15 – Sexually Transmitted Infections: Genital Ulcers Diseases (GUD) Speaker: Khalil Ghanem, MD

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15 –Sexually Transmitted Infections: Genital Ulcers Diseases (GUD) Speaker: Khalil Ghanem, MD

Disclosures of Financial Relationships with Relevant Commercial Interests

• None Sexually Transmitted Infections: Genital Ulcers Diseases (GUD)

Khalil G. Ghanem, MD, PhD Professor of Medicine Division of Infectious Diseases Johns Hopkins University School of Medicine

INCLUDED PHOTOS GENITAL ULCER DISEASES (GUD)

• Syphilis (Treponema pallidum) Please note: all photos are freely available • HSV-2 • HSV-1 from the following website unless otherwise • Chancroid (Haemophilus ducreyi) noted: • Lymphogranuloma venereum (LGV) http://www.cdc.gov/std/training/clinicalslide (Chlamydia trachomatis) s/slides-dl.htm • Granuloma inguinale (Donovanosis) (Klebsiella granulomatis)

PAIN AND GUD “KEY WORDS” IN GUD

Which ulcers are Which ulcers are • SYPHILIS: Single, painless ulcer or PAINFUL? PAINLESS? chancre at the inoculation site with • HSV • Syphilis* heaped-up borders & clean base; painless • Chancroid • LGV (but bilateral LAD (>30% of patients have multiple painful lesions) lymphadenopathy • HSV: multiple, painful, superficial, is PAINFUL) vesicular or ulcerative lesions with • Granuloma *>30% of patients have multiple erythematous base painful lesions inguinale

“KEY WORDS” IN GUD CONTINUED GUD: CONCEPTS TO KNOW

• CHANCROID: painful, indurated, ‘ragged’ genital ulcers & tender suppurative inguinal adenopathy • Organisms that cause disease (50%); kissing lesions on thigh • GI: Painless, progressive (destructive), • Geographic distribution for less “serpiginous” ulcerative lesions, without regional common agents lymphadenopathy; beefy red with white border & highly vascular • Diagnostic approach(es) • LGV: short-lived painless genital ulcer accompanied by painful suppurative inguinal • Therapeutic approach(es) lymphadenopathy; “groove sign”

QUESTION #1 QUESTION #1 Which of the following diagnostic tests is A 35-year-old woman presents with a inappropriate to obtain? painless ulcer on her vulva and one on her soft palate following unprotected vaginal A. Serum RPR and receptive oral sex 3 weeks earlier. She B. Serum VDRL has no other symptoms. C. Serum treponemal EIA D. Darkfield microscopy on a specimen obtained Examination reveals the two ulcers with from the oral ulcer heaped-up borders and a clean base. E. Darkfield microscopy on a specimen obtained from the vulvar ulcer

EARLY SYPHILIS: CLINICAL SYPHILIS: TAKE-HOME POINTS MANIFESTATIONS • Neurological and ocular manifestations may occur • Incubation ~3 weeks during any stage of syphilis • Primary: chancre; LAD; resolves 3-6 wks • Both treponemal and non-treponemal tests may be • Secondary: Systemic symptoms: low-grade fever, malaise, sore throat, adenopathy nonreactive in primary syphilis but they are almost • RASH: evanescent, copper-colored, macular (dry) rash; followed by a red papular eruption (involving palms and ALWAYS reactive in secondary and early latent soles); mucosal lesions (gray plaques or ulcers) ; syphilis (remember prozone reaction for non- condyloma lata- wart-like lesions that develop in moist areas treponemal test in secondary syphilis) • Other manifestations: uveitis, patchy alopecia, hepatitis (mild elevation of aminotransferases with • Treponemal tests are almost always reactive in late disproportionately high alkaline phosphatase), gastritis, syphilis (once positive always positive) irrespective periostitis, glomerulonephritis ft t thit

NEUROLOGICAL MANIFESTATIONS OF SYPHILIS • Can occur during any stage of infection • Can be either asymptomatic or symptomatic • Symptomatic Early Neurosyphilis • Occurs within the first year after infection • Mainly among HIV+ persons • Presents as meningitis (headache; photophobia; cranial nerve abnormalities; ocular symptoms) • Symptomatic Late Neurosyphilis (tertiary syphilis) • Usually occurs ~10 years AFTER primary infection • Divided into 2 categories: • Meningovascular • Parenchymatous

