Syphilis

History taking

This should cover:

• Previous STS testing: e.g. STI screening, blood donation, antenatal screening
• Previous STS diagnosis: timing, where, which treatment regimen received, previous serology results, etc
• Possibility of an endemic treponemal infection: residency in an endemic country, past skin infections, signs of yaws, etc
• Previous/ current symptoms: primary and secondary symptoms, neurological, ophthalmic or auditory symptoms, adverse pregnancy outcomes (e.g. miscarriages and still births), tertiary symptoms
• Sexual history, PN details (children)
• A history of living in countries where Yaws (Caribbean/Africa)-look for tissue paper scars on the anterior aspects of the legs and Pinta (Central and northern South America) and Bejel (Saharan Africa/Middle east) are endemic.

Examination

This should be guided by symptoms and stage of disease

In early infection:

• Genitalia, anus (when indicated), oral cavity, mucous membranes, skin (including palms and soles), scalp, and lymph nodes
• Neurological examination, including cranial nerves and ophthalmoscopy, if patient reports any neurological symptoms, eyesight or hearing changes Exclude papilloedema if lumbar puncture is being considered (patients with a negative RPR in peripheral blood are unlikely to have neurological involvement. (A RPR > 1:32 may predict CSF abnormalities)

In late infection:

• As above plus
• Examination of the cardiovascular system
• Examination of the musculoskeletal system (if congenital syphilis suspected)
• Neurological examination, including ophthalmoscopy
• Exclude papilloedema if lumbar puncture is being considered (patients with a negative RPR in peripheral blood are unlikely to have Neurosyphilis. A RPR > 1:32 may predict CSF abnormalities)

Investigations

Routine screening:

• Select from NASH ordering set – Syphilis Routine Testing if no previous syphilis infection or Syphilis. Follow-up if known previous infection.

     Positive syphilis serology cannot be interpreted independent of a clinical history.

Suspected early syphilis/syphilis contacts:

• Select from NASH ordering set – Syphilis: Suspect Early/known contact

PCR Testing

• This can be performed on all ulcers and MUST be performed if patient is MSM or ulcer is not typical of HSV. Take a swab from the base of an area of ulceration using the red topped PCR swab kit.
• If undertaking STS PCR testing, then serology MUST also be taken.
• Select from GP Lab ordering set, STI screen – herpes and syphilis PCR – swab in VTM

Interpretation of results

All new positive syphilis results should be reviewed by a senior GUM clinician (ie the first positive result received on any patient). The following general points are for guidance only. More information is available in Appendix 2.

Positive syphilis serology

• Always repeat positive tests to confirm the result.
• Serology should ALWAYS be repeated on the day treatment is initiated to provide a baseline to monitor response to treatment. This is because the RPR titre may rise between the initial diagnosis and the day treatment is started. If this rise is not documented it will be difficult to detect the true post treatment fall in titre and lead to the possible erroneous diagnosis of post treatment failure.
• Yaws or Pinta can give identical results to syphilis though the RPR is often negative or <1:8. It is not possible to exclude latent syphilis in this situation and therefore patients are managed as though they have acquired syphilis.

Biological False Positives

• If only one marker is positive within the range of syphilis screening tests this usually indicates a false positive test. Discuss with GUM senior. The patient should be informed and asked to provide a follow up sample 2 weeks after the initial sample. If there is no change in the titre this confirms a false positive.

Negative serology in suspected syphilis

• Serology may (occasionally) be negative in the primary stage. If the patient has signs of possible early syphilis with negative serology, review after 1-2 week and repeat the serology.

Contact of syphilis

• Offer testing and (epidemiological) treatment at initial visit if <12 weeks since exposure.
• The alternative is to abstain until syphilis is excluded.
• If patient declines epidemiological treatment, repeat screening is recommended at 6 weeks and then 12 weeks following the sexual contact.

All new cases of syphilis should be brought to the attention of a GUM senior/ consultant. All symptomatic cases: discuss with GUM senior covering clinic.

