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Genital-Anal-Oral Ulcer Disease Update

Genital-Anal-Oral Ulcer Disease Update

Genital-anal-oral disease update

Philipp Bosshard Department of University Hospital Zurich Switzerland

ESCMID eLibrary © by author Case 1

• 22 y.o. male, no medical history • Pain when swallowing, tonsils with white thrush • Gingival erosion for 3 weeks • Penile for 3 months • Night sweats

• DD? ESCMID eLibrary © by author Differential diagnosis of oral ulcers

Infectious Non-infectious Trauma

Syphilis Necrotizing sialometaplasia (inflamed salivary glands)

Necrotizing ulcerative Autoimmune blistering disorders (, ) (Coxsackie virus) Eosinophilic Ulcer Tuberculosis Fixed Other (CMV) Behçet syndrome … …

ESCMID eLibrary © by author Case 1

• 22 y.o. male, no medical history • Pain when swallowing, tonsils with white thrush • Gingival erosion for 3 weeks • Penile papules for 3 months • Night sweats

• DD STI (), aphthae, viral, Behçet… ESCMID eLibrary © by author Case 1

• Rapid Plasma Reagin (RPR) 1:32 • TPPA 1:81920 • IgM-ELISA >3.5

• Oral lesion swab T. pallidum PCR positive

• Diagnosis: secondary syphilis with plaques muqueuses and angina syphilitica ESCMID eLibrary © by author Differential diagnosis of genital ulcers

Infectious Non-infectious Behçet syndrome Syphilis Fixed drug eruption , C. trachomatis L1–L3 Lichen planus Genital tuberculosis Trauma

Chancroid Autoimmune blistering disorders (pemphigus, pemphigoid)

Granuloma inguinale (donovanosis) Lipschütz ulcer (reactive nonsexually related acute ) Other Viruses (EBV, VZV) … ESCMID eLibrary © by author Differential diagnosis of anorectal ulcers

Infectious Non-infectious Inflammatory bowel diseases trachomatis D–K Solitary rectal ulcer syndrome Lymphogranuloma venereum, C. trachomatis L1–L3 … Syphilis Herpes simplex virus …

ESCMID eLibrary © by author Literature

Keyword Hits number 2017 Topics Genital ulcers 110 - 37 STI (19 ) - 36 Behçet disease - 4 Lipschütz ulcers Genital ulcers (reviews) 12 - 2 STI - 7 Behçet disease Oral ulcers 15 - 2 STI pallidum PCR 16 - 7 STI Multiplex PCR STI 7 - 7 STI LGV 21 - 15 STI 192 Syphilis 771 ESCMID eLibrary © by author Epidemiology

ESCMID eLibrary © by author WHO estimates

• > 1 million STIs acquired every day • Estimates for 2012 (15-49 y): New cases per year 300

250

200

150

100

50

0 Chlamydia Gonorrhoea Syphilis 1995 2005 2012

Newman L et al. Global Estimates of the and Incidence of Four Curable Sexually Transmitted ESCMIDInfections in 2012 eLibraryBased on Systematic Review and Global Reporting. PLoS One, 2015,10. © by author ECDC

Chlamydia Syphilis Gonorrhoea

European Centre for Disease Prevention and Control. Annual Epidemiological Reports. Stockholm: ECDC; ESCMID2017. eLibrary © by author ECDC

Chlamydia LGV (C. trachomatis L1–L3)

European Centre for Disease Prevention and Control. Annual Epidemiological Reports. Stockholm: ECDC; ESCMID2017. eLibrary © by author ECDC

Chlamydia Syphilis Gonorrhoea

European Centre for Disease Prevention and Control. Annual Epidemiological Reports. Stockholm: ECDC; ESCMID2017. eLibrary © by author ECDC

Chlamydia Syphilis Gonorrhoea

European Centre for Disease Prevention and Control. Annual Epidemiological Reports. Stockholm: ECDC; ESCMID2017. eLibrary © by author Neisseria gonorrhoeae (NG)

• Genital: , • Anal: , no symptoms • Oral: often without symptoms -> reservoir

ESCMID eLibrary © by author Neisseria gonorrhoeae (NG)

