International Journal of STD & AIDS 2001; 12 (Suppl. 3): 14± 26

MANAGEMENT OF SPECIFIC INFECTIONS European guideline for the management of syphilis

B T Goh1 and P C van Voorst Vader2 1Department of Genitourinary Medicine, Royal London Hospital, London, UK, 2Department of Dermatovenereology, University Hospital, Groningen, The Netherlands

INTRODUCTION periostitis and glomerulonephritis. The rash may be itchy, particularly in dark-skinned patients4. Syphilis is classi® ed as acquired or congenital. Latent syphilis: positive serological tests for Acquired syphilis is divided into early and late syphilis with no clinical evidence of treponemal syphilis. Early syphilis: primary, secondary and infection. Arbitrarily classi® ed as early if acquired early latent (Centers for Disease Control [CDC]: 1 year previously and late if acquired 51 year acquired 1 year previously1; World Health 5 5 previously. Organization [WHO]: acquired 2 years pre- 5 Late syphilis includes: viously2). Late syphilis: late latent (CDC: acquired 51 year previously1; WHO: acquired 52 years . Gummatous syphilis: typical nodules/plaques previously2), tertiary, including gummatous, cardi- or ulcers ovascular and neurosyphilis (the latter two are also . Neurosyphilis: meningovascular, parenchy- sometimes classi® ed as quartenary syphilis). Con- matous (general paresis, tabes dorsalis), genital syphilis is divided into early (® rst 2 years of asymptomatic (abnormal cerebrospinal ¯ uid life) and late (apparent later in life), which includes (CSF)) the stigmata of congenital syphilis. . Cardiovascularsyphilis: aortitis (asymptomatic), angina, aortic regurgitation, coronary ostia stenosis5, aortic aneurysm (mainly thoracic).

DIAGNOSIS Laboratory Clinical features Treponema pallidum from lesions or infected lymph Incubation period: 10± 90 days before a chancre nodes in early syphilis, demonstrated by: (primary syphilis) develops, in symptomatic patients. Secondary syphilis develops 3± 6 weeks . Dark® eld microscopy after the appearance of the chancre. . Direct ¯ uorescent antibody testÐ for oral or Primary syphilis: an ulcer (chancre), usually with other lesions where contamination with com- regional lymphadenopathy. The ulcer is single, mensal treponemes is likely 6,7 painless and indurated with a clean base, dischar- . Polymerase chain reaction (PCR) . ging clear serum, in the anogenital region. Serological tests for syphilis include8,9: Occasionally it may be atypical: multiple, painful, purulent, destructive, extragenital (including . Reaginic tests (cardiolipin/non-treponemal syphilitic balanitis of Follmann3). Any anogenital tests): Venereal Disease Research Laboratory ulcer is syphilitic unless proven otherwise. test (VDRL), rapid plasma reagin test (RPR) Secondary syphilis: multisystem involvement due and variants to bacteraemia, which may recur up into the . Speci® c tests (treponemal tests): T. pallidum second year after infection. Generalized non-itchy haemagglutination assay (TPHA), micro- polymorphic rash often affecting the palms and haemagglutination assay for T. pallidum soles, condylomata lata, mucocutaneous lesions, (MHA-TP), T. pallidum particle agglutination generalized lymphadenopathy. Less commonly test (TPPA), ¯ uorescent treponemal antibody patchy alopecia, anterior uveitis (i.e. ocular absorption test (FTA-abs test), treponemal syphilis, which may also cause scleritis, iritis, enzyme immunoassay (EIA)/IgG (e.g. Captia), retinitis, papillitis, optic neuritis), meningitis, IgG immunoblot test for T. pallidum cranial nerve palsies, hepatitis, splenomegaly, . Speci® c anti-T. pallidum IgM antibody tests: 19S-IgM-FTA-abs test, IgM-immunoblot for T. pallidum, anti-T. pallidum IgM-antibody test using the EIA method (Captia EIA). Present Correspondence to: Dr B T Goh indication for IgM antibody test screening for E-mail: [email protected] congenital syphilis and recent infection. 14 Downloaded from std.sagepub.com at COLUMBIA UNIV on December 9, 2015 guide.medlive.cn Goh and van Voorst Vader. Management of syphilis 15

