Syphilis

Sources and selection criteria

This review is based on Pubmed and Medline searches for syphilis (key words: syphilis, English, human) for the past five years (2000 to February 2006). I supplemented this with the literature review done for the development (in 1999) and updating (in 2002) of the UK National Early and Late Syphilis Guidelines (I was a member of the working party that first developed and is currently updating these guidelines).^{w1,w2, w3}

Why is syphilis important?

Syphilis, caused by Treponema pallidum (box 1, fig 1⇓), is a common infection worldwide, with an estimated 10-12 million new infections each year.^w4 Early syphilis causes significant morbidity, and a systematic review of HIV transmission studies confirms that it is an important facilitator of HIV transmission.3 Congenital syphilis remains a major cause of stillbirth, childhood morbidity, and mortality worldwide.4 ^w4 The broad range of manifestations of late syphilis means that this diagnosis should be considered in a wide range of settings.

Fig 1 Treponema pallidum

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Who gets syphilis?

Syphilis is a sexually transmitted infection, and the more sexual partners that individuals (or other members of their sexual network) have, the more likely they are to acquire syphilis. Mobility, social disruption, and a collapse of medical services have all been recognised as factors that have contributed to syphilis epidemics: the UK during the second world war; the United States with the emergence of crack cocaine use in the late 1980s; the countries of the former Soviet Union in the mid-1990s.

In the late 1990s syphilis re-emerged as an important infection in western Europe. Between 1984 and 1997 acquisition of syphilis in the UK was rare (fig 2⇓),1 but since the late 1990s a sustained epidemic of syphilis has occurred in homosexual men. A disproportionate number of these men are also HIV antibody positive, raising important questions about sexual health promotion and care for sexually transmitted infections among homosexual men, particularly those who have HIV infection.

In parallel to the outbreak of syphilis in homosexual men, early syphilis among heterosexual men and women in the UK has also been increasingly recognised.5 Clusters of cases have been noted in Cambridgeshire and Walsall,^w6,w7 and syphilis outbreaks in south and east London (particularly associated with female commercial sex workers) have recently been described.^w8

Fig 2 Numbers of diagnoses of syphilis (primary, secondary, and early latent), by sex, recorded in genitourinary medicine clinics in England, Wales, and Scotland (equivalent Scottish data not available before 1945)

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How is syphilis transmitted?

It is estimated that 30-60% of sexual contacts of individuals with early syphilis will acquire syphilis themselves.^{w9 w10} Entry of T pallidum probably occurs through areas of “microtrauma,” usually in mucous membranes. In the current outbreak of syphilis among homosexual men, oro-anal intercourse (“rimming”) and oral sex seem to be important routes of transmission so that even individuals who consistently use condoms for penetrative sex may also acquire or transmit the infection.1 Most sexual transmission of syphilis probably occurs from the genital and mucous membrane lesions of primary and secondary syphilis.

How is syphilis classified?

The classification of syphilis has not changed for over 100 years and is usually described in terms of disease stages (box 2). Primary syphilis is the stage of initial inoculation of T pallidum; in secondary syphilis there is a bacteraemia and wide dissemination of T pallidum; and late (tertiary) syphilis relates to the chronic, end organ complications (particularly cardiovascular and neurological) of syphilis often many years after initial infection.

However, many individuals are diagnosed by positive serological tests alone and have no symptoms or signs of syphilis. This is called latent syphilis and is divided into early latent (less than two years' duration of infection according to UK classification and the World Health Organization; less than one year according to the US and European classification) and late latent syphilis (for asymptomatic infection beyond this time). This relatively arbitrary distinction is made for two main reasons. Firstly, individuals with late latent syphilis are less likely to transmit syphilis sexually and vertically, and, secondly, individuals with later stage syphilis may need longer courses of therapy (because of the possibly slower reproduction time of T pallidum in later stages of the disease^w11).

The pathophysiology (particularly reasons for the variation of symptomatology between individuals) of secondary and tertiary syphilis is not clearly understood.

What is the natural course of untreated syphilis?