• All patients with syphilis MUST be advised to have screening for other STI’s including HIV, taking into account relevant window periods. If baseline bloods are taken <4 weeks since last unprotected anal sex, then an appointment for a repeat HIV test out with the window period should be booked.
• Patients should be given verbal and written information about syphilis and the long term implications for them and their partners- see syphilis PIL.

A standard syphilis letter should be sent to the GP both at diagnosis and at 12 months (OR when serofast) to document the patients serofast serology – see Follow up below.

Treatment should be started as soon as possible following diagnosis. A confirmatory test is always required but it is not necessary to delay treatment until this is available if there is a clinical suspicion.

IF REQUIRED, PLEASE CHECK BASHH GUIDELINES FOR FURTHER TREATMENT OPTIONS IN EACH STAGE OF SYPHILIS AND DISCUSS WITH GUM SENIOR

Incubating syphilis/ Epidemiological treatment

• *Benzathine penicillin 2.4 MU IM single dose (if non penicillin allergic)

Alternative regimes:

• Doxycyline100mg orally bd for 14 days

Early syphilis (Primary, Secondary and Early Latent

• *Benzathine Penicillin 2.4 MU IM single dose

Alternative regimes:

• Doxycyline 100 mg orally bd for 14 days
• Ceftriaxone 500mg od for 10 days IM (if no anaphylaxis to penicillin)
• Amoxycillin 500 mg PO QDS plus probenecid 500 mg QDS for 14 days

Late Latent syphilis

• *Benzathine penicillin 2.4 MU IM weekly for 3 weeks (three doses on days 1, 8, 15)

Alternative regimens:

• Doxycyline 100 mg orally bd for 28 days
• Amoxycillin 2 g PO TDS plus probenecid 500 mg QDS for 28 days

Cardiovascular and Gummatous syphilis

• *Benzathine penicillin 2.4 MU IM weekly for three weeks (three doses)

Alternative regimens:

• Doxycyline 100 mg orally bd for 28 days
• Amoxycillin 2 g PO TDS plus probenecid 500 mg QDS for 28 days

Steroids should be given with all anti-treponemal antibiotics for cardiovascular syphilis; 60 mg prednisolone OD for three days starting 24 h before the antibiotics.

*Patients should be informed that Benzathine is unlicensed for this indication but has been commonly used over a long period for syphilis Rx and is considered both safe and effective. See Appendix 3 for preparation of Benzathine

Please refer to separate protocol for management of syphilis in pregnancy – protocol STI in pregnancy - and neurosyphilis.

Anaphylaxis:

Penicillin is one of the commonest causes of anaphylaxis. All staff should be familiar with the management of anaphylaxis. Facilities for resuscitation should be easily accessed.

See Appendix 4 for further information on penicillin allergy

(Includes neurological involvement in early and late disease, ocular syphilis and auricular syphilis)

Patients with suspected neurological involvement should always be discussed with a GUM Consultant for decision on a management plan

Please see neurosyphilis protocol and BASHH guidelines for further information on the investigation and management of neurosyphilis

This occurs most commonly following the treatment of early (secondary) syphilis and ALL patients should be warned about its possibility and how to manage it and this should be documented within the patient record. There is also information in the patient information leaflet. Symptoms commence 4 hours after the initiation of treatment for syphilis. (Patients with neurological, ophthalmic or auditory involvement should be considered for admission to hospital for treatment. They should also be pre-treated with prednisolone to reduce the risk of complications.) Management is paracetamol or ibuprofen and rest.

• All patients with syphilis should be referred to a health advisor for partner notification.
• In patients with primary syphilis all sexual partners in the past 3 months should be contacted. (50% of contacts of primary infection will also have syphilis)
• In patients with secondary or early latent syphilis partner notification should include all partners in the last 2 years (taking into account index patient’s last test)
• Asymptomatic contacts of early syphilis should have serology performed at presentation and then 6 and 12 weeks after last sexual contact with the index case.
• Epidemiological treatment for asymptomatic contacts of early syphilis should be considered especially when partners are unable or unwilling to attend at 6 and 12 weeks to exclude infection if initial serology is negative.
• In latent syphilis it is helpful to try and locate any previous serology (antenatal clinic, blood donation) or documented treatment. Those with late latent syphilis are usually unable to transmit infection to sexual partners. Although vertical transmission may occur at any time within the first 10 years of infection this becomes unusual more than 2 years after the onset of early syphilis.
• Sexual partners and children born to individuals diagnosed with late latent syphilis of Borders Sexual Health services unknown duration should undergo screening to exclude infection.
• Syphilis is an infection that causes risk of serious harm to others. Therefore it may be appropriate to disclose risk of infection to identifiable individuals who may be at risk of infection, without consent of the index patient, if the index patient has not informed them and cannot be persuaded to do so. This should be carried out only after discussion with the index patient’s consultant and after informing the index patient. Disclosure to other health care providers/GP, without consent may also be necessary as part of this process.

