Syphilis: a clinical update

1. Syphilis: a clinical update 24th May 2012 Dr John White Department of Genitourinary medicine

2. Syphilis update: objectives • Understand current epidemiology of syphilis • Recognise different stages of disease • Know your syphilis tests and how to interpret them • Advise on treatment regimens for syphilis • Learn to love the treponeme and become the local expert

3. Syphilis • Caused by Treponema pallidum ss pallidum • Transmitted via any sex, skin/mucosal contact • Primary, secondary, early latent stages (< 2 years) = infectious • Almost disappeared in 1990s • Now seen almost daily in GUM clinics • The Great Imitator – often seen in other medical settings

4. Case Reason for attendance : Referred by GP Unwell Fever, rash, anal pain

5. Case A 33 y.o. MSM: • Unwell 4/52 • Lethargy, feverish • Sore anus • Skin rash 3 days • HIV negative - 6/2010

6. Case Sexual Hx: • LSI – 1/52: • RMP AI rec/ins, no condoms • OI rec/ins • Previous SI – 4/12 ago • CMP OI rec/ins

7. Case O/E • T = 375 • Cervical, post  , axillary nodes • Mouth – ulcer side of tongue • Generalised maculopapular rash • Chest NAD • Abdo – splenomegaly • Penis/testes – lesions • Inguinal nodes large, rubbery, non tender • Perianal - lesion

8. Case Results • FBC – lymphocytosis, rest NAD • LFTs: Alk Phos 224, ALT 82, GGT 178 • CRP = 43 • HIV Ab/Ag = negative • Syphilis Ab = POS, RPR = 128 • Diagnosis? • Secondary syphilis

9.  Long-term trends in gonorrhoea and syphilis notifications in England and Wales. Ward H Sex Transm Infect 2007;83:i43-i49 ©2007 by BMJ Publishing Group Ltd

16. Syphilis & HIV • STIs remain an important risk factor in the transmission and acquisition of HIV • Genital ulcers = highest RR • Syphilis reported to be atypical, aggressive, more neurosyphilis in HIV+ • In HAART era mostly the same as HIV-ve • HIV+ MSM get more syphilis than anyone

17. MSM sexual health • High rates of GC, CT, LGV, syphilis, hepatitis C in MSM, especially in HIV+ • High risk sex, serosorting, drug use, ever increasing HIV+ MSM population • Apart from urethral GC and rectal LGV, most of these are asymptomatic

18. Age and STIs in UK MSM

19. Syphilis in MSM Common again - ?ever controllable now “Safe sex for HIV” not protective Protean manifestations Multiple sites of inoculation - primary lesion often missed/absent Anorectal and oropharyngeal chancres Enhanced HIV transmission

20. Secondary Syphilis – other manifestations Laryngitis, painless hoarse voice Nasal mucosal lesions with nasal discharge Gastritis, proctocolitis Hepatitis with hepatosplenomegaly Glomerulonephritis which can result in nephrotic syndrome Periosteitis/periostitis causing bone pain Arthralgia Patchy alopecia • Ophthalmic(non-ocular) • Anterior or pan-uveitis including acute retinitis • Optic neuritis/peri-neuritis • 3rd 4th 6th cranial nerve • Neurological (non-ocular) • Cranial nerve palsies – esp 7th and 8th • Meningovascular involvement including meningitis and stroke syndrome

21. Pigmented T. pallidum immunostaining in a lymph node specimen

22. Tertiary SyphilisNeurosyphilis, cardiovascular syphilis, gummata… • Rarely seen now in UK • Consider tertiary syphilis in: • chronic skin ulcers • dementia screen • strange neurology • aortic incompetence/aneurysm

23. In-clinic tests for Syphilis

24. In-clinic tests for Syphilis

25. In-clinic tests for Syphilis • Dark Ground microscopy • Still useful but few have skills to perform it • Primary and secondary lesions • T. pallidum PCR is emerging • Point of care tests • Many now available – lateral flow Trep Ag-based • Ideal for resource poor settings • Yet to show much utility in clinic but trials awaited