Preliminary screening tests10,11: The antibodies to endemic treponematoses such as endemic syphilis, framboesia (yaws) . TPHA, MHA-TP or TPPA are the best single and pinta cannot be distinguished from the screening tests. VDRL or RPR are sometimes antibodies induced by T. pallidum. A person also performed (in addition) with positive syphilis serology from a country . EIA/IgG-test is an alternative screening test with endemic treponematoses should be in- . FTA-abs test or EIA-IgM may be the ® rst test vestigated and treated as for syphilis as a to be positive if primary syphilis is suspected; 8 precautionary measure, unless previously the ® rst test is reactive in 70± 90% of cases . adequately treated for syphilis Con® rmatory tests if any screening test is posi- . The false-positive syphilis serology caused by tive10,11: the spirochaete Borrelia burgdorferi results from the antigenic relationship between T. pallidum . Treponemal EIA, FTA-abs test (i.e. another and B. burgdorferi, since both are spirochaetes. treponemal test, e.g. TPHA if EIA is used for This can usually be avoided by routine pre- screening, EIA if TPHA is used for screening) incubation with T. phagedenis. False-positive . IgG-immunoblot for T. pallidum if suspected treponemal reactions frequently occur how- false-positive TPHA/MHA-TP and/or FTA- ever with the FTA-abs test. Now that the abs test genome of T. pallidum has been mapped . Always repeat positive tests to con® rm results. completely12, new more speci® c test for Test for serological activity of syphilis and for T. pallidum may be developed monitoring the effect of treatment: . False-positive syphilis serology in pregnancy: Ð False-positive cardiolipin/non-treponemal . VDRL-test or RPR-test (or variants, i.e. other cardiolipin/non-treponemal tests). and treponemal reactions can occur in pregnancy, with treponemal tests the FTA- Laboratory: false-negative syphilis serology8,9 abs test is the one which may be false- positive . A false-negative reaginic (cardiolipin) test may Ð If a pregnant woman has been adequately occur in secondary syphilis due to the prozone treated for syphilis prior to the current phenomenon from using undiluted serum pregnancy, there are no rational arguments . A temporary negative reaginic (cardiolipin) for a so-called safety treatment. But in the test has occasionally been reported in second- case of a possible new syphilitic infection ary syphilis and in patients with concomitant (recheck sexual partner) and also if there is HIV infection (reactive on subsequent testing). any doubt about the adequacy of previous therapy, one should not hesitate to proceed Laboratory: false-positive syphilis serology8,9 with treatment. Biological false-positive (BFP) reaginic (cardio- . Laboratory tests to con® rm or exclude lipin/non-treponemal) tests can be divided as neurosyphilis1,13,14 acute (56 months) and chronic (56 months). Acute BFP may be seen in pregnancy, post- . Lumbar puncture for examination of CSF is immunization, recent myocardial infarction indicated in patients with1,14: and in many febrile infective illnesses. Chronic BFP may be seen in injecting drug users, Ð Clinical evidence of neurological involve- autoimmune diseases, leprosy, chronic liver ment pathology and old age. Occasional biological Ð Ocular, cardiovascular or gummatous sy- false-positive treponemal tests (FTA-abs test philis more than TPHA/MHA-TP) may be seen in Ð Concomitant HIV infection autoimmune diseases, HIV infection and Note: Lumbar puncture for CSF examina- during pregnancy and can be excluded with tion is an option in non-HIV-infected the IgG immunoblot test for T. pallidum patients with late latent syphilis or in whom the duration of latent syphilis infection is . False positive syphilis serology (treponemal and cardiolipin/non-treponemal) is also found unknown. This examination should exclude asymptomatic neurosyphilis, although in endemic treponematoses and borreliosis. 15 The treponematoses are caused by bacteria the bene® t may be marginal and the need from the group of spirochaetes, which include minimal, as the risk of developing Borrelia, Spirochaeta, Leptospira, Cristispira symptomatic neurosyphilis after standard and Treponema, such as: parenteral treatment appears to be small in such patients14,16± 18, although it has been Ð T. pallidum (venereal syphilis and endemic described18. syphilis) . Examination of CSF: TPHA/MHA-TP/TPPA Ð T. pertenue (`yaws’/framboesia tropica) (qualitatively), FTA-abs test (qualitatively), Ð T. carateum (pinta) VDRL test (quantitatively), total protein,

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albumin level, number of mononuclear cells. . Additional criteria in HIV-seronegative pa- Quantitative TPHA/MHA-TP and measure- tients suspected of symptomatic neuro- ment of IgG and IgM level in CSF can also be syphilis: TPHA-index (according to Luger, performed, together with measurement of see above) 470 and 5500: compatible with albumin, IgG and IgM level in serum neurosyphilis; TPHA-index (according to . Extra parameters in CSF: IgG-index, IgM- Luger, see above) 4500: de® nite neuro- index, albumin quotient. The IgG-index syphilis13 decreases after adequate therapy, but may . Other considerations: remain abnormal, as does the TPHA-index and the albumin quotient. IgM-index and the Ð Finding in CSF a positive TPHA, an number of mononuclear cells in the CSF increased number of mononuclear cells should become negative or normal within 1± 2 and a raised IgG- and/or IgM-index only years. The VDRL test in CSF may or may not provides circumstantial evidence for the become negative following therapy. The use of diagnosis of neurosyphilis. A positive the different TPHA-indexes and ITpA-indexes VDRL test in CSF is seen as more direct has been controversial13,19. The value of the evidence of neurosyphilis PCR for determination of the presence of Ð The number of mononuclear cells in CSF T. pallidum antigen(s) in CSF and diagnosis of can be normal in neurosyphilis, especially neurosyphilis is rather disappointing13,14. in parenchymatous neurosyphilis (tabes dorsalis, general paresis)18,19 Ð IgG-index (parameter for intrathecal IgG Ð The VDRL test in CSF can be negative in neurosyphilis13,18,19 synthesis, normal value: 50.70)13,18: Ð A positive TPHA/MHA-TP/TPPA or FTA- IgG level mg=l in CSF albumin level mg=l in CSF abs test in CSF by itself does not con® rm the … † : … † IgG level mg=l in serum albumin level mg=l in serum diagnosis of neurosyphilis, but a negative … † … † treponemal CSF test excludes neuro- Ð IgM-index (parameter for intrathecal IgM syphilis13 synthesis, normal value: 50.07)18,19: Ð Tests may be performed for the presence of HIV-RNA or HIV-p24 Ag in CSF of IgM level mg=l in CSF albumin level mg=l in CSF … † : … † HIV-infected individuals, which indicate IgM level mg=l in serum albumin level mg=l in serum … † … † HIV-infection of the central nervous system Ð Albumin-quotient (parameter for distur- Ð The criteria outlined above have not gen- bance of blood± brain barrier, normal erally been validated in HIV-seropositive value: 57.8)13,18,19: patients. albumin level mg=l in CSF … † 1000 albumin level mg=l in serum £ … † Screening test to exclude symptomatic Ð TPHA-index, according to Luger13 (para- cardiovascular syphilis meter for intrathecal synthesis of anti- T. pallidum-speci® c IgG). This TPHA-index . Chest radiograph was shown to have a speci® city of 100% and a sensitivity of 98.3% in one study involving Investigation for ocular syphilis 60 HIV-seronegative symptomatic neuro- syphilis patients and controls13. This leaves . Indicated if ocular complaints are present the question of reproducibility of the CSF- Note: Ocular assessment (slit lamp) may be TPHA (appears to be good), the sensitivity helpful to differentiate between acquired or of the index in oligo- and asymptomatic congenital ocular syphilis (interstitial keratitis) neurosyphilis and the in¯ uence of HIV- in cases of latent infection of uncertain infection. Con® rmation of the ® ndings of duration. Luger et al. has been limited so far13.