ESCMID eLibrary © by author NG resistance

Costa-Lourenço APRD et al. in Neisseria gonorrhoeae. Braz J Microbiol. ESCMID2017;48(4):617 -628.eLibrary © by author Voting What is your treatment for NG? 1. CRO 250 mg i.m. 2. CIP 500 mg p.o. + AZM 500 mg p.o. 3. CFX 400 mg p.o. + AZM 2 g p.o 4. CRO 250 mg i.m. + AZM 1 g p.o. 5. CRO 500 mg i.m. + AZM 2 g p.o. 6. SPC 2 g p.o. + AZM 2 g p.o.

5568 ESCMID eLibrary © by author Voting What is your treatment for NG? 1. CRO 250 mg i.m. 2. CIP 500 mg p.o. + AZM 500 mg p.o. 3. CFX 400 mg p.o. + AZM 2 g p.o CRO is unavailable, or i.v. injection impossible 4. CRO 250 mg i.m. + AZM 1 g p.o. U.S. recommendation 5. CRO 500 mg i.m. + AZM 2 g p.o. European recommendation 6. SPC 2 g p.o. + AZM 2 g p.o. Allergy to cephalosporin, or resistance

ECDC 2015: 58% received appropriate dual therapy

Bignell C et al. 2012 European guideline on the diagnosis and treatment of gonorrhoea in adults. Int J STD ESCMIDAIDS. 2013 Feb;24(2):85 eLibrary-92. © by author ECDC – NG resistance

Ceftriaxone: higher proportion of more susceptible gonococcal isolates CIP (>0.06) (MIC≤0.016 mg/L)

AZM (>0.5) CFX (>0.125)

European Centre for Disease Prevention and Control. Antimicrobial susceptibility surveillance in , ESCMID2015. Stockholm: ECDC;eLibrary 2017. © by author NG resistance – MDR, XDR

Reports about XDR N. gonorrhoeae G 1 (I) • 2011 first XDR NG in Japan Cefixime 4 (R) Ceftriaxone 2 (R) • 2012 three XDR cases in Spain Cefepime 16 (R) Ciprofloxacin >32 (R) 1 (R) High-level azithromycin-resistant NG (>256 mg) Spectinomycin 16 (S) 2 (R) • Sustained , England 2014-2017 • 70 HL-AziR strains (all CRO susceptible) • 37 of same strain type -> de facto monotherapy; CRO not protected

Lewis DA. Curr Opin Infect Dis. 2014;27(1):62-7 Unemo M. Antimicrob Agents Chemother. 2012;56(3):1273-80 ESCMIDFifer H. et al. Lancet InfecteLibrary Dis. 2018 Mar 6. pii: S1473-3099(18)30122-1 © by author Case 2

Clinical data Diagnostic test? Therapy/Remarks

Proctitis

ESCMID eLibrary © by author Case 2

Clinical data CT NG TPPA VDRL Therapy/Remarks

CT-NG-Proctitis, Ceftriaxon i.m. 500mg and no syphilis + + ± - Azithromycin p.o. 1 g symptoms No syphilis therapy

ESCMID eLibrary © by author Case 2

Clinical data CT NG TPPA VDRL Therapy/Remarks

CT-NG-Proctitis, Ceftriaxon i.m. 500mg and no syphilis + + ± - Azithromycin p.o. 2 g symptoms No syphilis therapy

Diagnosis of syphilis 2 month later: TPPA 1:2560; VDRL 1:16; IgM 2.37 ESCMID eLibrary © by author Case 2

Clinical data CT NG TPPA VDRL IgM Therapy/Remarks

CT-NG-Proctitis, Ceftriaxon i.m. 500mg and no syphilis + + ± - + Azithromycin p.o. 2 g symptoms No syphilis therapy

Diagnosis of syphilis 2 month later: TPPA 1:2560; VDRL 1:16; IgM 2.37 ESCMID eLibrary © by author Syphilis

Test Sensitivity (%)

