Syphilis is caused by the spirochete bacterium Treponema pallidum pallidum. Its genome is almost identical to those of the treponemes causing yaws (T. pallidum pertenue), pinta (T. carateum) and endemic syphilis (T. pallidum endemicum). These three conditions are not sexually transmitted but they are worthy of mention here because of the diagnostic confusion they can sometimes cause (see below).
Syphilis is usually transmitted by sexual contact but it can also be acquired transplacentally, perinatally and parenterally, e.g. by contaminated blood. In recent years a striking proportion of cases in men who have sex with men (20-40%) appear to have been acquired by fellatio alone. There are case reports of other modes of non-sexual transmission, e.g. from bites, but this is uncommon.
Until the mid-1990s, syphilis had been in steady decline in the UK. The infection had become so rare in the US that in 1998 the Centers for Disease Control set up a syphilis eradication program with the headline target of ridding the country of the infection by 2005. Unfortunately the decline did not continue, and since 2000 there has been an increase in the number of cases diagnosed in the US.
Since 1998 syphilis has returned to the UK, although cases are unevenly distributed throughout the country and population. Most diagnoses are made in London, Glasgow, the South East and the North West of England. Men are more likely to have syphilis than women and men who have sex with men (MSM) are more likely to have it than heterosexuals. It is still a fairly rare condition but it is worth keeping in mind as a differential diagnosis. One disturbing aspect of the epidemiology of syphilis is the high proportion of people who have co-infection with HIV. In London in 2001 54% of MSM with syphilis had HIV.
Presentation of Syphilis
‘Know syphilis in all its manifestations and relations, and all other things clinical will be added unto you.’ This oft-repeated aphorism of Sir William Osier is perhaps an exaggeration, but it gets the idea over quite nicely that syphilis can cause virtually any symptom and sign. It might help to relate the myriad symptoms if you remember that the underlying disease mechanism is vasculitis. For brevity’s sake only the most likely or important modes of presentation will be covered here.
Syphilis is categorized in various ways, most commonly into primary, secondary, early latent, late latent and tertiary stages according to the symptoms experienced. It can also be called early or late with the threshold being 2 years in the UK but 1 year in the US.
Another distinction is between infectious and non-infectious syphilis. ‘Infectious’ usually refers to primary or secondary syphilis versus other stages, but this is potentially confusing for two reasons. Firstly, during early latent syphilis intermittent mucosal ulceration can lead to transmission and secondly, syphilis has been transmitted to a fetus up to 8 years after acquisition.
When a fetus acquires this infection possible outcomes include miscarriage, still-birth and congenital syphilis. Congenital syphilis is also divided into early and late stages although a detailed discussion of its features is outwith the scope of this book.
The main feature of primary syphilis is the chancre. A pinkish red macule appears 9-90 days after inoculation. This becomes papular and then ulcerates. Classically the ulcer is solitary, painless and indurated. Sometimes more than one chancre appears and they can be tender if secondarily infected. The ulcers usually last for 1-3 weeks; longer than most cases of herpes, so persistent ulcers should raise suspicion of syphilis. Another distinguishing feature of syphilis versus herpes is that the regional lymphadenopathy that occurs with syphilis is usually non-tender. Dual infections (e.g. syphilis and herpes or chancroid) can occur and cause problems with diagnosis.
In the secondary stage of syphilis the treponemes spread haematogenously causing a multitude of symptoms or sometimes none at all. Rash is the commonest symptom with about 75% of people having one at some point over the following 2 years. The rash is usually reddish brown and macular and can cover all the body, including the palms and soles. It is not usually itchy. In moist areas such as the perineum and armpits the rash can take on a fleshy papular form called condylomata lata.
About a third of people will develop mucosal ulceration that affects the mouth and genitals. This is more likely to be confused with herpes than is the primary chancre, since the ulcers are smaller and multiple. The ulcers and moist papules are infectious sexually and through contact with someone’s broken skin.
Other less common symptoms and signs include generalized lymphadenopathy; patchy alopecia; fever; hepatitis and CNS manifestations including meningism, cranial nerve palsies and uveitis. Symptoms can be intermittent over the 2 years following acquisition.
