Genital Ulcer Disease Clinical Presentation, Diagnosis, and Management

Kenneth A. Katz, MD, MSc, MSCE Epidemic Intelligence Service, CDC STD Prevention and Control Services San Francisco Department of Public Health

Tabitha Clinic, Kibera, Nairobi, Kenya 2 April 2009 Genital Ulcer Disease (GUD)

• Aetiologies of GUD – –Herpes – – – Donovanosis • Clinical management – Aetiologic – Syndromic • Bonus: Drug resistance! Genital Ulcer Disease (GUD)

• Aetiologies of GUD – Syphilis –Herpes – Chancroid – Lymphogranuloma venereum – Donovanosis • Clinical management – Aetiologic – Syndromic • Bonus: Drug resistance! Genital Ulcer Disease (GUD)

• Aetiologies of GUD – Syphilis –Herpes KAIS 2007: – Chancroid Seroprevalence – Lymphogranuloma venereum • Women: 1.7% – Donovanosis • Clinical management• Men: 1.9% – Aetiologic – Syndromic • Bonus: Drug resistance! Syphilis: Microbiology

•Bacterium • Treponema pallidum subspecies pallidum •Spirochete • Obligate human pathogen • Cannot be readily cultured in vitro Syphilis: Natural history

Primary Exposure syphilis

• Sexual or nonsexual contact, congenital, occupational, bloodborne • 30–50% risk of infection following exposure • develops in ~21 days (range, 10–90 days), lasts 2–6 weeks Primary syphilis Syphilis: Natural history

Primary Secondary Exposure syphilis syphilis

• Can develop during or after primary syphilis • Lasts 3–8 weeks • Lesions on trunk, palms, soles, scrotum • “Moth-eaten” alopecia • Mucous patches • Condylomata lata • Systemic symptoms Secondary syphilis

www.merckmedicus.com Syphilis: Natural history

Primary Secondary Latent Exposure syphilis syphilis syphilis

• Latent syphilis: no signs or symptoms • Early latent: <1 year • Late latent: >1 year • 25% secondary relapse • Can last 2–20 years Syphilis: Natural history

Primary Secondary Latent Tertiary Exposure syphilis syphilis syphilis syphilis

• ~33% develop tertiary disease, if untreated • Can affect heart, bones, nerves, brain Syphilis: Neurosyphilis

• Can occur at any stage of disease • Can be asymptomatic • Neurologic or ophthalmic signs and symptoms • Cranial nerve palsies (III, VIII) • Strokes • Meningitis • < 5% of all cases • Neurologic examination is critical Syphilis: Syphilis and HIV infection

• Multiple • Overlapping primary and secondary manifestations • Slower decline of serologic titers • Increased HIV viral load and decreased CD4 counts Syphilis: Diagnosis

• Clinical suspicion • Rapid tests: Darkfield microscopy / Stat RPR • Non-treponemal tests: RPR / VDRL • Treponemal tests: TPPA / FTA-ABS / EIA • Neurosyphilis • Lumbar puncture and CSF analysis • CSF lymphocyte count > 10 cells/mm3, or • Positive CSF VDRL Syphilis: Indications for CSF analysis

• Signs of neurosyphilis • Hearing or vision loss • Tinnitus • Dizziness/imbalance • Cranial nerve abnormalities • Treatment failure • HIV infection and late latent stage • Tertiary disease Syphilis: Treatment of primary, secondary, and early latent syphilis

• Penicillin G benzathine 2.4 million units (MU) intramuscular (IM) once • Penicillin-allergic • Non-Pregnant: Doxycycline 100 mg orally twice daily for 14 days • Pregnant: Desensitize, treat with penicillin G benzathine 2.4 MU IM once • Jarisch-Herxheimer reaction • Fever, headache, myalgia within 24 hours of treatment Syphilis: Treatment follow-up

• Repeat serologic tests at 3, 6, 12 and 24 months – 4-fold decline in titer at six months consistent with cure • Clinical follow-up • Repeat CSF analysis for neurosyphilis • Screen for HIV infection and other STDs Syphilis: Post-Exposure Treatment

• Treat all sex partners within past 90 days • Penicillin G benzathine 2.4 MU IM once • Penicillin allergic • Non-Pregnant: Doxycycline 100 mg po BID x 14 days • Pregnant: Desensitize, treat with penicillin G benzathine 2.4 MU IM once Syphilis: Screening of Pregnant Women