LATE NEUROSYPHILIS (TERTIARY) OTHER TERTIARY MANIFESTATIONS

Meningovascular Parenchymatous Cardiovascular Late benign syphilis • Endarteritis of the small • Due to actual destruction of • 15-30 years after latency • ‘Gummas’ blood vessels of the nerve cells • Men 3X> women • Granulomatous process meninges, brain, and spinal cord. • Tabes Dorsalis: shooting • Aortic aneurysm; aortic involving skin, cartilage, bone (less commonly in • Typical clinical pains, ataxia, cranial nerve insufficiency; coronary manifestations include abnormalities; optic atrophy artery stenosis; viscera, mucosa, eyes, brain) strokes (middle cerebral • General Paresis: dementia, myocarditis artery distribution is • Exceedingly rare in the psychosis, slurring speech; classic) and seizures U.S. Argyll Robertson pupil

SYPHILIS: EYES AND EARS SYPHILIS SEROLOGICAL TESTING Eyes Ears Nontreponemal tests Treponemal tests • Ocular manifestation may occur during • Sensorineural hearing loss • RPR (serum) or VDRL (serum or CSF) any stage and may involve any portion w/vestibular complaints • MHA-TP, TPPA, FTA-Abs, EIAs, CIA of the eye • May be used as screening test (sudden or fluctuating • Detect IgG +/- IgM antibodies • Uveitis & neuroretinitis: mainly (traditional algorithm) against treponemal antigens secondary stage hearing loss, ringing or • False+: endemic treponematoses, old • Interstitial keratitis: occurs in both vertigo) age, pregnancy, autoimmune disease • Usually used as confirmatory test congenital (typically at age 5-20; • Congenital (early and late) (APS), viral infections if nontreponemal test reactive 80% bilateral) and acquired (both • Acquired (secondary and late • Reactive result must be confirmed with • Once reactive, always reactive early and late infections) stages) treponemal test • False + may occur with endemic • CSF examination normal in • CSF examination is normal • False negative: PROZONE effect treponemal infections (e.g. yaws, ~30% of cases of ocular in >90% of cases of otic • Four-fold (i.e. 2-dilution) decline after pinta, bejel)or with Lyme disease syphilis syphilis treatment = CURE (irrespective of the end-titer)

SEROLOGICAL TESTING: SYPHILIS: DIAGNOSTICS DIFFERENT ALGORITHM +EIA/ –RPR / –FTA Abs +EIA/ –RPR / +FTA Abs • Darkfield microscopy for genital ulcers of primary syphilis; sensitivity of serology • False positive EIA • The patient had syphilis in the past and was adequately treated in primary syphilis only~70% • See previous slide • The patient had syphilis in the • Sensitivity of serology for secondary past but was not adequately or early latent syphilis ~100% treated • The patient has early syphilis and • Over time, non-treponemal serological the EIA became positive before titers decline and may become the RPR did (this is rare) nonreactive even in the absence of • Prozone reaction in secondary therapy while treponemal titers remain syphilis reactive for life*

SYPHILIS: DIAGNOSTICS CONTINUED SYPHILIS THERAPY

• No single test can be used to diagnose • Early stages (primary, secondary, early latent) neurosyphilis • 2.4 MU of long-acting benzathine penicillin or doxycycline • 50% of neurosyphilis cases may have negative CSF 100mg PO BID X 14 days VDRL; it is highly specific, but insensitive • Late latent/unknown duration • CSF treponemal tests are very sensitive but NOT specific • 2.4 MU of long acting benzathine penicillin G IM X3 (over (i.e. high false+) 2 weeks) [7.2 MU total] or doxycycline 100mg po BID X • May be used to rule out neurosyphilis 4 weeks • ~30% of persons with LATE neurosyphilis may have nonreactive SERUM nontreponemal test

