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For the full versions of these articles see bmj.com CLINICAL REVIEW
Syphilis remains common worldwide, and since the SUMMARY POINTS
late 1990s infectious early syphilis has re-emerged as Syphilis remains a common disease worldwide, and an important disease in western Europe, including the infectious syphilis has re-emerged in western Europe United Kingdom.1 The clinical presentation of both Syphilis causes considerable morbidity and facilitates HIV early and late syphilis is diverse, and patients may BMJ 2007;334:143-7
present to a wide range of services and clinicians, The clinical presentation of syphilis is diverse, with patients including general practitioners. This review will empha- presenting to a wide range of practitioners and services sise the clinical presentation of syphilis because once A high index of suspicion of syphilis and a low threshold for syphilis has been suspected diagnosis and curative treat- Diagnosing and treating syphilis are usually straightforward 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 for the UK National Early
and Late Syphilis Guidelines
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 morbid-
ity, 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
Who gets syphilis?
Syphilis is a sexually transmitted infection, and the
In the late 1990s syphilis re-emerged as an important more sexual partners that individuals (or other mem- infection in western Europe. Between 1984 and 1997 bers of their sexual network) have, the more likely they acquisition of syphilis in the UK was rare,1 but since the are to acquire syphilis. Mobility, social disruption, and late 1990s a sustained epidemic of syphilis has occurred a collapse of medical services have all been recognised as factors that have contributed to syphilis epidemics: In parallel to the outbreak of syphilis in homosexual the UK during the second world war; the United States men, early syphilis among heterosexual men and women with the emergence of crack cocaine use in the late in the UK has also been increasingly recognised.5 Clus- 1980s; the countries of the former Soviet Union in the ters 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 Box 1| Characteristics of Treponema pallidum• Coiled, motile spirochaete bacterium How is syphilis transmitted and classified?
It is estimated that 30-60% of sexual contacts of • Genome sequenced, very small, circular2 individuals with early syphilis will acquire syphilis • Obligate parasite (limited metabolic capabilities) themselves.w9 w10 Entry of T pallidum probably occurs through areas of “microtrauma,” usually in mucous CLINICAL REVIEW
Box 2 | Stages of syphilis• Primary syphilis Incubation period 2-3 weeks (range 9-90 days) Incubation period 6-12 weeks (range 1-6 months); Asymptomatic syphilis of <2 years’ duration Asymptomatic syphilis of 2 years’ duration • Late symptomatic syphilis (tertiary syphilis) Fig 3 | Rash on palms accompanying secondary syphilis
Cardiovascular syphilis, neurosyphilis, gummatous which is often widespread and may also involve the scalp, palms (fig 3), and soles. Occasionally this rash membranes, and most sexual transmission of syphilis is predominantly papular, and rarely these papules probably occurs from the genital and mucous mem- ulcerate. This can be associated with generalised brane lesions of primary and secondary syphilis. The lymphadenopathy and mucosal ulceration. w11 w13 These classification of syphilis has not changed for over 100 ulcers may coalesce on the bucal mucosa, forming years and is usually described in terms of disease “snail track” ulcers, and in the genital regions (where stages (box 2, and more detail on bmj.com).
there are opposing membranes) they can cause wart-like lesions called condylomata lata. These features are What is the natural course of untreated syphilis?
often accompanied by constitutional symptoms such as The lesion of primary syphilis occurs at the site of initial The widespread vasculitis during secondary syphi- inoculation of T pallidum. It is usually single and pain- lis may lead to a broad range of syndromes such as less but can be multiple and painful. It tends to begin as hepatitis, iritis, nephritis, and neurological problems a macule that becomes a papule, which then ulcerates. (early meningovascular syphilis) with headache and A two to three week incubation period usually occurs involvement of the cranial nerves, particularly the between the inoculation of T pallidum and development V (auditory) nerve. These complications of second- of the lesion (the range of incubation period is reported ary syphilis are relatively uncommon, occurring in as being 9-90 days). Local, non-tender lymphaden- opathy is often associated with this lesion. Figure 2 shows primary syphilis lesions on the penis. Relapsing secondary syphilis and latent syphilis If left untreated, a lesion heals spontaneously four Individuals with secondary syphilis who do not have or five weeks later (range of healing 3-10 weeks).w12 w13 treatment improve spontaneously over three to six Because the ulcers are usually painless and can occur weeks. About a quarter of patients have relapsing at sites where they are not visible (perianally or in episodes of secondary syphilis, with recurrence of rash, the anal canal, vagina, or cervix) or not recognised mucosal ulceration, and fevers. These relapses are rare (mouth ulceration), many individuals with primary after one year and almost never occur after two years.6 syphilis do not present to services or are not diag- The infection then becomes asymptomatic (latent).