• First prenatal visit • 28 weeks Genital Ulcer Disease (GUD)

• Aetiologies of GUD – Syphilis –Herpes KAIS 2007: – Chancroid HSV-2 Seroprevalence – Lymphogranuloma venereum • Women: 42% – Donovanosis • Clinical management • Men: 26% – Aetiologic – Syndromic • Bonus: Drug resistance! Herpes (HSV-2) “Textbook” case • Grouped vesicles on an erythematous (red) base • Painful • Incubation: 4 days (range, 2-12) • -2 (sometimes 1)

Grouped vesicles on an erythematous (red) base Herpes

“Textbook” case • Grouped vesicles on an erythematous (red) base • Painful • Incubation: 4 days (range, 2-12) • Herpes simplex virus-2 (sometimes 1)

Grouped vesicles on an erythematous (red) base Not (yet) ulcers – these are vesicles Herpes

Vesicles may rupture, leaving “punched out” erosions (areas missing the top layer of the skin)

Grouped erosions Herpes

Vesicles (blisters with clear fluid)

Pustules (blisters with yellow fluid)

Crust (scab)

Grouped pustules, some with crust, on erythematous base Herpes

Pustules, circumferential around foreskin Herpes

Grouped erosions with exudate (discharge) on

Grouped erosions Herpes

Grouped pustules on hair follicles • Auto-inoculation • No shaving!

Grouped pustules Herpes

More subtle presentation in recurrent disease • May be less painful • Patient may not be aware of outbreak

Grouped erosions Herpes

Bilateral labial erosions, tender inguinal lymphadenopathy

Kimberlin D and Rouse D. N Engl J Med 2004;350:1970-1977 Herpes

Perianal presentation • Grouped pustules on an erythematous base Herpes

More florid presentation with primary (first) episode • More widespread • More painful • Urination/defection may be difficult • May be HSV-1 Herpes

Chronic presentation in HIV-infected patient • Gluteal cleft • May be resistant to acyclovir • Less common with effective HIV therapies (ART) Genital Ulcer Disease (GUD)

• Aetiologies of GUD – Syphilis –Herpes – Chancroid – Lymphogranuloma venereum – Donovanosis • Clinical management – Aetiologic – Syndromic • Bonus: Drug resistance! Bacterial diseases – chancroid • Caused by Gram-negative bacillus Haemophilus ducreyi • One or more deep or superficial tender genital ulcers • Painful inguinal lymph node inflammation (bubo) in 50% • Begins 1-5 days (up to 14 days) after exposure • Extragenital disease reported Bacterial diseases – chancroid

Fitzpatrick TB, et al. Color Atlas and Synopsis of Clinical Dermatology, 2001 Bacterial diseases – lymphogranuloma venereum • Caused by trachomatis serovars L1, L2, L3 • Suppurative (pus-draining) inguinal lymph node inflammation with matted lymph nodes, inguinal bubo with ulceration, and constitutional symptoms – Begins 3-20 days after exposure with a painless lesion on the distal penis, vulva, vagina, or cervix – 2 weeks later: enlargement of lymph nodes (1/3 bilateral) – Violaceous color, tender swelling, and skin breakdown1-5 days (up to 14 days) after exposure – Systemic symptoms may occur (malaise, joint pains, conjunctivitis, loss of appetite, weight loss, and fever – Skin manifestations may include erythema nodosum, , photosensitivity, and scarlatiniform rashes • LGV can also manifest as proctitis Bacterial diseases – lymphogranuloma venereum

http://tmcr.usuhs.mil/tmcr/chapter20/epidemiology.htm Bacterial diseases –

• Caused by • Begins as single or multiple nodules (bumps) that erode through the skin to produce typically painless lesions • Lesions are typically “vegetative,” beefy red, soft, and bleed readily • 90% of cases involve genital region • Enlarge by auto-inoculation • Appear 8-80 days after exposure, usually 2-3 weeks • Leads to sinus formation and scarring Bacterial diseases – granuloma inguinale

http://dermatology.cdlib.org/127/case_reports/inguinale/khachemoune.html Genital Ulcer Disease (GUD)

• Aetiologies of GUD – Syphilis –Herpes – Chancroid – Lymphogranuloma venereum – Donovanosis • Clinical management – Aetiologic – Syndromic • Bonus: Drug resistance! Aetiologic vs. Syndromic Management

Aetiologic Management Aetiologic vs. Syndromic Management

Aetiologic Management Aetiologic vs. Syndromic Management

Aetiologic Management

What’s causing that that ? Aetiologic vs. Syndromic Management

Aetiologic Management

What’s causing that that ?