SYPHILIS THERAPY CONTINUED QUESTION #2

• Neurosyphilis/Ocular syphilis A pregnant HIV+ woman (CD4 260 cells/mm3; HIV RNA <50 copies/ml) on ART presents with a diffuse rash. • Aqueous penicillin 18 to 24 MU IV X 10-14 days • Procaine penicillin 2.4 MU IM qd + probenecid 500 mg po On examination, she has a temperature of 38.3°C and a macular QID X 10-14 days rash on her trunk and extremities including her palms. • Ceftriaxone 1-2g IV/IM X 10-14 days (2nd line regimen) Serum RPR is reactive at a titer of 1:2048 and FTA-ABS is • Jarisch-Herxheimer: within 6 hours (up to 24 reactive hours) after therapy of (usually) early syphilis; She has a history of severe hives to penicillin but has tolerated antipyretics only; may induce early labor cephalosporins.

QUESTION #2 SYPHILIS & HIV

Which of the following antibiotics is most • Clinical manifestations similar but timeline may appropriate? be compressed • HIV+ patients more susceptible to early neurosyphilis A. Azithromycin • Testing and therapy similar to HIV-uninfected B. Benzathine penicillin G • Serological failure is more likely among HIV+ • Serological response may be slower among HIV+ C. Ceftriaxone • Follow-up is more frequent (every 3 months) D. Doxycycline

SYPHILIS & PREGNANCY HSV TAKE-HOME MESSAGES

• Screen all women at 1st prenatal visit • Both HSV-1 (particularly among young women and MSM)and 2 cause genital infections • Screen all high risk women and those women living in high- • Most people are unaware that they are infected prevalence areas twice in the 3rd trimester: at 28-32 weeks • Asymptomatic shedding is the most common reason for and again at the time of delivery transmission • Screen all women who deliver a stillborn infant after 20 • Condoms and antiviral suppressive therapy decrease risk of weeks’ gestation male to female transmission by 30% and 55% over time, respectively (condoms less effective from female to male) • Pregnant penicillin-allergic women with syphilis need • Currently, no formal screening recommendations to be desensitized to penicillin and treated with a • C-section ONLY in women who have active lesions at the time penicillin-based regimen. There are NO OTHER of delivery OPTIONS (not even ceftriaxone)

HSV HSV: DIAGNOSTICS

• Both HSV-1 and HSV-2 cause genital Patient presents with Asymptomatic Patient disease genital ulcer • HSV-1 is now becoming a more frequent cause of • Use Glycoprotein G-based type-specific genital disease (especially in young women and • Tzanck smear (40% assays (gG1 & gG2) MSM) • If gG2 is reactive, patient has genital sensitive) • In general, HSV-1 recurrences are less severe herpes* • Culture (sensitivity • If gG1 is reactive, patient either has oral and less frequent and asymptomatic shedding is herpes or genital herpes** less frequent 30-80%) • Positive predictive value is low in low • Prior infection with HSV-1 may attenuate severity • Antigen detection prevalence settings of HSV-2 infection • Serologic testing NOT routinely (~70% sensitive) recommended for screening • Classical presentation of multiple, painful, • Never obtain IgM or try to interpret IgM superficial, vesicular or ulcerative lesions with • PCR (FDA cleared, results! erythematous base may be absent >90% sensitive) * Assay has low specificity depending on cutoff ** Assay has low sensitivity

HSV: PREGNANCY QUESTION #3

• Risk of vertical transmission if mom acquires FIRST episode (i.e. primary infection) of herpes at time of delivery= up to 80% A 32 year-old man presents with a single, non- • Risk of vertical transmission if mom has RECURRENT episode of herpes at time painful, clean-based penile ulcer that developed 3 of delivery <1% days earlier • C-sections are recommended ONLY IF ACTIVE LESIONS OR PRODROMAL SYMPTOMS (i.e. vulvar pain/burning) PRESENT AT DELIVERY • ACOG: “For women with a primary or nonprimary first-episode genital HSV infection He was in India for 2 weeks 5 months ago during the 3rd trimester of pregnancy, cesarean delivery MAY BE OFFERED due to the possibility of prolonged shedding”. ACOG Practice Bulletin #220, May 2020 • Efficacy data on routine acyclovir use during 3rd trimester of pregnancy to His physical examination is otherwise unremarkable prevent HSV vertical transmission are lacking. • ACOG: Women with a clinical history of genital herpes should be offered suppressive viral therapy at or beyond 36 weeks of gestation ACOG Practice Bulletin #220, May 2020 & Serum RPR is negative Cochrane Systematic Review 2008: https://doi.org/10.1002/14651858.CD004946.pub2