About 35% of individuals with late latent syphilis will Four to eight weeks after primary syphilis, T pallidum develop the late manifestations of syphilis (tertiary becomes a systemic infection with bacteraemia. This syphilis).6 The three main manifestations of late syphilis secondary stage of syphilis is characterised by a gener- are neurosyphilis, cardiovascular syphilis, and gumma- alised and usually symmetrical macular papular rash, tous syphilis, and all these complications are currently rare outside resource poor countries.7 Neurosyphilis
As well as being a manifestation of secondary syphi-
lis, meningovascular syphilis can also occur in terti-
ary 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 incuba- Fig 2 | Primary syphilis lesion on penis
tion period of this is usually 10-20 years. The spinal CLINICAL REVIEW
cord syndrome is called tabes dorsalis, and the brain Box 4 | Treponemal tests v non-treponemal tests
syndrome is called general paralysis of the insane (see extra boxes on bmj.com). Both syndromes remain • T pallidum particle agglutination assay (TPPA): incubation important differential diagnoses for a wide range of neurological presentations, including dementia, psychi- • T pallidum haemagglutination assay (TPHA): incubation • Enzyme immunosorbant assay (EIA) IgG/IgM: incubation Cardiovascular syphilis
Cardiovascular syphilis usually occurs 15-30 years after primary syphilis and may occur in any large vessel. It is • Rapid plasma reagin (RPR): incubation period 4 weeks characterised, however, by an aortitis usually affecting • Venereal Disease Reference Laboratory (VDRL): the proximal aorta. It may cause aortic incompetence (which may be complicated by heart failure), coronary ostial stenosis (presenting as angina), and aortic medial • 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 Gummatous syphilis
practice most patients with suspected yaws are managed 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 *Usually only positive if current or past syphilis; usually positive lifelong after treatment commonly present when they affect skin or bone.
†Incubation period is the usual time after infection that the test becomes The pathophysiology (particularly reasons for the vari- positive ‡Give a titre that acts as measure of disease “activity” (titre reduced with ation of symptomatology between individuals) of second- treatment, raised with reinfection); biological false positives occur with ary and tertiary syphilis is not clearly understood.
other acute and chronic infections/autoimmune disease Congenital syphilis
in Europe, individuals who have been diagnosed with Pregnant women with syphilis can transmit the infec- HIV are at particular risk of acquiring syphilis.4 w14 All tion to the fetus. Transmission is usually transplacental patients diagnosed with syphilis must therefore be tested and is particularly likely during the first two years of for HIV, and those having follow-up for HIV must have infection. About a third of babies born to mothers with early syphilis are born without infection and a third The clinical presentation, serological tests, and treat- with congenital syphilis; a third of pregnancies will ment response among individuals with HIV infection result in miscarriage or stillbirth. Between half a million who also have syphilis are usually the same as among and a million cases of congenital syphilis occur each individuals without HIV infection who acquire syphi- year worldwide,4 and in some resource poor countries lis,10 11 but with some variation (box 3). up to a fifth of neonatal mortality is directly attributable Some specialists recommend that a possible differ- ence in the natural course and treatment response (par- Almost all cases of congenital syphilis are easily pre- ticularly the possibility that neurosyphilis is a greater vented by antenatal screening for syphilis and treat- risk among individuals with HIV infection16) justifies ment during pregnancy.9 Even in countries where this the use of higher doses of antibiotics and longer courses is an unusual condition (such as the UK), an increase for adequate treatment. But most evidence suggests that in cases has recently been reported,5 and continuing identical management of HIV positive and negative vigilance remains vital.w5 Congenital syphilis is classi- patients is reasonable, especially in early infection.17 fied as either early or late congenital syphilis depending on whether it presents before or after 2 years of age (see What questions should be asked?