CSF-TPHA titre Albumin quotient MANAGEMENT5,14,16,20 General . Criteria for the diagnosis of neurosyphilis13,14: . A treponemicidal level of antimicrobial should TPHA/MHA-TP and/or FTA-abs test positive (in CSF) be achieved in the serum, and in the CSF in the and case of neurosyphilis. A penicillin level of 3 Increased number of mononuclear cells (410/mm in CSF) 40.018 mg/l is considered treponemicidal, but plus IgG-index 50.70 and/or IgM-index 50.10 (in CSF) is substantially lower than the maximally or effective in vitro level of concentration, which positive VDRL test (in CSF). is far higher (0.36 mg/l)5,16

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. Duration of treponemicidal level of antimi- low, indicating that treatment is effective crobial should be at least 7± 10 days to cover a and suggesting that host immune responses number of division times (30± 33 hours) of in early syphilis play an essential part. treponemes in early syphilis with a subtrepo- However, standard treatment with parenteral nemicidal interval of not more than 24± 30 benzathine penicillin has been associated with hours5. Longer duration of treatment is failure in pregnant women36± 38 needed as the duration of infection increases . Benzathine penicillin is available as Penidur- (more relapses were seen in that stage after al1 and is widely used because of ease of short courses of treatment), possibly because treatment. Using lidocaine solution as part of of more slowly dividing treponemes in late the solvent reduces the pain associated with syphilis. Treponemes have shown to persist injection and may improve compliance. Com- despite apparently successful treatment20. The pliance with daily intramuscular injections signi® cance of this ® nding, if any, is un- with procaine penicillin has been good in the known UK39. Although both penicillins appear to be . Long-acting benzathine penicillin 2.4 million effective in the parenteral regimens used for units provides a treponemicidal penicillinae- early and late syphilis, these regimens have not mia for up to 3± 4 weeks (21± 23 days)5,21. With yet been comparatively studied16. Nor has daily parenteral treatment with procaine parenteral procaine penicillin plus oral probe- penicillin a `safety margin’ is provided by necid been compared with intravenous peni- giving courses lasting 10± 14 days in early cillin in the treatment of neurosyphilis. The syphilis and 10± 21 days in late syphilis. optimal treatment schedule for syphilis in However, well controlled clinical data are pregnant women is not known. The exact value lacking on the optimal dose, duration of of the serum titre response of cardiolipin/non- treatment and long-term ef® cacy of antimi- treponemal tests has never been fully eluci- crobials, even of penicillin, which has been dated; universally accepted standards for cure used most extensively16 or failure using the serological response do not . The recommendations are based mainly on exist. The control of syphilis over the past 50 laboratory considerations, biological plausi- years has been excellent, however, compared bility, practical considerations, expert opi- to the pre-penicillin age. Late complications of nion, case studies and past clinical experi- syphilis and/or failures of treatment are ence16 uncommon, even in patients with concomitant . Parenteral rather than oral penicillin treatment HIV infection, indicating that the treatment has generally been the treatment of choice schedules presently used seem fairly adequate, because parenteral therapy is supervised with although there remains a need for properly guaranteed bioavailability. Oral fenoxymethyl- controlled studies penicilline is an option however22, and amox- . The risk of a syphilis patient with a con- icillin given orally in combination with comitant HIV infection of developing a more probenecid resulted in treponemicidal CSF aggressive course with (early) neurosyphilis, penicillin levels23,24 ocular syphilis, treatment failure and relapse . Non-penicillin antibiotics that have been appears to be slightly increased1,14,16,40. Con- evaluated are tetracyclines, including doxycy- sequences thereof: (a) HIV-antibody test cline, which is the preferred tetracycline with should always be offered to patients with penetration into the CSF16,20,25, and erythro- syphilis of any stage not yet adequately mycin, all taken orally. Erythromycin is least treated, as the HIV-status may affect the effective and does not penetrate the blood± policy for diagnosis, follow-up and rarely of brain or placental barriers well20. Newer treatment; (b) careful follow-up of syphilis antitreponemal regimens include oral azithro- patients with concomitant HIV-infection, in- mycin16,26± 28 and intramuscular or intravenous cluding CSF examination 2 years after treat- ceftriaxone29,30. The latter has good CSF ment of early syphilis and at the initial penetration. More data are required, however, diagnostic stage of an HIV-infected patient before either can be generally recommended, with late latent syphilis or latent syphilis of although both may be preferable to erythro- unknown duration mycin and tetracycline . The Russian Federation has devised regularly . The host immune response is important as updated treatment recommendations, lastly 60% of untreated patients go through life from 1999 (see Appendix). These carefully without developing late complications31. CSF worked-out recommendations often differ involvement is common in early syphilis32,33. from those issued in other European coun- Although both benzathine penicillin and tries and the USA. The vast experience in the standard regimens of parenteral procaine Russian Federation does therefore not pro- penicillin do not achieve treponemicidal vide other countries with answers, due to CSF levels14,16,34,35 the prevalence of late differences of dosage and duration of com- syphilis, including neurosyphilis, remains monly used antibiotics.