CHLAMYDIA TRACHOMATIS L1-L3: QUESTION #3 LGV What is the most appropriate next step? • Classical manifestation is a short-lived painless genital ulcer accompanied by A. Obtain a tissue biopsy to evaluate for Klebsiella painful inguinal lymphadenopathy granulomatis • Outbreaks in US and Western Europe B. Obtain a serum FTA-Abs associated with proctitis particularly among C. Perform darkfield microscopy on a swab from the MSM***************** ulcer • Rectal pain, tenesmus, rectal bleeding/discharge D. No further testing; treat with doxycycline for two • May be mistaken for inflammatory bowel disease histologically (early syphilitic proctitis may also be weeks mistaken for IBD on histology) E. Serum glycoprotein G-based testing

LGV LGV DIAGNOSIS & THERAPY

“Groove sign” • Routine NAATs do not distinguish between serotypes D-K and L1-L3 (LGV). Multiplex PCR can be performed for specific serotypes. Serology may support the clinical diagnosis but is not a definitive diagnostic test; four-fold rise of IgM and IgG antibody is diagnostic of active infection. A single IgM antibody >1:64 or single IgG >1:256 are considered positive for invasive disease (standardized for genital infections). • Therapy: doxycycline 100mg PO BID X 3* weeks or Genital azithromycin 1g PO q week X 3 weeks elephantiasis *Experts feel that in mild LGV proctitis, 1 week of doxycycline or 2g of azithromycin is sufficient (chronic)

GRANULOMA INGUINALE OR CHANCROID DONOVANOSIS • Haemophilus ducreyi • Klebsiella granulomatis (Calymmatobacterium granulomatis) • Endemic in parts of the southern US/ Rates have gone down • Not endemic in US; common in SE Asia (India), & Southern Africa • Increased risk with HIV infection and commercial sex work (recently eradicated in Australia) • Symptoms: painful, indurated, ‘ragged’ genital ulcers & • Painless, progressive (destructive), “serpiginous” ulcerative lesions, tender suppurative inguinal adenopathy (50%); kissing without regional LAD (pseudobuboes occasionally); beefy red with lesions on thigh; 10% of patients co-infected with white border & highly vascular syphilis or HSV; bacterial superinfection not uncommon • Dx: tissue biopsy (no culture test; PCR not FDA cleared); • Dx: culture (80% sensitive) [antigen detection and PCR demonstrating the organisms in macrophages, called Donovan not widely available] bodies, using Wright-Giemsa stain (NOT Gram’s stain) • Rx: Azithromycin 1g PO X1 OR Ceftriaxone 250mg IM X1 • Rx: Doxycycline 100mg PO BID X 3 weeks (or until resolution) OR (erythromycin and ciprofloxacin may also be used) azithromycin 1g PO q week X3 (can also use trimethoprim/sulfa, • Treat all partners in preceding 60 days and ciprofloxacin) +/- aminoglycoside if slow to improve

GUD Pain Characteristics Diagnosis Treatment

HSV 1 & 2 Painful Multiple, superficial, -NAATs -Acyclovir etc. vesicular/ulcerative, -Culture (sensitivity -Foscarnet erythematous base ~70%) -Cidofovir -Serology

Syphilis Painless Single, well circumscribed, - Serology -Penicillin (T. pallidum) heaped-up borders, clean base -PCR -Doxycycline

Chancroid Painful Indurated, tender suppurative -Culture -Azithromycin (H. ducreyi) inguinal LAD (50%); kissing -PCR -Ceftriaxone lesions on thigh -Erythromycin -Ciprofloxacin LGV Painless short-lived ulcer, painful - NAATs -Doxycycline (C. trachomatis) suppurative LAD, “groove sign” - Serology -Azithromycin PROCTITIS -Culture(rarely)

Granuloma Inguinale Painless Progressive “serpiginous” without - Biopsy -Doxycycline (Klebsiella LAD; beefy red with white border -Azithromycin granulomatis) & highly vascular -Bactrim -Ciprofloxacin -Aminoglycosides