extra box on bmj.com). The prognosis is particularly The diagnosis of syphilis (and the interpretation of poor if symptoms of syphilis are present in the first few syphilis serology) is often thought to be complex, but The history is guided by presenting symptoms. HIV infection and syphilis
A brief sexual history may be useful to identify those As syphilis is an ulcerative sexually transmitted disease, individuals most at risk of syphilis; this is particularly individuals with syphilis are at increased risk of acquiring important in asymptomatic patients. A history of nega- and transmitting HIV. In the current syphilis outbreak tive syphilis tests (such as at sexually transmitted infec-tion clinics or at blood donor sessions or antenatal screening)—as well any previous diagnosis and treat- Box 3 | How syphilis affects patients with HIV
ment for syphilis—may also be useful in evaluating • Primary syphilis: larger, painful multiple ulcers12 13 patients and interpreting positive serology.
• Secondary syphilis: genital ulcers more common and higher titres with rapid plasma reagin testing and Tests for syphilis
Venereal Disease Reference Laboratory testing12 13 As culture of T pallidum is not possible in vitro and • Possibly more rapid progression to neurosyphilis14 15 culture in animal models is purely a research tool, CLINICAL REVIEW
of 85-98% compared with TPHA/TPPA testing and a UK guidelines for syphilis treatment, 2005 specificity of 93-98%.w17 These tests may increase the coverage of syphilis screening programmes by allow-ing testing in settings without laboratory facilities. All Benzathine penicillin 2.4 megaunits (intramuscular, single dose), or procaine penicillin 600 000 units serological tests may be negative in incubating syphilis Benzathine penicillin 2.4 megaunits (intramuscular, Screening for syphilis is usually done with an enzyme three injections over 2 weeks: days 0, 7, 14), or immunosorbant assay test. Several syphilis testing algo- procaine penicillin 900 000 units (intramuscular, rithms are available to allow the rational use of these Procaine penicillin 2.4 units once daily Patients with symptoms or signs of possible neuro- (intramuscular, for 17 days) with oral probenecid syphilis should have a cerebrospinal fluid examination. Most patients with neurosyphilis will have positive non- diagnosis testing depends on direct identification of treponemal tests in the cerebrospinal fluid examination, the bacterium and serological tests.
as well as a raised white cell count and protein.w18 How is syphilis treated?
Identification of T pallidum (seen as a motile spiro- Penicillin was established as a highly effective treat- chaete in a saline solution) by dark ground micro- ment for syphilis long before randomised clinical trials scopy from samples taken from the genital lesions of became the norm for determining treatment efficacy. primary and secondary syphilis allows the immediate Penicillin in a variety of doses and regimens was shown diagnosis of syphilis, with a sensitivity rate of up to to cure rapidly the lesions of early syphilis and to pre- 97% being reported in a study from 2004.18 But it is vent the clinical progression of early and latent syphilis rarely feasible to perform this test outside special- ist services. DNA amplification (polymerase chain Standard antisyphilis therapy rarely fails to cure the reaction) may prove to be important in the diagnosis disease, and strains of T pallidum that are intrinsically of early syphilis—with a sensitivity of 94.7% and a resistant to penicillin have not been described. The specificity of 98.6% in primary syphilis (compared table shows the current UK syphilis treatment recom- with clinical diagnosis with serological confirmation) mendations, and box 5 shows online sources of the major national and international syphilis guidelines. Newer treatments
Serological tests for syphilis remain the mainstay of An effective single dose oral therapy for syphilis would diagnosis. There are two groups of tests: treponemal (or be a major advance in syphilis control, and a recent specific) and non-treponemal (or non-specific). The most large prospective randomised trial suggested that 2 g important of these tests and their different and comple- oral azithromycin is as effective in treating early syphi- mentary characteristics are summarised in box 4.
lis as benzathine penicillin.22 This important study will In the past five years, enzyme immunosorbant assay probably lead to the increasing use of azithromycin (EIA) tests have become established as the screening for the treatment of early syphilis, but the study find- test of first choice in syphilis.w15 These tests can be ings have been treated with some caution as macrolide automated and are generally reliable. A recent Health treatment failure is well recognised and seems to be Protection Agency assessment of 10 such tests showed associated with intrinsic macrolide resistance in some the sensitivity of nine of these tests to be 100% (con- fidence interval 98.5% to 100%) with a specificity of 100% in seven tests (97% to 100%).w16 Further management and follow-up
Recently, several rapid simple dipstick treponemal All individuals with syphilis should be tested for tests have been developed. These tests have sensitivities other sexually transmitted infections, including HIV. The patient’s partner(s) should be notified, but Box 5 | National and international treatment guidelines for
the role of partner notification is limited in syphilis outbreaks where many partners are not identifiable World Health Organization. Guidelines for the managment of sexually transmitted infections. http://whqlibdoc.who.