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Early syphilis (primary, secondary and early . Tetracycline 500 mg 4 times daily for 28 days1 latent acquired 51 year previously), . Erythromycin 500 mg 4 times daily 28 days20. recommended regimen1,14,16,41± 45

First-line therapy options: Neurosyphilis and ocular syphilis, recommended . Benzathine penicillin (Penidural1) 2.4 million regimen units intramuscularly (IM) (each buttock 1.2 million units) on day 11,5,41,42,44,45. Using . Biological plausibility suggests that regimens lidocaine solution as part of the solvent reduces that achieve treponemicidal levels of an the discomfort associated with injection antibiotic in CSF should be the treatment of . Procaine penicillin 600 000 units IM daily for choice. Options are intravenous (IV) or par- 10± 14 days5,41,42,46. If unable to give daily enteral (IM)/oral therapy using probenecid. procaine penicillin on the weekend, one may Data comparing these two options are lacking give long-acting Biclinocillin (benethamine . There are con¯ icting data over the effective- penicillin 1 million units) 1.67 million units ness of producing a treponemicidal CSF IM on Friday to cover the weekend42. Some penicillin level using the procaine penicillin/ physicians recommend a larger dose of probenecid combination20,47,48. Concern that procaine penicillin (1.2 million units)41, cer- the CSF penicillin level is increased at the tainly for heavier patients (e.g. 80± 100 kg) expense of the central nervous system (CNS) 47,49 . Benzyl penicillin 1 million units IM daily for tissue level may not be relevant, because 10± 14 days44. the levels in both CSF and CNS tissue are in fact higher with probenecid than without, with Penicillin allergy or parenteral treatment refused: a relatively much higher level in the CSF20. The . Doxycycline 200 mg daily (either 100 mg twice experience in the UK with treatment of daily or as a single 200 mg dose) for 14 neurosyphilis with the procaine penicillin/ days1,16,20,25 probenecid combination has been positive so . Tetracycline 500 mg four times daily for 14 far. The availability of probenecid may be a days1,16,20 problem however . Erythromycin 500 mg four times daily for 14 . In ocular syphilis, also in uveitis syphilitica of days16,20 short duration, effective treatment can be . Other options: azithromycin 500 mg once daily realized with parenteral benzathine penicil- for 10 days16,26± 28, ceftriaxone 250± 500 mg IM lin50,51, but in patients with serious ocular once daily for 10 days29,30. involvement (cave: ocular syphilis is often associated with (a)symptomatic neurosyphilis), or ocular involvement of longer duration (with Late latent (acquired 51 year previously or of threat of permanent loss of vision), treatment as unknown duration), cardiovascular and for neurosyphilis should be preferred. gummatous syphilis, recommended regimen First-line therapy: First-line therapy options: . Benzyl penicillin 12± 24 million units IV daily, . Benzathine penicillin (Penidural1) 2.4 million as 2± 4 million units every 4 hours for 10± 21 units IM (each buttock 1.2 million units) days1,41,43,44 1,41,43± 45 weekly on day 1, 8 and 15 . Reconstitu- . Benzyl penicillin 0.15 million units/kg/day tion of benzathine penicillin with lidocaine IV, spread over 6 doses (every 4 hours) for 10± reduces the discomfort associated with injec- 14 days45,49 tion . Procaine penicillin 1.2± 2.4 million units IM . Procaine penicillin 600 000 units IM daily for daily PLUS probenecid 500 mg orally 4 times 17± 21 days41,43. If unable to give daily procaine daily, both for 10± 21 days1,41,43. penicillin on the weekend, one may give long- acting Biclinocillin (benethamine penicillin 1 Penicillin allergy or parenteral treatment refused: million units) 1.67 million units IM on Friday . Doxycycline 200 mg twice daily for 28± 30 42 to cover the weekend . Some physicians days25,41,43,45. recommend a larger dose of procaine penicil- lin (1.2 million units)41, certainly for heavier patients (e.g. 80± 100 kg) Follow up . Benzyl penicillin 1 million units IM daily for 21 Repeat CSF examination should be performed not days44. earlier than 1± 2 years after treatment of neuro- syphilis, unless clinical deterioration occurs. If Penicillin allergy or parenteral treatment refused: performed earlier, e.g. at 3 or 6 months, non- . Doxycycline 200 mg daily (either 100 mg twice relevant CSF ® ndings suggesting aggravation due daily or as a single 200 mg dose) for 21± 28 to the so-called paradoxical response may cause days1,20,25,41,43± 45 unnecessary confusion52. In meningovascular

Downloaded from std.sagepub.com at COLUMBIA UNIV on December 9, 2015 guide.medlive.cn Goh and van Voorst Vader. Management of syphilis 19 neurosyphilis the number of mononuclear cells in . All infants born to sero-positive mothers CSF generally normalizes faster (within 6± 12 should be treated with a single dose of months) than in parenchymatous neurosyphilis benzathine penicillin 50 000 units/kg IM, (within 1± 2 years). As has been stated above, whether or not the mother was treated during the number of mononuclear cells in CSF and the pregnancy, especially in high-prevalence IgM-index should become normal within 1± 2 countries1,41. years, while albumin quotient, IgG-index and TPHA-index may remain abnormal and the CSF- VDRL-test positive. Congenital syphilis Diagnosis Con® rmed congenital infection: SPECIAL SITUATIONS T. pallidum demonstrated by dark-® eld micro- Pregnancy . scopy, immuno¯ uorescent microscopy, PCR or In pregnant women with untreated early syphilis, speci® c staining of specimens for histopatho- 70± 100% of infants will be infected, with stillbirths logical examination, e.g. from skin lesions, in up to one-third of cases. Standard treatment has navel, placenta or autopsy material14. been used with good results, but because of some 1,42,55 reports of insuf® cient response in mother and Presumed congenital infection : infant, more aggressive treatment has been . A stillborn neonate with a positive treponemal advocated1,16,36± 38. test for syphilis First-line options for treatment of early syphilis . Children with a positive treponemal test for (acquired 52 years previously): syphilis in combination with one of the following: . Benzathine penicillin (Penidural1) 2.4 million units IM (each buttock 1.2 million units) Ð Persistent rhinitis, condylomata lata, ostei- weekly on days 1 and 81 tis, periostitis, osteochondritis, ascites, cu- . Procaine penicillin 600 000 or 1.2 million units taneous and mucous membrane lesions, IM daily for 10± 14 days42. hepatitis, hepatosplenomegaly, glomerulo- nephritis, haemolytic anaemia Penicillin allergy: Ð Radiological abnormalities of the long bones suggestive of congenital syphilis . Desensitization to penicillin may be consid- Ð A positive VDRL test in CSF 1 ered followed by ® rst-line treatment Ð A 4-fold increase or more of the TPHA/ . Alternative options: MHA-TP titre in the child’s as opposed to Ð Azithromycin, 500 mg once daily for 10 the mother’s serum (both obtained simulta- days, which has been used for chlamydial neously at birth) infection in pregnant women as reported in Ð A 4-fold increase or more of the titre of a a Cochrane analysis53. Published evidence cardiolipin/non-treponemal test in the of safety of use during pregnancy is limited child’s as opposed to the mother’s serum however (both obtained simultaneously at birth) Ð Ceftriaxone, 250± 500 mg IM daily for 10 Ð A 4-fold increase or more of the titre of a days, may also be given during preg- cardiolipin/non-treponemal test within 3 nancy54. Published evidence of safety of months after birth use during pregnancy is limited however Ð A positive 19S-IgM-FTA-abs test, EIA-IgM Ð Consideration might be given on re- and/or IgM-immunoblot for T. pallidum in treating mothers with doxycycline after the child’s serum delivery. Ð A mother, in whom syphilis was con® rmed during pregnancy, but who was not ade- Prevention of congenital syphilis by serological quately treated either before or during screening during pregnancy and preventive neo- pregnancy natal treatment: . A child 412 months-of-age with a positive . Serological screening is recommended in the treponemal serological test for syphilis. USA at: (a) initial pregnancy control; (b) 28 Late congenital syphilis including stigmata: weeks of gestation; (c) delivery, if high-risk for congenital syphilis1. In The Russian . Interstitial keratitis, Clutton’s joints, Hutchin- Federation it is recommended at: (a) initial son’s incisors, mulberry molars, high palatal pregnancy control; (b) 21 weeks of gestation; arch, rhagades, deafness, frontal bossing, short (c) 36 weeks of gestation. Each country maxilla, protuberance of mandible, saddlenose should decide on its own screening policy, deformity, sterno-clavicular thickening, par- if possible based on a cost-effectiveness oxysmal cold haemoglobinuria, neurological analysis or gummatous involvement