This is to exclude relapse and re-infection.

All post treatment positive syphilis serological tests will be reviewed and commented on by a senior GUM doctor – the “Summary of syphilis” serology record can be found in the Documents//Letters section on NaSH Patient Summary page.

General points

• Once a patient has been treated for STS the ROUTINE follow-up plan is always repeat serology titres at 3, 6 and 12 months post completion of treatment.
• However, repeat HIV serology at 1-month in anyone at high risk
• Usually, all patients should get a 1-year test before discharge from follow-up and sending a letter to their GP.
• The follow-up period may require to be extended if titres are still falling, the GUM senior will write this down in syphilis summary if this is the case.
• In some patients, for example, late latent STS and a negative RPR from the start of treatment, the number of follow-up tests can be reduced. For example, they may only require follow-up serology at 3-month and then at 12-months. GUM seniors can suggest this reduced follow-up for individual patients they think appropriate.
• The GUM seniors will usually only document a comment in the syphilis summary sheet (e.g. serofast). This is not queued to anyone.
• If something out of routine follow-up is required, for example, recall for early re-test or offer retreatment, they will write this in the clinical note and queue to the health advisors for action.
• Health advisors have a database of all patients treated for syphilis. They are marked for follow-up on a virtual tab at one year. At one year, guided by the GUM seniors comments (e.g. serofast), the health advisors will either discharge patient from follow-up then (and send a letter to the GP) or keep under follow-up (e.g. still falling titres). The GP is only sent a final letter at time of completion of follow-up (when RPR 0 or sero-fast, as decided by senior GUM doctor).

Early syphilis

Patients should have repeat syphilis serology on the day of treatment and then at 3, 6 and 12 months, and then 6 monthly until the RPR is negative or serofast (serofast is two RPR titres taken at least 3 months apart that are the same and of a titre 1:8 or lower).

In treated primary and secondary syphilis the RPR titre should fall by four-fold within 3-6 months and by eight-fold within 6-12 months of treatment. Normally the RPR will become negative at some point of follow-up. Around 15% of individuals with primary or secondary syphilis are expected to fail to show adequate serological response to treatment and may need further investigation and/or treatment.

Late syphilis

The fall in the RPR is much slower after treatment of late infection. Occasionally, it may remain positive at low titre (<16) during follow-up (serofast). Serological follow up is at baseline then 3, 6, and 12 months post completion of treatment and then 6 monthly until serofast (serofast is two RPR titres taken at least 3 months apart that are the same and of a titre 1:8 or lower).

Once the RPR is negative or serofast at 1:2 titre at one year the patient may be discharged from follow-up. If the titres are 1:4 or higher, then a senior physician should decide if serology is serofast or not, documenting in syphilis summary. Higher titres of RPR would be expected only if the early infection was with a very high (usually over 1:128) titre. Serofast levels above 1:8 are unusual and persistent infection/reinfection would need to be ruled out.

Relapse and re-infection

This is indicated by sustained 4-fold increase in RPR in individuals whose RPR had previously dropped, or recurrence of signs or symptoms in patients who have been treated. Re-infection is common and the most likely cause. Where re-infection is thought unlikely, retreatment with 3 doses of benzathine penicillin as per late syphilis treatment protocol should be considered after discussion with a GUM senior, and consider CSF examination.