Primary Secondary Early latent n=151 n=198 n=58

VDRL/RPR 58-62 97-100 88-96 TPPA 93-100 100 100 IgM 80-96 91-92 68-84

Knaute DF et al., Clin Infect Dis. 2012 Dec;55(12):1615-22 ESCMIDBosshard PP, J Infect.eLibrary 2013 Jul;67(1):35-42 © by author Syphilis serology

Test Sensitivity (%)

Primary Secondary Early latent n=151 n=198 n=58

VDRL/RPR 58-62 97-100 88-96 TPPA 93-100 100 100 IgM 80-96 91-92 68-84 -100

Knaute DF et al., Clin Infect Dis. 2012 Dec;55(12):1615-22 ESCMIDBosshard PP, J Infect.eLibrary 2013 Jul;67(1):35-42 © by author Syphilis serology

Zurich algorithm (modified reverse algorithm)

Treponemal test (TPPA)

Suspected primary syphilis: TPPA + IgM-ELISA

If positive

Confirmatory test (IgG-EIA), Non-treponemal test (RPR), IgM-EIA ESCMID eLibrary © by author Syphilis treatment

14th-19th century From 1941 on ESCMID eLibrary © by author Syphilis treatment

2014 European guideline • Early syphilis First line: Benzathine penicillin G 2.4 million units IM

• Late syphilis First line: 3x Benzathine penicillin G 2.4 million units IM ESCMIDJanier M et al. 2014eLibrary European guideline on the management of syphilis, JEADV, DOI: 10.1111/jdv.12734 © by author Syphilis treatment

2014 European guideline • Early syphilis First line: Benzathine penicillin G 2.4 million units IM

Second line: Procaine penicillin 600,000 units IM daily for 10-14 days Ceftriaxone 500mg-1 g subcutaneously or IV daily for 10 days 200 mg daily orally for 14 days Azithromycin 2 g oral single dose

• Late syphilis First line: 3x Benzathine penicillin G 2.4 million units IM ESCMIDJanier M et al. 2014eLibrary European guideline on the management of syphilis, JEADV, DOI: 10.1111/jdv.12734 © by author Syphilis treatment

MLST T. pallidum subsp. pallidum

• 3 loci (TP0136, TP0548 and TP0705) + 23S rDNA for r/s

• 120 Swiss and French clinical samples • TP0136, TP0548 and TP0705: 23 allelic profiles • 23S rDNA: 79% macrolide resistant

Grillova L et al. Molecular characterization of subsp. pallidum in Switzerland ESCMIDand France with a neweLibrary Multilocus Sequence Typing scheme. Submitted. © by author Case 3 (RM Cymerman et al.)

• 15 y.o. female, no medical history • Painful • Denies sexual activity

• DD – STI (sexual abuse?) – Non-infectious

ESCMIDCymerman RM et al.eLibrary International Journal of Dermatology 2017, 56, 361– 369 © by author Voting: what is the aetiology?

1. Syphilis 2. HSV 3. LGV 4. Impetigo 5. Behçet disease 6. Lipschütz’s ulcer

5592 ESCMID eLibrary © by author Case 3 (RM Cymerman et al.)

• 15 y.o. female, no medical history • Painful • Denies sexual activity

• Investigations: – STI negative – Bacteriology negative – EBV serology: IgG and IgM  Reactive Nonsexually Related Acute Genital Ulceration (Lipschütz’s ulcer) ESCMIDCymerman RM et al.eLibrary International Journal of Dermatology 2017, 56, 361– 369 © by author Reactive Nonsexually Related Acute Genital Ulceration

Patients Symptoms Diagnostic criteria Treatment Young women, Genital painful ulcers, Reactive to EBV, CMV, Supportive therapy 10-19y single or multiple influenza, viral (analgesics and topical with , gastroenteritis, viral corticosteroids) after febrile illness respiratory , , Lyme borreliosis

Self-resolving within 2-3 weeks

Also called Lipschütz’s ulcer

ESCMIDCymerman RM et al.eLibrary International Journal of Dermatology 2017, 56, 361– 369 © by author Other non-infectious aetiologies

Aetiology Symptoms Diagnostic criteria Treatment Behçet syndrome Oral aphthous and Recurrence, eye lesions, Spontaneous regression, genital ulcers cutaneous lesions, interferon, corticosteroids, pathergy test, histology cyclosporine A, anti-TNF, … Fixed drug Varied ulcerations Ulcers resolve after drug Self-limited, topical analgesics eruptions withdrawal or anti-inflammatory agents, as needed

Behçet Fixed drug eruption

Roett MA et al. American Family Physician, 2012;85:254 ESCMIDRios Scherrer MA eteLibrary al. An Bras Dermatol. 2017;92:452-464 © by author Case 4

• 18 y.o. female • Painful ulcers • Returned from Thailand 3 weeks ago • Protected oral and vaginal sex with a other Swiss tourist in Thailand

• DD?

