests T. pallidum IgG chemiluminescent immunoassay (CLIA) and the T. pallidum particle agglutination (TPPA). The non-treponemal rapid plasma reagin (RPR) flocculation test is used to assess disease activity.

An EIA/CLIA, preferably detecting both IgM and IgG is the screening test of choice. All these tests will also be positive in secondary and early latent syphilis. They will also be unable to differentiate between other treponemal diseases - eg, yaws. All positive tests should then be confirmed by using a different test (not the FTA-abs).

Negative serological tests for syphilis should be repeated at six and 12 weeks after an isolated episode which is high risk for exposure to syphilis and at two weeks after possible chancres that are dark-ground and/or PCR negative are observed.

Cardiolipin or non-treponemal tests

• Venereal disease reference laboratory (VDRL) or rapid plasmin reagin (RPR) - quantitative VDRL can be used as an indication of the stage of syphilis and is also used for monitoring treatment.

• Provide a titre, thus an indication of disease activity.

• Perform VDRL/RPR when treponemal tests are positive.

• False negatives may occur in secondary or early latent syphilis - thus, there may be a need to repeat.

Demonstration of T. pallidum

• From lesions or infected lymph nodes in early syphilis.

• Dark field microscopy.

• Direct fluorescent antibody (DFA) test.

• PCR, if available.

Syphilis treatment and management

• Treatment should be within a sexual health clinic, with enquiries about sexual contacts.

• Patients who acquire syphilis are at significant risk of re-infection, and should therefore be regularly screened for syphilis and given sexual health promotion. All patients should be offered screening for other sexually transmitted infections, including HIV.

Drugs⁶

Recommended regimes for adults:

• Primary, secondary, early latent syphilis: benzathine penicillin 2.4 mega units (intramuscular (IM), single dose) is first-line, with procaine penicillin as an alternative.

• Resistance to macrolide antibiotics means they should only be used where no alternative is possible and when follow-up can be assured.

• Parenteral rather than oral treatment has been the treatment of choice because therapy is supervised and bioavailability is guaranteed.

• Late latent syphilis: benzathine penicillin weekly for three weeks is first-line, or doxycyline 100mg twice daily for 28 days is recommended by the British National formulary.

• Neurosyphilis: procaine penicillin 1.8-2.4 units once daily (IM, for 14 days) with oral probenecid 500 mg four times a day.

• Pregnancy:

  • Treatment depends upon which trimester the presentation is in: first and second trimesters - give single dose benzathine penicillin; third trimester - two doses of benzathine penicillin one week apart.

Jarisch-Herxheimer reaction

• This is a reaction to treatment.¹⁰

• It is an acute febrile illness with headache, myalgia, chills and rigors and resolves within 24 hours.

• It is common in early syphilis but is usually not important unless there is neurological or ophthalmic involvement or in pregnancy when it may cause fetal distress and premature labour.

• This reaction occurs in up to 44% of pregnant women with syphilis and can cause contractions, fetal heart rate abnormalities and even stillbirth in the most severely affected pregnancies.¹¹

• It is uncommon in late syphilis but may be life-threatening.

• Management should include advice to use antipyretics if it occurs and reassurance.

• There is no evidence that the use of steroids prevents these serious consequences; however, there is evidence in early syphilis that steroids prevent the fever associated with the Jarisch-Herxheimer reaction.⁶

Prevention of syphilis

• Treatment of asymptomatic contacts.

• Use of condoms.

• All pregnant women in the UK are offered syphilis screening.¹²

Intrauterine syphilis⁶

• Maternal syphilis infections and congenital syphilis are increasing in both high and low resource settings.¹³

• A quarter of pregnancies to in women with untreated syphilis will result in a second trimester miscarriage or stillbirth, around 10% result in a neonatal death at term. In addition, 13% of these pregnancies result in a preterm or low birth.¹⁴

• In pregnant women with untreated early syphilis, 70-100% of infants will be infected.¹⁵

• Diagnosis:

  • Early (first two years): rash including condylomata lata, vesiculobullous lesions, snuffles, haemorrhagic rhinitis, osteochondritis, periostitis, pseudoparalysis, mucous patches, perioral fissures, hepatosplenomegaly, generalised lymphadenopathy, glomerulonephritis, neurological or ocular involvement, haemolysis, thrombocytopenia.

  • Late, including stigmata: interstitial keratitis, Clutton's joints (arthritis of the knees), Hutchinson's incisors, mulberry molars, high palatal arch, rhagades, deafness, frontal bossing, short maxilla, protuberance of mandible, saddle nose deformity, sternoclavicular thickening, paroxysmal cold haemoglobinuria, neurological or gummatous involvement.

• Investigations:

  • Serological tests that detect IgG may be positive due to passive transfer of maternal antibodies.

  • A positive anti-treponemal EIA IgM is indicative of congenital infection.

  • Serological tests may be negative in infants infected in late pregnancy and should be repeated.

• Treatment:
  

  • It is essential that women with positive screening tests are referred as quickly as possible to a genitourinary (GU) physician. This requires clear and timely communication between the screening laboratory, midwifery and obstetric services, GU medicine and paediatrics.⁶

  • The WHO recommends benzathine penicillin 2.4 million units intramuscularly as a single dose for pregnant women with early syphilis.¹⁶

  • Infants born to mothers diagnosed and/or treated for syphilis during the present pregnancy require RPR/VDRL and IgM tests at birth and at 3 months of age, then three-monthly until negative. If these titres remain stable or increase, the child should be evaluated and treated.

  • Older siblings should be screened for congenital syphilis.

  • Parents, all siblings and any sexual partner should be screened for syphilis.