Primary syphilis

The lesion of primary syphilis occurs at the site of initial inoculation of T pallidum. It is usually single and painless but can be multiple and painful. It tends to begin as a macule that becomes a papule, which then ulcerates. A two to three week incubation period usually occurs between the inoculation of T pallidum and development of the lesion (the range of incubation period is reported as being 9-90 days). Local, non-tender lymphadenopathy is often associated with this lesion. Figure 3⇓ shows primary syphilis lesions on the penis.

Fig 3 Primary syphilis lesion on penis

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If left untreated, a lesion heals spontaneously four or five weeks later (range of healing 3-10 weeks).^{w12 w13} Because the ulcers are usually painless and can occur at sites where they are not visible (perianally or in the anal canal, vagina, or cervix) or not recognised (mouth ulceration), many individuals with primary syphilis do not present to services or are not diagnosed at presentation.

Secondary syphilis

Four to eight weeks after primary syphilis, T pallidum becomes a systemic infection with bacteraemia. This secondary stage of syphilis is characterised by a generalised and usually symmetrical macular papular rash (fig 4⇓), which is often widespread and may also involve the scalp, palms (fig 5⇓), and soles. Occasionally this rash is predominantly papular, and rarely these papules ulcerate. This can be associated with generalised lymphadenopathy and mucosal ulceration. ^{w11 w13} These ulcers may coalesce on the bucal mucosa, forming “snail track” ulcers, and in the genital regions (where there are opposing membranes) they can cause wart-like lesions called condylomata lata (fig 6⇓). These features are often accompanied by constitutional symptoms such as fevers and malaise.

Fig 4 Rash accompanying secondary syphilis

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Fig 5 Rash on palms accompanying secondary syphilis

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Fig 6 Condylomata lata

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The widespread vasculitis during secondary syphilis may lead to a broad range of syndromes such as hepatitis, iritis, nephritis, and neurological problems (early meningovascular syphilis) with headache and involvement of the cranial nerves, particularly the VIII (auditory) nerve. These complications of secondary syphilis are relatively uncommon, occurring in less than 10% of individuals.^w12

Neurosyphilis

As well as being a manifestation of secondary syphilis, meningovascular syphilis can also occur in tertiary syphilis. The incubation period is usually 5-12 years, and its symptoms are similar to those of early meningovascular syphilis.

Parenchymatous neurosyphilis is involvement of the spinal cord (predominantly dorsal columns) and brain (and occasionally both) by syphilis. The incubation period of this is usually 10-20 years. The spinal cord syndrome is called tabes dorsalis (box 3). The brain syndrome is called general paralysis of the insane (box 4). Both syndromes remain important differential diagnoses for a wide range of neurological presentations, including dementia, psychiatric disease, and mobility problems.7

Cardiovascular syphilis

Cardiovascular syphilis usually occurs 15-30 years after primary syphilis and may occur in any large vessel. It is characterised, however, by an aortitis usually affecting the proximal aorta. It may cause aortic incompetence (which may be complicated by heart failure), coronary ostial stenosis (presenting as angina), and aortic medial necrosis causing aortic aneurysm.

Gummatous syphilis

These are granulomatous locally destructive lesions which usually occur three to 12 years after primary syphilis. They can occur in almost any tissue but most commonly present when they affect skin or bone.

Congenital syphilis

Pregnant women with syphilis can transmit the infection to the fetus. Transmission is usually transplacental and is particularly likely during the first two years of infection. It is rare after four years, although cases of transmission up to 10 years after acquisition of syphilis have been reported. About a third of babies born to mothers with early syphilis are born without infection and a third with congenital syphilis; a third of pregnancies will result in miscarriage or stillbirth. Between half a million and a million cases of congenital syphilis occur each year worldwide,4 and in some resource poor countries up to a fifth of neonatal mortality is directly attributable to syphilis.8

Almost all cases of congenital syphilis are easily prevented by antenatal screening for syphilis and treatment during pregnancy.9 Even in countries where this is an unusual condition (such as the UK), an increase in cases has recently been reported,5 and continuing vigilance remains vital.^w5 Congenital syphilis is classified as either early or late congenital syphilis depending on whether it presents before or after 2 years of age (box 5). The prognosis is particularly poor if symptoms of syphilis are present in the first few weeks after birth.