ESCMIDLuchsinger I et al. eLibrarySex Transm Infect 2015;91:493–496 © by author Voting: what is the aetiology?

1. HSV 2. Impetigo (S. aureus) 3. Chancroid (H. ducreyi) 4. Fungal infection 5. (Donovanosis) 6. Contact

5593 ESCMID eLibrary © by author Case 4

• 18 y.o. female • Painful ulcers • Returned from Thailand 3 weeks ago • Protected oral and vaginal sex with a other Swiss tourist in Thailand

• Herpes 1+2 PCR negative • STI screening negative (syphilis, HIV, CT/NG) • Bacteriology negative ESCMIDLuchsinger I et al. eLibrarySex Transm Infect 2015;91:493–496 © by author Case 4

• 18 y.o. female • Painful ulcers • Returned from Thailand 3 weeks ago • Protected oral and vaginal sex with a other Swiss tourist in Thailand

• Herpes 1+2 PCR negative • STI screening negative (syphilis, HIV, CT/NG) • Bacteriology negative ESCMIDLuchsinger I et al. eLibrarySex Transm Infect 2015;91:493–496 © by author Case 4

• Culture: Trichophyton mentagrophytes • Zoophilic

• Terbinafine 250 mg/d + local antiseptics and imazole cream • After 3 d without improvement: itraconazole 200 mg/d for 7 we • Healing with

ESCMIDLuchsinger I et al. eLibrarySex Transm Infect 2015;91:493–496 © by author ESCMID eLibrary © by author Tinea genitalis

• 7 patients with tinea genitalis with T. mentagrophytes • Sexual intercourse 1–2 weeks earlier in South East • 4 male patients had sexual contacts with local prostitutes • All patients declared the use of condoms

• Infection that can be sexually transmitted (but not an STI)

• Additional cases, also autochthonous cases • In one presumably dog also infected

ESCMIDLuchsinger I et al. eLibrarySex Transm Infect 2015;91:493–496 © by author Tinea genitalis

ESCMIDLuchsinger I et al. eLibrarySex Transm Infect 2015;91:493–496 © by author Other rare infectious aetiologies

ESCMID eLibrary © by author

Chancroid % of GUD cases, example Zimbabwe • 1979; 38% • 1995; 3% • 2017; 0%

• Similar decline (or virtual disappearance) in countries where it was previously endemic

ESCMIDMungati M et al. SexuallyeLibrary Transmitted Diseases, 2018;45:61 © by author Haemophilus ducreyi

Chronic ulceration in children and adults in the Pacific region and

ESCMIDLewis DA and MitjaeLibraryO. Curr Opin Infect Dis. 2016 Feb;29(1):52-7 © by author Haemophilus ducreyi

• Chronic skin ulceration in children and adults in the Pacific region and Africa

ESCMIDLewis DA and MitjaeLibraryO. Curr Opin Infect Dis. 2016 Feb;29(1):52-7 © by author Haemophilus ducreyi

Yaws (T. pallidum ssp. pertenue) endemic region

Papua New Guinea

ESCMIDLewis DA and MitjaeLibraryO. Curr Opin Infect Dis. 2016 Feb;29(1):52-7 © by author Multiplex PCR

ESCMID eLibrary © by author Multiplex PCR

Home-brew assays

ESCMID eLibrary © by author Home-brew assay

1 Swab 1 PCR 4 Results; TP, HD, HSV1, HSV2

Pathogen Sensitivity, % (95% CI) Specificity, % (95% CI) T. pallidum 100 (88-100) 100 (97-100) Herpes simplex type 1 100 (82-100) 98 (95-99) Herpes simplex type 2 100 (77-100) 98 (95-100)