Early latent syphilis
In the UK this is defined as syphilis acquired less than 2 years previously but with no clinical features of the infection.
Late latent syphilis
Many people fall into this category. In the UK it is defined as syphilis acquired more than 2 years previously but with no clinical features of the infection.
It is the usual diagnosis for people with syphilis of unknown duration who have no symptoms or signs. It is important to try to distinguish between true late latent syphilis and congenital syphilis. The history and examination might help with this but not everyone with congenital syphilis has obvious signs. If in doubt consult an experienced genitourinary physician.
This is very rare in the UK now. Historically 25-40% of people with untreated syphilis would go on and develop tertiary syphilis, which consists of three pathologies: gummatous syphilis, cardiovascular syphilis and neurosyphilis. Symptoms develop 2-30 years after initial infection. It is unclear what proportion of people infected in post-industrial nations today would go on to get tertiary syphilis if left untreated. In the West, treponemicidal antibiotics (penicillins, cephalosporins, tetracyclines and macrolides) are widely used for other indications and it is likely that during the decades of asymptomatic infection a person will take these drugs and either kill the spirochetes or suppress the infection so that tertiary complications are made less likely. If you would like more information about the features of tertiary syphilis, see site.
Complications of Syphilis
Any of the more severe symptoms of syphilis could be regarded as complications. This would include neurological involvement at any stage and cardiovascular syphilis. Foetal infection is almost universal if the mother has primary or secondary infection, but it is unusual in the late latent stage. This can result in stillbirth or congenital syphilis which causes numerous signs including organomegaly, skeletal deformity, anaemia and a wide variety of rashes. Due to the UK antenatal screening program, congenital syphilis is extremely rare with only about 30 cases per year. Most cases occur in women who have not been screened. With the recent rise in the incidence of syphilis, more cases of congenital syphilis will occur, including children born to women who acquired syphilis in pregnancy but after their screening serology.
Diagnosis of Syphilis
Most people are diagnosed using serological analysis of a blood specimen. A wide variety of assays are used but can be divided into treponemal tests (detect antibodies to treponemes) and non-treponemal tests (detect antibodies to cardiolipin). The former almost always stay positive, even after treatment, whereas the latter usually become negative after successful treatment .
Different labs use different tests, but popular ones are the IgG and IgM enzyme immunoassays, which are treponemal tests, and the rapid plasma reagin (RPR), which is non-treponemal. Other treponemal tests include the treponema pallidum particle agglutination assay (TPPA), the treponema pallidum haemgglutination assay (TPHA) and the fluorescent treponemal antibody (FTA) tests. The only other non-treponemal test in common usage is the Venereal Diseases Research Laboratory test (VDRL). Tests become positive from about 2 weeks after acquisition [the IgM enzyme immunoassay (EIA) usually being the first to react], although it is sensible to allow a window of 3 months in case of delayed seroconversion. Positive non-treponemal tests are presented as titres (neat, 1:2, 1:4, 1:8 etc) and treponemal tests are usually presented as positive or negative.
A treponemal test is not specific for T. pallidum pallidum. All the serological tests also react if the person has a non-venereal treponeme (see introduction). A youth spent outside Europe could give a clue that this might not be syphilis. Unusual scarring of the shins could suggest yaws.
In the absence of a clear history of an alternative diagnosis, treat for syphilis. If the person does have yaws, pinta or endemic syphilis, they will be cured by the drugs given for syphilis.
Interpreting syphilis serology can be difficult: this is particularly true if trying to determine whether the person has had a satisfactory response to treatment. This depends on the speed of the fall in the RPR titre and can be influenced by the stage of syphilis and whether the patient has had it before. If the person has antibiotics early in the infection it can modify the serological response; HlV-impaired humoral immunity can also lead to an unusual response or no seroconversion at all. A variety of conditions can lead to false-positive results, this is particularly a problem with the RPR and VDRL tests.
In general it is best to discuss positive syphilis serology with an experienced GU physician.