HIV infection and syphilis

In the past five years the relation between HIV and syphilis has been extensively debated and researched. Syphilis is most common among individuals who are at risk of other sexually transmitted infections, such as HIV. As syphilis is an ulcerative sexually transmitted disease, individuals with syphilis are at increased risk of acquiring and transmitting HIV. In the current syphilis outbreak in Europe, individuals who have been diagnosed with HIV are at particular risk of acquiring syphilis.4 ^w14 All patients diagnosed with syphilis must therefore be tested for HIV, and those having follow-up for HIV must have regular screening for syphilis.^w14

The clinical presentation, serological tests, and treatment response among individuals with HIV infection who also have syphilis are usually the same as among individuals without HIV infection who acquire syphilis.10 11 But good evidence shows that some differences in clinical presentation do exist between HIV positive and negative individuals presenting with early syphilis (box 6).12 13 Late syphilis may also develop more rapidly in HIV positive individuals, but the evidence for this is confined to case reports.14 15.

Some specialists recommend that a possible difference in the natural course and treatment response (particularly the possibility that neurosyphilis is a greater risk among individuals with HIV infection16) justifies the use of higher doses of antibiotics and longer courses for adequate treatment. But most evidence suggests that identical management of HIV positive and negative patients is reasonable, especially in early infection.17

How is syphilis diagnosed?

The diagnosis of syphilis (and the interpretation of syphilis serology) is often thought to be complex, but diagnosis is usually straightforward. After diagnosis, most patients should be referred to a specialist for further assessment and management, or advice on management should be sought from services experienced in treating the disease.

Tests for syphilis

As culture of T pallidum is not possible in vitro and culture in animal models is purely a research tool, diagnosis testing depends on direct identification of the bacterium and serological tests.

Serology

Serological tests for syphilis remain the mainstay of diagnosis. There are two groups of tests: treponemal (or specific) and non-treponemal (or non-specific). The most important of these tests and their different and complementary characteristics are summarised in box 7

Box 7: Treponemal tests v non-treponemal tests

Treponemal tests*

• T pallidum particle agglutination assay (TPPA): incubation period† 4-6 weeks

• T pallidum haemagglutination assay (TPHA): incubation period† 4-6 weeks

• Enzyme immunosorbant assay (EIA) IgG/IgM: incubation period 3 weeks

Non-treponemal tests‡

• Rapid plasma reagin (RPR): incubation period 4 weeks

• Venereal Disease Reference Laboratory (VDRL): incubation period 4 weeks

Serological response to yaws

• The serological response to yaws (caused by the non-sexually transmitted organism T pertenue, which rarely causes serious late disease) is identical to syphilis, so in practice most patients with suspected yaws are managed as though they have syphilis

*Usually only positive if current or past syphilis; usually positive lifelong after treatment

†Incubation period is the usual time after infection that the test becomes positive

‡Give a titre that acts as measure of disease “activity” (titre reduced with treatment, raised with reinfection); biological false positives occur with other acute and chronic infections/autoimmune disease

In the past five years, enzyme immunosorbant assay (EIA) tests have become established as the screening test of first choice in syphilis.^w15 These tests can be automated and are generally reliable. A recent Health Protection Agency assessment of 10 such tests showed the sensitivity of nine of these tests to be 100% (confidence interval 98.5% to 100%) with a specificity of 100% in seven tests (97% to 100%).^w16 An enzyme immunosorbant assay test is not useful in identifying reinfection with syphilis.

Recently, several rapid simple dipstick treponemal tests have been developed. These tests have sensitivities of 85-98% compared with TPHA/TPPA testing and a specificity of 93-98%.^w17 These tests may increase the coverage of syphilis screening programmes by allowing testing in settings without laboratory facilities.

The main cause of false negative tests in syphilis serology is testing in early infection. All serological tests may be negative in incubating syphilis and early primary infection. Non-treponemal tests may revert to negative in untreated late syphilis.