Patients who acquire syphilis are at significant risk int/publications/2003/9241546263.pdf (last updated of reinfection, so recommending regular serological screening for syphilis and providing sexual health pro- Centers for Disease Control and Prevention (US motion are essential parts of syphilis management.
guidelines). www.cdc.gov/std/treatment/ (last updated 2006)International Union Against STIs (European). www.iusti.
Syphilis in the future
Syphilis is likely to remain a common disease world- Clinical Effectiveness Group, British Association for Sexual wide, and some awareness of its prevention, presen- Health and HIV (UK guidelines). www.bashh.org (last tation, diagnosis, and treatment is important for all clinicians. Many of the tools for effective syphilis con- CLINICAL REVIEW
upon a re-study of the Boeck-Bruusgard material. Acta Derm Venereol 7 Danielsen AG, Weismann K, Jorgensen BB, Heidenheim M, Fugleholm AM. Incidence, clinical presentation and treatment of neurosyphilis in Establishing effectiveness of single dose oral therapy Denmark 1980-1997. Acta Derm Venereol 2004;84:459-62.
Developing cheap, bedside diagnostic tests 8 Watson-Jones D, Changalucha J, Gumodoka B, Weiss H, Rusizoka M, Ndeki L, et al. Syphilis in pregnancy in Tanzania. 1. Impact of maternal syphilis on outcome of pregnancy. J Infect Dis 2002;186:940-7.
9 Watson-Jones D, Gumodoka B, Weiss H, Changalucha J, Todd J, Mugeye K, et al. Syphilis in pregnancy in Tanzania. II. The Adler M, Cowan F, French P, Mitchell H, Richens J, eds. ABC effectiveness of antenatal syphilis screening and single dose of sexually transmitted infections. 5th ed. London: BMA benzathine penicillin treatment for the prevention of adverse pregnancy outcomes. J Infect Dis 2002;186:948-57.
10 Goeman J, Kivuvu M, Nzila N, Behets F, Edidi B, Gnaore E, et al. Similar Holmes KK, Frederick Starling P, Mardh P-A, Lemon SM, serological response to conventional therapy for syphilis among HIV- Stamm WE, Piot P, et al, eds. Sexually transmitted positive and HIV-negative women. Genitourin Med 1995;71:275-9.
11 Rolfs RT, Joesoef MR, Hendershot EF, Rompalo AM, Augenbraun diseases. New York: McGraw Hill, 1999. MH, Chiu M, et al. A randomised trial of enhanced therapy for early Goh BT. Syphilis in adults. Sex Transm Dis 2005;81:448-52.
syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group. Pox: genius, madness and the mysteries of syphilis. New York: Basic Books, 2003.
12 Rompalo AM, Joesoef MR, O’Donnell JA, Augenbraun M, Brady W, Radolf JD, et al. Clinical manifestations of early syphilis by HIV status trol (such as antenatal screening to prevent congenital and gender: results of the syphilis and HIV study. Sex Transm Dis syphilis) are already well established but have not been fully implemented in many parts of the world.
13 Rompalo AM, Lawlor J, Seaman P, Quinn TC, Zenilman JM, Hook EW 3rd. Modification of syphilitic genital ulcer manifestations by The likely absence of a syphilis vaccine in the fore- coexistent HIV infection. Sex Transm Dis 2001;28:448-54.
seeable future means that syphilis control will depend 14 Johns DR, Tierney M, Felsenstein D. Alteration in the natural history of neurosyphilis by concurrent infection with the human largely on reducing risk taking among individuals and immunodeficiency virus. N Engl J Med 1987;316:1587-72.