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. Serological tests can be negative in infants Treatment of syphilis in patients with concomitant HIV infected in late pregnancy and should be infection repeated. When the mother is treated during the last trimester of pregnancy, the treatment . Treatment should be given as for non-HIV- can be inadequate for the child and the child infected patients. may still develop congenital syphilis. Note (1): Careful follow-up is essential (see above and at follow-up). Investigations Note (2): In the UK, where neurosyphilis is often treated with procaine penicillin IM plus probenecid . VDRL, TPHA/MHA-TP (quantitative), anti- orally, which regimen can be given on an out- treponemal IgM (19S-IgM-FTA-abs test and/or patient basis, it has been suggested that HIV- IgM-immunoblot or EIA-IgM) from infant’s infected syphilis patients should be treated with blood and not umbilical cord blood, because 55 the procaine regimen mentioned, to prevent the false-positive and -negative tests may result development of neurological involvement. Hard . Blood: full blood count, liver function, electro- evidence for this policy is lacking, however42,43. lytes, albumin, IgG, IgM . CSF: cells, albumin, IgG, IgM, TPHA, VDRL . X-rays of long bones Reactions to treatment . Ophthalmic assessment as indicated. Patients should be warned of possible reactions to Treatment options treatment. Facilities for resuscitation should be available in the treatment area. . Benzyl penicillin 150 000 units/kg IV daily (administered in 6 doses every 4 hours) for 10± Jarisch± Herxheimer reaction 14 days1,41,44 . Procaine penicillin 50 000 units/kg IM daily . An acute febrile illness with headache, myal- for 10± 14 days1,41,42 gia, chills and rigors, resolving within 24 hours . If CSF is normal: benzathine penicillin 50 000 . Common in early syphilis, but is usually not units/kg IM (single dose)1,41. important unless there is neurological or ophthalmic involvement or in pregnancy, HIV-infected patients when it may cause fetal distress and pre- General remarks mature labour . Uncommon in late syphilis, but can potentially . Serological tests for syphilis in patients with be life-threatening if involvement of strategic HIV co-infection are generally reliable for the sites (e.g. coronary ostia, larynx, nervous diagnosis of syphilis and for evaluation of system) treatment response . Prednisolone can abolish the febrile episode56, . False-negative and -positive tests and delayed but is unproven in ameliorating local in¯ am- appearance of seroreactivity have been mation. Nevertheless, severe clinical deteriora- reported1,14,16 tion in early syphilis with optic neuritis and . In HIV-infected individuals with clinical uveitis has been reported following treatment. suspicion of syphilis and (repeatedly) negative As a steroid is also used in the management syphilis serology, it is advisable to perform per se, biological plausibility would suggest other diagnostic tests apart from the prelimin- that it may help ary screening test, e.g. histological, immuno- . Systemic treatment with a blocker of tumour ¯ uorescent or PCR examination of a biopsy necrosis factor (TNF) may be more effective from a clinically suspected lesion and direct than systemic treatment with a corticosteroid57 dark-® eld microscopy of the exudate of early . Management: syphilitic lesions for spirochaetes . HIV-infected patients with early syphilis Ð If cardiovascular or neurological involve- appear to have a slightly increased risk of ment (including optic neuritis) exists, in- (early) neurological and ocular involvement patient management is advisable and higher rate of treatment failure with Ð Prednisolone 10± 20 mg 3 times daily for 3 benzathine penicillin including more frequent days, starting anti-treponemal treatment serological relapse1,14,16,40. Therefore careful after 24 hours of commencing predniso- follow-up is essential lone . CSF examination is advisable1,14,16: Ð Antipyretics.