Screening for syphilis is usually done with an enzyme immunosorbant assay test. Several syphilis testing algorithms are available to allow the rational use of these tests (fig 7⇓).20

Simplified testing algorithm for screening for syphilis using treponemal enzyme immunosorbant assay (EIA) tests. Adapted from Public Health Laboratory Service (Syphilis (Treponemal) Screening and Interpretation algorithm)20

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Patients with symptoms or signs of possible neurosyphilis should have a cerebrospinal fluid examination. Most patients with neurosyphilis will have positive non-treponemal tests in the cerebrospinal fluid examination, as well as a raised white cell count and protein.^w18

How is syphilis treated?

Penicillin was established as a highly effective treatment for syphilis long before randomised clinical trials became the norm for determining treatment efficacy. Penicillin in a variety of doses and regimens was shown to cure rapidly the lesions of early syphilis and to prevent the clinical progression of early and latent syphilis to later stages of the disease.21

Parenteral penicillin is the treatment of choice for all stages of syphilis,17 although the duration of treatment and the types of penicillin vary between guidelines. Benzathine penicillin (unlicensed in the UK) 2.4 million units given intramuscularly as a single dose (divided into 1.2 million units in each buttock) is the treatment of choice for early syphilis.

Problems establishing the best therapeutic approach have been compounded by T pallidum not being cultured in vitro (the rabbit inoculation model is often used to study its biology), and the tools to assess treatment response remain unsatisfactory. This has led to difficulties assessing newer therapies (such as oral therapies) and best treatment in new clinical situations (namely, HIV infection.)

Standard antisyphilis therapy rarely fails to cure the disease, and strains of T pallidum that are intrinsically resistant to penicillin have not been described. Doxycycline can be used as a second line therapy for patients who decline parenteral treatment or who are allergic to penicillin (see table 1⇓ for the current UK syphilis treatment recommendations and box 8 for online sources of the major national and international syphilis guidelines).

Newer treatments

An effective single dose oral therapy for syphilis would be a major advance in syphilis control, and a recent large prospective randomised trial suggested that 2 g oral azithromycin is as effective in treating early syphilis as benzathine penicillin.22 This important study will probably lead to the increasing use of azithromycin for the treatment of early syphilis, but the study findings have been treated with some caution as macrolide treatment failure is well recognised and seems to be associated with intrinsic macrolide resistance in some strains of T pallidum.23

Further management and follow-up

All individuals with syphilis should be tested for other sexually transmitted infections, including HIV. The patient's partner(s) should be notified, but the role of partner notification is limited in syphilis outbreaks where many partners are not identifiable or contactable.1 ^w19

Patients with symptomatic early syphilis should have clinical evaluation at follow-up to confirm resolution of symptoms, and patients with a positive result with rapid plasma reagin (RPR) testing or with Venereal Disease Reference Laboratory (VDRL) testing should have a serological follow-up until the rapid plasma reagin test becomes negative (or “serofast”—identical titres from RPR or VDRL testing three months apart). A fourfold decrease in RPR or VDRL titre is considered to indicate an adequate treatment response. Patients with late syphilis will require long term follow-up from appropriate specialists.

Patients who acquire syphilis are at significant risk of reinfection, so recommending regular serological screening for syphilis and providing sexual health promotion are essential parts of syphilis management.

Syphilis in the future

Syphilis is likely to remain a common disease worldwide, and some awareness of its prevention, presentation, diagnosis, and treatment is important for all clinicians. Many of the tools for effective syphilis control (such as antenatal screening to prevent congenital syphilis) are already well established but have not been fully implemented in many parts of the world.

The likely absence of a syphilis vaccine in the foreseeable future means that syphilis control will depend largely on reducing risk taking among individuals and communities affected by syphilis and on the diagnosis and treatment of individuals with early syphilis. Comprehensive sexual health promotion programmes have been shown to reduce syphilis prevalence,24 as have new treatment approaches such as syndromic management of genital ulcer disease.25 Primary prevention, together with provision of easily accessible syphilis diagnostic and treatment services, will remain the cornerstone of syphilis control.