communities affected by syphilis and on the diagnosis 15 Berry CD, Hooton TM, Collier AC, Lukehart SA. Neurologic relapse of syphilis after benzathine penicillin therapy for secondary syphilis in a and treatment of individuals with early syphilis. Com- patient with HIV infection. N Engl J Med 1987;316:1587-9.
prehensive sexual health promotion programmes have 16 Marra CM, Maxwell CL, Smith SL, Lukehart SA, Rompalo AM, been shown to reduce syphilis prevalence,24 as have Eaton M, et al. Cerebral spinal fluid abnormalities in patients with syphilis: association with clinic and laboratory features. J Infect Dis new treatment approaches such as syndromic manage- ment of genital ulcer disease.25 Primary prevention, 17 Parkes R, Renton A, Meheus A, Laukamm-Josten U. Review of current evidence and comparison of guidelines for effective treatment in together with provision of easily accessible syphilis Europe. Int J STD AIDS 2004;15:73-88.
diagnostic and treatment services, will remain the 18 Wheeler HL, Agarwal S, Goh BT. Dark ground microscopy and treponemal tests in the diagnosis of early syphilis. Sex Transm Infect 2004;80:411-4.
I thank Debbie Sumner and Tim Gerrard for reviewing this manuscript.
19 Palmer HM, Higgins SP, Herring AJ, Kingston MA. Use of PCR in the Contributors: PF is the sole contributor. diagnosis of early syphilis in the United Kingdom. Sex Transm Dis 20 Egglestone SI, Turner AJL, for the PHLS Syphilis Serology Working 1 Simms I, Fenton KA, Ashton M, Turner KM, Crawley-Boevey Group. Serological diagnosis of syphilis. Commun Dis Public Health EE, Gorton R, et al. The re-emergence of syphilis in the United Kingdom: the new epidemic phases. Sex Transm Dis 21 Hahn RD, Cutler JC, Curtis AC, Gammon A, Heymann E, Johnwick JH, et al. Penicillin treatment of asymptomatic central nervous system 2 Fraser CM, Norris SJ, Weinstock GM, White O, Sutton GG, Dodson R, et syphilis. 1. Probability of progression to symptomatic neurosyphilis. al. Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science 1998;281:375.
22 Riedner G, Rusizoka M, Todd J, Maboko L, Hoelscher M, Mmbando D, 3 Rottingen JA, Cameron DW, Garnett GP. A systematic review of the et al. Single dose azithromycin versus penicillin G benzathine for the epidemiologic interactions between classic sexually transmitted treatment of early syphilis. N Engl J Med 2005;353:1236-44.
diseases and HIV: how much is really known? Sex Transm Dis 23 Lukehart SA, Godornes C, Molini BJ, Sonnett P, Hopkins S, Mulcahy F, et al. Macrolide resistance in Treponema pallidum in the United 4 Saloojee H, Velaphi S, Goga Y, Afadapa N, Steen R, Lincetto O. The States and Ireland. N Engl J Med 2004;351:154-8.
prevention and management of congenital syphilis: an overview 24 Celentano DD, Nelson KE, Lyles CM, Beyrer C, Eiumtrakul S, Go VF, et and recommendations. Bull World Health Organ 2004; al. Decreasing incidence of HIV and sexually transmitted diseases in young Thai men: evidence for the success of the HIV/AIDS prevention 5 Health Protection Agency, UK. 2005 STI data. www.hpa.org.
program. AIDS 1998;12(5):F29-36.
uk/infections/topics_az/hiv_and_sti/epidemiology/ 25 Mayaud P, Mosha F, Todd J, Balira R, Mgara J, West B, et al. Improved treatment services significantly reduce the prevalence of sexually 6 Gjestland T. The Oslo study of untreated syphilis: an epidemiologic transmitted diseases in rural Tanzania: results of a randomised investigation of the natural course of the syphilitic infection based controlled trial. AIDS 1997;11:1873-80.
ENDPIECEWhat is research?There are two kinds of researchers: some who are just assistants, and others whose mission is to invent. Inventions should be made in all areas, even in the humblest search for facts or the simplest experiment. Science cannot begin to exist without personal and original effort.
Henri Bergson (1859-1941) in his presidential address to the Society for Psychical Research in 1913 Submitted by Amar Bhat, senior house officer, Doncaster Royal Infirmary

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