Ð As part of the initial diagnostic programme Procaine reaction (procaine psychosis, procaine mania, in HIV-infected patients with late latent Hoigne syndrome) syphilis or latent syphilis of unknown duration (see earlier in the text) . Due to inadvertent intravenous injection of Ð 2 years after treatment of early syphilis (not procaine penicillin; may be minimized by the advised for non-HIV infected patients). `aspiration technique’ of injection

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. Characterized by fear of impending death, . Immediate epidemiological treatment for sex- may cause hallucinations or ® ts immediately ual partners should be considered (especially after injection. Lasts less than 20 minutes of pregnant partners), unless partners are able . Management: to attend regularly for exclusion of syphilis through clinical and serological examination Ð Exclude anaphylaxis Serological tests for syphilis should be per- Ð Calm and verbal reassurance: restraint may . formed at the ® rst visit and repeated at 6 be necessary weeks and 3 months Ð Diazepam rectally/IV/IM if convulsions. . Noti® cation of syphilis to the relevant author- ity is required in many European countries, Anaphylactic shock particularly early syphilis and congenital syphilis. . Facilities for treatment of anaphylaxis should be available as penicillin is one of the commonest causes FOLLOW UP . Management: The follow up to ascertain cure and detect Ð Epinephrine (adrenaline) 1:1000 IM 0.5 ml, reinfection or relapse is achieved by assessing the followed by: clinical and serological response. Ð IM/IV antihistamine, e.g. chlorpheniramine . For early syphilis, minimum clinical and 10 mg serological (cardiolipin/non-treponemal tests: Ð IM/IV hydrocortisone 100 mg. VDRL or RPR) assessment according to the following follow-up scheme might be used: monthly during the ® rst 3 months after MANAGEMENT OF PARTNERS treatment, then at 6 and 12 months. Follow- up of HIV-infected patients treated for early . All patients with syphilis should be seen for syphilis should be more frequent, e.g. at 1, 2, 3, partner noti® cation (noti® cation by the patient 6, 9, 12, 18 and 24 months1,42, and may be = patient referral, by a health department = ended by CSF examination14 provider referral), health education, STD Ð After treatment of early syphilis the titre of prevention and con® rmation of any past cardiolipin/non-treponemal tests (e.g. treatment history VDRL and/or RPR) should decline by 2 . Although the division of latent syphilis in dilution steps (4-fold) within 6 months early and late stages has been useful for (within 1 year for HIV-positive patients)1. treatment and partner noti® cation, this classi- Ð If this does not occur, should additional ® cation can be problematic for use in surveil- treatment be given (according to the CDC1: lance, as a substantial number of late, benzathine penicillin 2.4 million units IM hypothetically non-infectious, latent syphilis on day 1, 8 and 15)? If the clinical response cases (latent syphilis of unknown duration was has been adequate, one might decide classi® ed as late latent) turned out to be against additional treatment. If the clinical probable early, infectious, latent syphilis 14 response was inadequate or impossible to according to one report monitor as in latent syphilis, one might . Secondary syphilis relapse can occur within decide in favour of additional treatment the ® rst 2 years of infection, and syphilis is thought to be infectious through intercourse . In late (latent) syphilis the serological response for up to 2 years after acquisition of cardiolipin/non-treponemal tests is often . Partner noti® cation assists community efforts absent. In non-HIV-infected late latent syphilis to reduce the disease burden, ful® ls ethical patients with a reactive cardiolipin/non- obligations to warn the unsuspecting and, treponemal test, which remains stable in the probably not unimportant, can delineate the lowest titre range, follow-up after treatment is risk networks hosting transmission. Partner generally not indicated noti® cation programmes may have poor re- . Early clinical relapse tends to occur in the oral sults though, which poses a problem because and anal regions syphilis may cause serious morbidity14 . An increase of 42 dilution steps (4-fold) in a . For patients with primary syphilis, sexual cardiolipin/non-treponemal test suggests re- partners within the past 3 months should be infection or reactivation noti® ed as the incubation period is up to 90 . Follow-up examination of CSF should be days. Partner noti® cation may have to extend performed 1± 2 years after treatment of neuro- to 2 years for patients in secondary syphilis syphilis with clinical relapse or in early latent syphilis . Speci® c treponemal tests may remain positive . 46± 60% of contactable sexual partners, includ- for life following effective treatment; proper ing pregnant women, of patients with early documentation is necessary to prevent unne- syphilis are likely to be infected cessary re-treatment