Letter to GP

All patients should have a first letter sent to their GP documenting the diagnosis and treatment.  A second letter documenting the patients serology after completing follow up (see standard letters on NASH) should be sent once the patient is serofast - normally at 12 months post completion of treatment. Please discuss with patients the benefits of GP involvement as their RPR and IgG may remain positive for life. This documentation is required to prevent unnecessary re treatment. These letters are normally sent by the health advisors once senior doctors have checked the patient’s serology. The 12 month letter will be sent once the senior doctor has agreed the serology is serofast. A letter can be created in document store on NASH.

Patients who do not attend follow-up

If patients fail to attend our service for follow up health advisors will attempt contact with the patient and the GP to remind them that serology is required (at 3 month and 12 months only).

Pathophysiology

Syphilis is caused by the spirochete bacterium Treponema pallidum subspecies pallidum. It is a slender, spiral, motile organism and divides at intervals of 30-36 hours. Humans are its only natural host. Both pathogenic and commensal Treponemal strains can infect humans.

Transmission

Syphilis transmission is generally by sexual intercourse; through abrasions on epithelial surfaces or penetration of mucous membranes. Syphilis is therefore transmitted efficiently by oral as well as penetrative sexual intercourse. Approximately 45-60% of sexual contacts of patients with infectious (early) syphilis will themselves be infected. Patients with late stage syphilis (>2 years post acquisition) are not considered infectious to sexual partners.

Mother to child transmission of syphilis can also occur, causing congenital infection, as well as other adverse pregnancy outcomes. Transmission risk is highest in early infection; risk reduces with time, though possible even in late disease.

Natural history

Syphilis is classified as either congenital or acquired infection. Congenital infection is by mother to child transmission and is not discussed further in this protocol. If there is concern of congenital infection, the case should be discussed with a GUM Consultant.

Acquired infection is acquired except through MTC transmission, usually by sexual intercourse.  Acquired syphilis is further classified as either EARLY or LATE stage, depending on time from infection acquisition.

Classification of Acquired syphilis

Infectious/ early syphilis

Syphilis within 2 years of infection acquisition. Early syphilis is infectious to sexual partners. Early syphilis is divided into primary, secondary or early latent stages.

Primary syphilis

This is localised early infection, with the lesion appearing 10-90 days after infection acquisition.

The lesion occurs at the site of infection inoculation, initially a papule, progressing to the characteristic primary ulcer (chancre). There is frequently associated regional lymphadenopathy (usually rubbery, discrete and painless). The classical appearance of a chancre is a single, painless and indurated ulcer, with a clean base discharging clear serum. However, up to 30% of chancres are atypical and may be multiple, painful, tender, purulent or destructive. Chancres in HIV patients or in the anal region are more likely to be atypical.

Syphilis should therefore always be considered as a differential diagnosis in patients presenting with genital (or oral) ulceration not typical of HSV infection and PCR testing and a complete syphilis serology panel should be undertaken.

Chancres will resolve spontaneously over a few weeks even if untreated.

Secondary syphilis

This is symptomatic, disseminated, early infection, affecting >25% of infected patients. Symptoms appear within 6 months of infection acquisition (average 3 months). As disease is systemic now, symptoms may affect almost any body system.

Common features of secondary syphilis include:

• Constitutional symptoms (fever, myalgia, malaise, sore throat)
• Rash: typically, a generalised macular-papular erythematous rash, non-pruritic and non-sparing of palms and soles of feet
• Generalised painless lymphadenopathy
• Muco-cutaneous lesions: mucous membrane patches (painless, shallow and transient ulcers within the mouth and on the mucous membranes of the genitalia), condylomata lata (are flat, warty lesions on moist perianal and perineal skin) or non-scarring alopecia. Both mucous membrane patches and condylomata latas are highly infectious. .

Less common symptoms include:

• Ophthamological involvement: uveitis, keratitis, iridiocyclitis, optic neuritis, retinitis
• Neurological involvement: aseptic meningitis, cranial nerve palsies, nerve deafness, (syphilitic stroke)
• Hepatitis
• Splenomegaly
• Glomerulonephritis (nephrotic syndrome)
• Periostitis
• Pneumonitis

Secondary syphilis symptoms will settle within 3-12 weeks even if untreated. Symptoms however can relapse within the first two years if the patient remains untreated.