26. Laboratory tests for Syphilis

27. Screening Test • Treponemal Antibody test • Mostly EIA/CLIA • Antibodies against specific Treponema antigens • Both IgG ± IgM (but don’t differentiate) • Highly sensitive • Occasionally non-specific • Won’t differentiate between syphilis and other non-venereal treponematoses such as yaws, pinta

28. Confirmatory Tests • T. pallidum Particle Agglutination (TPPA) • T. pallidum Haemagglutination (TPHA) • Most labs favour TPPA • In secondary and early latent syphilis, all the tests should be positive.

29. Typical UK serology algorithm Architect CLIA = Reactive TPPA RPR Assessment of disease activity Test for cardiolipin antibodies – not specific for Treponemes Confirmation using another specific Treponemal test High RPR titre (≥ 16) 4 x rise in titre = significant disease activity TPPA + = “confirmed Treponemal Infection at some time”

30. TPPA and RPR • Read by human eyes • Subjective • Labour intensive • Variation between readers and batches of reagents • Both can be negative in early primary syphilis • Patients with past infection don't need repeat EIA and TPPA: only RPR for these patients

31. Discrepant EIA and TPPA - GSTT • Architect reactive, TPPA negative (0.5% of all samples tested) • All such samples (234 in 2010) go to HPA STBRL for a second opinion • Tests done in Ref Lab: Total Ab EIA, IgM, RPR +/- InnoLipa (a line probe assay): • Most turn out to be negative (false positive CLIA) • Some are very weak positives due to past infection • A proportion remain indeterminate and continue to be indeterminate on repeats • Might be early primary – repeat in a week

32. T. pallidum IgM • Standalone EIA • IgM only • Theoretically detect early infection, last for 6-18 months • Seem prone to false positives • Not much clinical value: • Architect detects both IgG and IgM • Early disease activity detected by RPR • Treatment success monitored by RPR, not IgM • Useful in noenates born to mothers with syphilis during pregnancy

33. Mercia Syphilis M kit (Microgen)

34. Neurosyphilis tests • Only investigate if Trep abs +ve in blood • Send paired serum and CSF • Do routine biochemistry and microscopy in CSF • RPR titre in CSF • Any detectable RPR titre in CSF • Compare TPPA titre in CSF and serum • CSF TPPA titre > 640 • CSF titre > serum titre • ?Role for PCR in CSF – studies needed

35. Syphilis - Treatment • Penicillins still treatment of choice: • Benzathine penicillin IMI weekly 1-3 weeks • Procaine penicillin IMI Daily 10-17 days • Benzyl penicillin IVI – tertiary disease • Oral Amoxycillin in some circumstances • Oral Doxycycline – useful for penicillin allergic or needle decliners • - 100mg bd for 14-28 days for early/late disease

36. Antibiotic resistance • 23S rRNA A2058G and A2059G mutations confer macrolide resistance (n.b. azithromycin in guidelines) • The prevalence in clinical specimens increasing: • from 4% (2002) to 76.5% (2005) in San Francisco • from 9% (2002) to 56% (2008) in Seattle • July 2006–January 2008 at St Mary’s London: • 66% macrolide resistant – all MSM • Tipple et al, Sex Transm Infect 2011;87:486-488

37. Other treponematoses • Serology cross reacts with other treponemal antibodies / diseases: yaws, pinta, bejel • often confused with syphilis, esp. in African/Caribbean populations • common scenario: elderly, dementia screen, Trep Ab +ve, RPR negative • symptomatic tertiary syphilis almost always has positive RPR • examine, exclude 30 disease, treat to cover late latent syphilis

41. Key points • Think of syphilis! Every time! • Take sexual history, esp MSM • Link Trep Abs to HIV testing • Educate colleagues • Consult with GUM team • Be prepared to be deceived by the Great Imitator!