N = 229

ESCMIDGlatz M et al., Clin eLibraryMicrobiol Infect. 2014 Dec;20(12):O1020-7. © by author Home-brew assay

4 years of experience • 684 samples (51% genital swabs, 15% oral, 20% anal, 14% others)

Aetiology Requested PCR, Positive PCR, No. No. (%) TP 637 90 (14%) HSV1 383 35 (9%) HSV2 386 46 (12%) H. ducreyi 295 0

ESCMIDUnpublished eLibrary © by author Home-brew assay

4 years of experience (preliminary data)

PCR Serology + Serology – (active infection) (negative or serofast) TP + 51 12 TP - 1 probable 71 4 possible 5 healed ulcer

TP-PCR Sensitivity 93% Specificity 100% RPR Sensitivity 88% Specificity 69%

ESCMIDUnpublished eLibrary © by author Commercial assay urethritis/cervicitis

• AnyplexTM II STI-7, Seegene • 1575 samples (1167 cervical, 105 vaginal, 177 seminal, 126 male urethra)

ESCMIDDel Prete R et al. InfectioneLibrary (2017) 45:469–477. © by author POCT

• “Accurate and inexpensive POC tests are urgently needed to control the costly epidemics of STIs in the world today, so that patients can receive timely diagnoses and needed treatment for these ” (Gaydos and Hardick)

• “POC test should be done in a population where traditional testing is not practical” (Morshed)

Gaydos C and Hardick J. Expert Rev Anti Infect Ther. 2014 Jun;12(6):657-72 ESCMIDMorshed MG. Adv eLibraryExp Med Biol. 2014;808:51-64 © by author POCT

ESCMIDGaydos C and HardickeLibraryJ. Expert Rev Anti Infect Ther. 2014 Jun;12(6):657 -72 © by author Dual POCT HIV/syphilis

Meta-analysis of dual POCT for HIV and syphilis

Test No. HIV Sens HIV Spec Syphilis Sens Syphilis Spec studies SD BIOLINE HIV/Syphilis Duo Test 12 >98 97-100 89-100 (1x 67) 91-100

MedMira Multiplo Rapid TP/HIV 4 >98 (1x 94) 92-100 81-95 93-100 Test Chembio DPP HIV/Syphilis Assay 6 >98 100 46-97 100

 To be used as screening for pregnant women  And MSM, transgender people, injecting drug users and sex workers  More cost-effective and more effective at preventing adverse pregnancy outcomes than testing for HIV alone or using separate POCT for HIV and syphilis ESCMIDGliddon HD et al. SexeLibrary Transm Infect 2017;93:S3–S15 © by author Summary

• Incidence; CT, HIV ± constant; NG, Syphilis increasing • NG resistance; ± constant level, but MDR, XDR • Syphilis diagnostic algorithm • Syphilis macrolide resistance • H. ducreyi changing epidemiology • Rare infectious (Tinea genitalis) • Multiplex PCR • POCT ESCMID eLibrary © by author ESCMID eLibrary © by author Lymphogranuloma venereum (LGV) Genital painless ulcer

Unilateral lymphaden- pahty

C. trachomatis D-K LGV (C. trachomatis L1–L3) Ano-genital • Epidemic in Europe since 2003 ulcer • Mainly MSM • 70% HIV positive

ECDC. Annual Epidemiological Reports. Stockholm: ECDC; 2017. Latini A et al. BMC Infectious Diseases (2017) 17:386 ESCMIDHaber R et al. Sexually eLibrary Transmitted Diseases (2017) 44:310 © by author Lymphogranuloma venereum (LGV)

Diagnosis 2 step procedure • 1. Commercial C. trachomatis PCR from rectal or genital swab, aspirate • 2. LGV specific PCR (TaqMan real-time pcr)

Therapy • First line: Doxycycline, 100 mg orally twice daily for 21 days • Second line: base, 500 mg orally four times daily for 21 days • Also reported: Azithromycin, 2 g on days 1, 8, and 15 ESCMID eLibrary © by author

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