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. Reinfection or relapse should be re-treated Complex of serologic reactions (CSR): preferably with supervised treatment sche- . Reaction of microprecipitation (RMP, i.e. dules to ensure compliance, and sexual VDRL test or RPR) partners should be rescreened. and . Two complement-® xation reaction (CFR) tests APPENDIX using reaction of Wassermann (RW) with a Syphilis treatment recommendations for the cardiolipin and a treponemal antigen. Russian Federation, formulated by the Central Follow-up tests (parameter of serologic res- Research Institute for Skin and Venereal Disease, ponse): Moscow, approved by the Ministry of Health . RMP or CSR Introduction The management of syphilis in the former USSR Antibiotics (in alphabetical order) recommended for was always strictly regulated. The ® rst regulations treatment of syphilis were published in the USSR in 1948. Those regulations concerned both diagnosis and treat- 1 Azithromycin ment of the disease. Since 1948 the regulations have 2 Ampicillin been updated several times. The epidemic of 3 Benzathine benzylpenicillin (dibenzylethylene- syphilis that occurred in the Russian Federation diamine salt of penicillin, BBP) (Bicillin-1, during the last decade necessitated a change in the Retarpen1, Extencillin1) management of syphilis. Here, the last treatment 4 Bicillin-3 (combination of dibenzylethylene- regulations of 1999 are given. diamine, novocaine and sodium salts of peni- cillin in a rate of 1:1:1) Principles of syphilis management 5 Bicillin-5 (combination of dibenzylethylene- 1 Speci® c treatment: symptoms suggestive of diamine and novocaine salts in a rate of 4:1) syphilis, con® rmed by positive laboratory tests 6 Benzylpenicillin sodium salt (SBP) 2 Preventive treatment: absence of clinical and 7 Benzylpenicillin novocaine salt (NBP) laboratory abnormalities, but a history of sexual 8 Ceftriaxone or other close physical contacts 52 months 9 Doxycycline previously with a patient, then suffering from 10 Erythromycin an early form of syphilis 11 Oxacillin 3 Prophylactic treatment: 12 Procaine benzylpenicillin (PBP) (a) of a pregnant woman, who was treated for 13 Tetracycline. syphilis in the past, but still has positive serological tests Preventive treatment (b) of a pregnant woman, who acquired syphilis during that pregnancy 1 BBP (Extencillin1, Retarpen1, Bicillin-1) 2.4 (c) of a newborn, from a woman who acquired million units IM once, Bicillin-3 1.8 million units syphilis during the pregnancy or Bicillin-5 1.5 million units IM twice (within 4 Treatment ex juvantibus: no evident laboratory one week) abnormalities, but patients have lesions in 2 PBP 1.2 million units IM once daily or NBP internal organs suspected to be due to syphilis 600 000 units IM twice daily for 7 days 5 Syndromic treatment: clinical symptoms sug- 3 In patients, who received seropositive blood gestive of syphilis without opportunity to per- from a donor: treatment as in primary syphilis if form con® rmatory laboratory tests. transfusion 53 months previously or serologic tests if transfusion 53 months previously. Serologic tests Part of a separate statutory protocol, formulated by If contact with a syphilis patient was 42 months the Central Research Institute for Skin and previously, serologic tests (CSR plus FTA-abs test) Venereal Diseases, Moscow, approved and issued should be performed twice within a period of 2 as a law early in 2001 by the Ministry of Health. months, if contact was 44 months previously, Primary screening tests (in 2001 the TPHA has serologic tests (CSR plus FTA-abs test) should be been introduced as a primary screening test for a performed once. validation period of 2 years; in blood donors that test was already routinely used): Management of primary syphilis Reaction of microprecipitation (RMP, i.e. . 1 BBP (Extencillin1, Retarpen1) 2.4 million units VDRL test or rapid plasma reagin (RPR) test) IM twice with 7 days’ interval (day 1 and 8) or or Bicillin-1 2.4 million units IM thrice with 5 days’ Complex of serologic reactions (CSR) or TPHA . interval (day 1, 6 and 11) or EIA. 2 Bicillin-3 1.8 million units IM or Bicillin-5 1.5 Con® rmation tests: million units IM for a total of 5 doses given . TPHA or EIA or FTA-abs test or TPI twice a week

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3 PBP 1.2 million units IM daily for 10 days or In tertiary syphilis with cutaneous lesions with- NBP 600 000 units IM twice daily for 10 days out visceral involvement and late latent syphilis the 4 SBP 1 million IM 4 times daily (every 6 hours) following regimens are recommended: for 10 days. 1 SBP 1 million units IM 4 times daily for 28 days, followed by the same course for 14 days after 2 Management of secondary and early latent syphilis (52 weeks’ interval years previously acquired) 2 NBP 600 000 units IM twice daily for 28 days, followed by the same course for 14 days after 2 1 BBP (Extencillin1, Retarpen1) 2.4 million units weeks’ interval IM thrice with 7 days’ interval (day 1, 8 and 15) 3 PBP 1.2 million units IM once daily for 20 days, or Bicillin-1 2.4 million units IM 6 times with 5 followed by the same course for 10 days after 2 days’ interval (day 1, 6, 11, 16, 21 and 26) weeks’ interval. 2 Bicillin-3 1.8 million units IM or Bicillin-5 1.5 million units IM for a total of 10 doses given Note on the use of PBP: a course of 28 days is twice a week recommended, as in late visceral syphilis, unless 3 PBP 1.2 million units IM daily for 10 days or adverse reactions prevent prolongation of the NBP 600 000 units IM twice daily for 20 days course. 4 SBP 1 million units IM 4 times daily (every 6 hours) for 20 days. Management of late visceral syphilis and late neurosyphilis The last two regimens (3 and 4) are recommended De® nition of late visceral syphilis: cardiovascular in early latent syphilis 46 months previously syphilis and/or gummatous involvement of inter- acquired and in secondary syphilis with leukoder- nal organs. ma or alopecia. De® nition of late neurosyphilis: speci® c paren- chymatous involvement of the central nervous Management of early visceral syphilis or early system, i.e. tabes dorsalis, dementia paralytica, neurosyphilis taboparalysis, primary atrophy of the optical nerve. De® nition of early visceral syphilis: speci® c in- volvement of internal organs during the early stage (A) Late visceral syphilis: of syphilis (52 years previously acquired). 1 SBP 400 000 units IM 8 times daily for 28 days, De® nition of early neurosyphilis: speci® c invol- followed by a second course for 14 days after 2 vement of the central nervous system (meningo- weeks’ interval vascular syphilis) in the ® rst 3 years after infection. 2 NBP 600 000 units IM twice daily or PBP 1.2 Note: These patients must be treated as in-patients million units IM once daily for 28 days, followed under the supervision of a physician. by a second course for 14 days after 2 weeks’ interval. (A) Therapy of early visceral syphilis: Treatment should be initiated, before the ® rst 1 SBP 1 million units IM four times daily for 20 penicillin course, by 2 weeks of an oral broad days spectrum antibiotic (tetracycline or erythromycin 2 NBP 600 000 units IM twice daily or PBP 1.2 46500 mg a day). million units IM once daily for 20 days In all cases additional symptomatic therapy is (B) Late neurosyphilis: the recommended regi- recommended (e.g. systemic corticosteroids). mens are the same as in early neurosyphilis, but with an additional second course after 2 (B) Therapy of early neurosyphilis: weeks interval. 1 SBP 10 million units IV in 400 ml of isotonic Penicillin allergy: alternative regimens for the solution twice daily during 1.5± 2 hours of management of syphilis infusion for 14 days 2 SPB 2± 4 million units IV 6 times daily for 14 1 Doxycycline 26100 mg or tetracycline 46500 mg days. orally for 10, 15 or 30 days (for preventive treatment, treatment of primary and secondary syphilis and treatment of early latent syphilis Management of tertiary and late latent syphilis (52 respectively) years previously acquired) 2 Semisynthetic penicillines: oxacillin or ampicil- De® nition of tertiary syphilis: gummatous and/or lin 1 g IM 4 times daily for 10, 14 or 28 days (for tubercular cutaneous lesions with or without preventive treatment, treatment of primary or (cardiovascular and/or gummatous) visceral in- secondary syphilis and treatment of early latent volvement. syphilis respectively) In tertiary syphilis with cutaneous lesions with 3 Ceftriaxone 250 mg IM once daily for 5 or 10 concomitant speci® c involvement of internal or- days (for preventive treatment and treatment of gans the recommended regimens are the same as in primary syphilis respectively), 500 mg IM once late visceral syphilis. daily for 10 days (secondary and early latent