In a patient with an ulcer, more diagnostic options are available. Probably the oldest diagnostic test available is dark-field microscopy, which uses a modified condenser lens to examine a thin film of exudate taken from a chancre or lesion of secondary syphilis. This is also a good test for people with primary syphilis, when serology might still be negative. It cannot be used for examining oral lesions since commensal spirochetes in the mouth can give a false-positive result. Another problem is that the test is only available if you have the patient near a microscope, so in general this means it is limited to genitourinary medicine clinics.
PCR tests for syphilis are becoming available that allow diagnosis from a swab taken from an ulcer. Some of the tests use multiple primers to test for syphilis, chancroid and herpes from a single swab. If you have a patient with a possibly syphilitic ulcer, ask your lab if the PCR test is available.
Tests using oral fluid and urine are in development and could facilitate screening in the future.
Treatment of Syphilis
The most widely used drug for treating syphilis is penicillin given intramuscularly. The amount used and the length of treatment depends on the stage of syphilis and whether the person has HIV. Unfortunately, the long-acting versions of penicillin that are most convenient to give are not widely available and there is no international consensus on what constitutes adequate treatment.
The following are commonly used regimens in UK genitourinary medicine clinics and are recommended in the UK National Guidelines on the Management of Syphilis.
• primary syphilis
– benzathine penicillin 2.4 MU (1.8 g) i.m. once
• secondary (unless; neurological symptoms/signs) and early latent syphilis
– benzathine penicillin 2.4 MU (1.8 g) i.m. once per week, two doses
• late latent, gummatous and cardiovascular-syphilis
– beazathine penicillin 2.4 MU (1.8 g) i.m. once per week, three doses
• neurosyphilis (including neurological features to early syphilis) and co-infection with HIV
– procaine penicillin 2.4 MU i.m. o.d. plus probenecid 500 mg p.o. q.d.s. for 17 days.
The evidence base for using alternative agents is very scanty. Ceftriaxone, doxycycline and azithromycin are probably effective, but they require further evaluation before they can be recommended as first-line agents. There are increasing reports of T. pallidum strains being resistant to azithromycin, although resistance to penicillin has not been reported. This does not mean that the treatment will always lead to an adequate serological response, however.
About 4 hours after the start of treatment, an acute febrile episode (called the Jarisch-Herxheimer reaction) can occur. This is particularly likely in early syphilis. It is unpleasant but rarely causes any major problems. In late pregnancy it can result in premature labour, and in neuro/cardiovascular syphilis it might lead to a worsening of symptoms. The symptoms can be partially relieved by pre-dosing with paracetamol. Despite persisting treponemal antibodies, patients should be informed that they are not immune to syphilis and can catch it again.
Treating in pregnancy requires the same course of penicillin as would be used for the woman if she was not pregnant. Alternative agents should not be used.
If treatment is completed by a month prior to delivery, then it is likely to be successful in preventing congenital syphilis. At the very least, the child will require syphilis serology to be done at birth, 1 month, 3 months and 6 months. Tests should include the IgM EIA.
In its early stages, syphilis is highly infectious, including by oral sex. Therefore, all sexual contacts at risk should be traced and tested. Syphilis can only be transmitted sexually for the first 2 years after acquisition; unfortunately, it is often hard to say when those 2 years have passed, particularly in the common situation where someone is found to have positive serology, no symptoms and no prior testing.
Other management of Syphilis
All people diagnosed with syphilis should be offered an HIV test. This is for three reasons:
1. If they have HIV, they will need prolonged treatment.
2. Syphilis increases the risk of acquiring and transmitting HIV by a factor of four.
3. HIV can result in unusual antibody responses that could make it harder to judge an adequate response to treatment.
Patients should also be offered screening for other STIs.
All people treated for syphilis need follow-up to ensure that the RPR titre is falling at an adequate rate. People treated for neurosyphilis need repeated sampling of the CSF for the same purpose. If the RPR starts to rise again it could indicate treatment failure or reinfection.
Duration of follow-up depends on the stage of syphilis treated, the kind of treatment, whether the patient has HIV and the rate of RPR fall. There is an element of subjectivity involved in deciding whether someone has been cured; whether the person has been adherent to the treatment is an important consideration. For this reason injectable agents are likely to remain popular.