A B C

D E F Aetiologic vs. Syndromic Management

Aetiologic Management

What’s causing Laboratory that that ? testing

A B C

D E F Aetiologic vs. Syndromic Management

Aetiologic Management

What’s causing Laboratory that that ? testing

A B C

D E F Aetiologic vs. Syndromic Management

Aetiologic Management

What’s causing Laboratory that that ? testing

A B C

D E F Diagnosis: B Aetiologic vs. Syndromic Management

Aetiologic Management

What’s causing Laboratory that that ? testing

A B C

D E F Diagnosis: B

Treat for B alone Aetiologic vs. Syndromic Management

Aetiologic Management

What’s causing Laboratory that that ? testing

A B C

D E F Diagnosis: B

Follow up Treat for B alone Aetiologic vs. Syndromic Management

Syndromic Management

What’s causing that that ?

A B C

D E F Aetiologic vs. Syndromic Management

Syndromic Management

What’s causing that that ?

A B C

D E F

Treat for A, B, C, D, E, and F Aetiologic vs. Syndromic Management

Syndromic Management

What’s causing that that ? No tests! A B C

D E F

Treat for A, B, C, D, E, and F Aetiologic vs. Syndromic Management

Syndromic Management

What’s causing that that ? No tests! A B C

D E F

Treat for A, B, C, Follow up D, E, and F Aetiologic vs. Syndromic Management

Aetiologic Syndromic

Pros • More specific • No laboratory costs treatment • No waiting time • Less expertise Cons • Laboratory costs • Less specific • Waiting time treatments • Requires expertise Aetiologic vs. Syndromic Management

Aetiologic Syndromic

Pros • More specific • No laboratory costs treatment • No waiting time • Less expertise Cons • Laboratory costs • Less specific • Waiting time treatments • Requires expertise

Syphilis in San Francisco

600 552 551 527 495 500 428 419 400 354

300 185 200 Reported cases 71 100 41 44

0 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year Syphilis in San Francisco: Emergence of azithromycin resistance

600 Azithromycin (1 g) 552 551 for sex partners of 527 495 500 syphilis patients 428 419 400 Azithromycin (2 g) 354 for penicillin- 300 allergic patients 185 200 Reported cases 71 100 41 44

0 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year Partner Packs for Syphilis Patients in San Francisco, 2002–2004 • April 2003: Treatment failure in primary syphilis patient • September 2002–July 2003: 7 more treatment failures • All patients male and reported sex with men • All responded to subsequent treatment with penicillin or doxycycline

Encodes a structural component of 50S ribosomal subunit in T. pallidum, where macrolides bind, interfering with bacterial protein synthesis AÆG mutation at position 2058 precludes macrolide binding, conferring resistance • Historical strain • No resistance reported • Wild type 23S rRNA gene • Collected in 1976 • Clinically resistant to erythromycin • A2058G mutation in 23S rRNA gene • Collected during 1999–2003 in California, Ireland, and Washington • Clinically resistant to azythromycin or treated with other antibiotics • A2058G mutation Azithromycin resistance in T. pallidum specimens — San Francisco, 1999–2006

100 90 77% 77% 80 70 54% 60 50 38% 40 30 20 10 5%

% resistant to azithromycin % resistant 0 1999–2002 2003 2004 2005 2006 Azithromycin resistance in T. pallidum specimens — San Francisco, 1999–2006

• SFDPH stops using 100 azithromycin for early syphilis 90 • Penicillin recommended, 77% 77% 80 doxycycline alternative 70 54% 60 50 38% 40 30 20 10 5%

% resistant to azithromycin % resistant 0 1999–2002 2003 2004 2005 2006 • Equivalence trial, penicillin and azithromycin • Tanzania • 328 subjects •Cure rates – 97.7% in azithromycin group – 95.0% in penicillin group – Difference of 2.7% (95% CI, -1.7–7.1%) Drug Resistance: Neisseria gonorrhea Drug Resistance: Neisseria gonorrhea

Emerging: Resistance to cephalosporins Drug Resistance: Haemophilus ducreyi Genital Ulcer Disease (GUD)

• Aetiologies of GUD – Syphilis –Herpes – Chancroid – Lymphogranuloma venereum – Donovanosis • Clinical management – Aetiologic – Syndromic • Bonus: Drug resistance!