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syphilis) or 1000± 2000 mg IM once daily for 14 (A) Newborn with normal CSF: days (late latent and neurosyphilis). 1 SBP 100 000 units/kg/day IM 6 times daily 4 Azithromycin 500 mg orally once daily for 10 for 14 days days for early syphilis (primary, secondary and 2 NBP 50 000 units/kg/day IM twice daily or early latent syphilis). PBP 50 000 units/kg/day IM once daily for 14 days 3 BBP 50 000 units/kg/day thrice with 7 days Speci® c and prophylactic treatment in pregnancy interval (day 1, 8 and 15), provided the Speci® c treatment: newborn is not 52 kg in weight (B) Newborn with abnormal CSF or CSF not (A) Speci® c treatment of pregnant women before investigated: the 18th week of pregnancy is the same as in 1 The same regimens as for (A), but BBP is non-pregnant women not recommended (B) For speci® c treatment after the 18th week of pregnancy the following regimens are recom- Penicillin allergy, alternative treatment: mended: 1 Oxacillin or ampicillin or ceftriaxone (80 mg/ . Primary syphilis: kg/day for 14 days). 1 PBP 1.2 million units IM daily or NBP 600 000 units IM twice daily for 10 days Speci® c treatment of late congenital syphilis: 2 SBP 1 million units IM 4 times daily 1 PBP 50 000 units/kg/day IM once daily or NBP (every 6 hours) for 10 days 50 000 units/kg/day IM twice daily for 28 days, . Secondary and early latent syphilis: followed by a second course for 14 days after 2 1 The same regimens as in primary syphilis, weeks’ interval but for 20 days. 2 SBP 50 000 units/kg/day IM 6 times daily for 28 days, followed by a second course for 14 days Prophylactic treatment of pregnant women, who after 2 weeks’ interval. have been treated for syphilis in the past, but are still seropositive: Clinico-serological follow up after treatment of syphilis (A) Treatment, the same regimen as for primary Follow up: syphilis, is usually started after the 20th week . After preventive treatment of adults and of pregnancy. children and after treatment of primary (B) If speci® c treatment is given after the 18th syphilis: at 3 months week, that treatment should be followed by . After treatment of early forms of syphilis in prophylactic treatment. patients with a positive CSR (RMP): until complete negativation and for 6 months there- Alternative therapy in case of penicillin allergy: after erythromycin or semisynthetic penicillins. . After treatment of late forms of syphilis and after treatment of neurosyphilis: during 3 Management of syphilis in children years (serum CSR every 6 months during 2nd Prophylactic treatment of a newborn is indicated if and 3rd year after treatment, speci® c seroreac- the mother, seropositive at the time of labour, of a tions once a year); after treatment of neuro- clinically asymptomatic newborn was not treated syphilis: examination of CSF every 6 months or treated too late (after the 32nd week of during 3 years pregnancy): . Seroresistant patients are followed during 3 years (A) If the mother was not treated, the prophylactic . Newborns free from congenital syphilis, but regimen for the newborn is the same as in born from mothers with syphilis, are followed congenital syphilis during 1 year irrespective of prophylactic (B) If the mother was insuf® ciently treated or if she treatment. was still seropositive at labour after adequate treatment, the following regimens are recom- Seroresistance and additional treatment: mended: . Seroresistance is de® ned as a persistently 1 SBP 100 000 units/kg/day IM 6 times daily positive CSR 41 year after adequate speci® c for 10 days treatment of early syphilis 2 NBP 50 000 units/kg/day IM twice daily or . Delayed return to negative serology: decline in PBP 50 000 units/kg/day IM once daily for titre of reagins, at least 4-fold (2 steps), 51 10 days year after adequate speci® c treatment 3 BBP 50 000 units/kg twice with 7 days . In such cases the following additional treat- interval (day 1 and 8). ment regimens are recommended: 1 SBP 1 million units IM 6 times daily for 20 days Speci® c treatment of a newborn with early 2 PBP 1.2 million units IM once daily or NBP congenital syphilis, symptomatic or asymptomatic: 600 000 units IM twice daily for 20 days

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3 BBP 2.4 million units IM thrice with 7 days’ study of all patients in Denmark with neurosyphilis interval (day 1, 8 and 15) disclosed in the years 1971± 1979. Acta Dermatovener (Stockh) 4 Ceftriaxone 1000mg IM daily for 10 days. 1981(suppl 96):3± 14 18 Van Eijk RVW, Wolters EC, Tutuarima JA, Hische EAH, Bos Prerequisites for cure: JD, Van Trotsenburg L, et al. Effect of early and late syphilis on central nervous system: cerebrospinal ¯ uid changes and . Administration of adequate treatment neurological de® cit. Gentourin Med 1987;63:77± 82 . Normalization of clinical symptoms 19 Wolters EC, Hische EAH, Tutuarima JA, et al. Central . Normalization of serologic reaginic reactions nervous system involvement in early and late syphilis: the and other relevant laboratory tests. problem of asymptomatic neurosyphilis. J Neurol Sciences 1988;88:229± 39 Removal of a patient from the register requires: 20 Dunlop EMC. 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