Early latent syphilis

This is diagnosed on the basis of a positive syphilis serology with no symptoms and signs, within the first two years of infection. Often the diagnosis is made on the basis of a previous negative serology result within the last 2 years. Sometimes sexual history (partner diagnosis with infectious syphilis) may help point towards this stage. Patients with early latent infection are infectious to sexual partners.

Late syphilis

Late syphilis is divided into late latent and tertiary (symptomatic) disease.

Late latent syphilis

Diagnosed when the serological tests are positive but there are no symptoms or signs of syphilis and there is no evidence of negative syphilis serology in the preceding 2 years (i.e. the infection has been present for more than 2 years). Where the duration of infection is unknown, for example, where there is no previous negative syphilis serology, patients should be treated with a regimen of treatment as for late infection.

Symptomatic late stage syphilis (Tertiary syphilis)

This will develop in 30-40% of untreated patients (average 10-40 years from initial infection).

Tertiary disease is however extremely uncommon now due to infection being controlled by antibiotics given for other reasons. There are three possible presentations:

• Gummatous/ benign syphilis (15% of patients with untreated syphilis)
• Cardiovascular syphilis (10% of patients)
• Neurosyphilis (7% of patients)

Features of tertiary syphilis:

All syphilis serology results are reviewed and commented on by a senior GUM doctor – the syphilis serology record can be found on panel view on NASH. The following is some general points only.

The diagnosis of the stage of infection is made on the individuals’ history and the clinical features together with serological tests for syphilis. Different stages of syphilis can have the same serological results. Therefore blood results, clinical picture, knowledge of previous infection and treatment and dates of any previous negative testing are needed to accurately stage the infection.

An RPR >8 and a positive IgM suggest early, active syphilis. However these test results are not reliable guides and can be misleading. 

Pattern of results of serological tests in different stages of acquired syphilis:

Key: + positive; - negative; +/- usually positive at low titre but may be negative; -/+ usually negative but may be positive at low titre

Contraindications: Allergy to penicillin or lidocaine; concomitant anticoagulant therapy; bleeding diathesis (e.g. Haemophilia); patient declines IM therapy

Administration

Reconstitute the vial of Benzathine penicillin with 6-8ml of 1% Lidocaine Hydrochloride BP solution (depending on type of Benzathine being used). (The bottle usually requires to be shaken to create a homogeneous suspension.) If the pt has a known allergy to Lidocaine then water for injections can be used instead.

Split the resultant solution into two equal volumes.

The solution should be administered by intramuscular injection at two different sites (left and right upper outer quadrant of each buttock or ventro-gluteal sites).

Use 19G (1.10) needle owing to recognised needle-clogging with concentrated formulation.

Note: Solutions in lidocaine MUST NOT be administered intravenously. Inadvertent intravenous administration of lidocaine can cause the patient to suffer bradycardia (which may lead to cardiac arrest), fitting and/or sedation. Use the ‘aspiration technique’ of injection to minimize the risk of this happening.

For de-labelling: Contact SDEC

For desensitisation: will require a referral to RIDU (Dr Sutherland)

De-labelling or desensitation procedures should be performed as inpatient and require referral to the relevant service

Only 10%, or so, of patients with a penicillin allergy label have actually experienced a true hypersensitivity reaction.

Therefore removing a penicillin allergy label can be a really useful procedure for patient care and safety and a great thing to do for antimicrobial stewardship.

Refer to the Scottish Antimicrobial Prescribing Group (SAPG) guidance on the NHS Lothian antimicrobial companion for assessing patients for penicillin de-labelling and referral pathway - https://www.antimicrobialcompanion.scot/nhs-lothian/penicillin-allergy/.

Penicillin de-labelling is not suitable for patients with anaphylaxis or angioedema or a history of a Severe Cutaneous Adverse Reaction (SCAR). If in doubt ask the GUM senior.

If penicillin de-labelling is not appropriate it is worth considering desensitisation to penicillin (this is performed as an inpatient). With the passage of time after a hypersensitivity reaction to Penicillin, most individuals cease to produce specific IgE and can safely be given the drug. About 10% of people however remain hypersensitive.