Current Threats of Increased Syphilis. Disclosures. Objectives

Transcription

1 Current Threats of Increased Syphilis Anne Rompalo, MD, ScM Professor of Medicine Johns Hopkins School of Medicine Disclosures No Relevant Relationships Objectives At the end of this presentation, participants should be able to: Describe some of the less common clinical manifestations of syphilis Discuss the challenges in controlling the latest syphilis pandemic Identify some novel approaches to controlling the reemergence of syphilis 1

2 Part 1 LESS COMMON CLINICAL MANIFESTATIONS Patient 1 36 year old gay man with sudden onset of fluctuating bilateral hearing loss and tinnitus Sensorineural with poor word discrimination Diffuse maculopapular rash on trunk sparing palms and soles Serum CIA reactive; RPR 1:2048 CSF examination negative IV aqueous crystalline penicillin G 4,000,000 units IV q 4 hours + steroids X 10 days JH reaction after 1 st dose of penicillin Complete resolution of symptoms 1 month after therapy Otosyphilis Diagnostic criteria: cochleovestibular dysfunction and syphilis infection without an alternate diagnosis; ~50% bilateral Diagnosis is presumptive; CSF examination is normal in 90% of cases Therapy: IV penicillin (+ corticosteroids) Prognosis: 23% experience improvement in hearing; up to 80% experience improvement in tinnitus and vertigo Absence of hearing fluctuations, longer duration of symptoms, and age >60 years are bad prognostic indicators Laryngoscope 1973; 83: Laryngoscope 1983; 93:154 Laryngoscope 1977;87: Laryngoscope 1984; 94: Laryngoscope 1992; 102:

3 Patient 2 48 year old man with a history of Hepatitis C infection and alcohol abuse presents to ED with a pustular rash, decreased PO intake, and nausea Pustular rash on arms, back, and abdomen; no stigmata of chronic liver disease AST 52 U/L; ALT 58 U/L; AP 1260 U/L; t-bili 1.2 mg/dl Serum CIA reactive; RPR 1:128 BPG 2.4 MU IM X1 Sent to ultrasound for HCC screening and discharged after PCN therapy Syphilitic Hepatitis Involvement of the liver in late stages of the disease as fibrosis, gumma, and hepar lobatum well documented in the pre-antibiotic era Early stage asymptomatic involvement usually as a disproportionally elevated alkaline phosphatase in the setting of secondary syphilis is a more recent observation- but is not universal Clinical:? Association with rash and anorectal lesions Histology: pericholangiolar inflammation; mild (proliferation of sinus endothelial cells and Kupffer cells, eosinophils, and lymphocytes) to severe (diffuse necrosis especially in periportal region and central vein) In half of the cases spirochetes were found in the necrotic foci, walls of sinusoids, and in the endothelial cells Incidence of LFT abnormalities in both immunocompetent and HIVinfected persons in secondary syphilis noted in up to 38% -but majority are asymptomatic Treatment: 2.4 MU of BPG IM X1 Lancet. 1975;2(7941):896-9 West J Med. 1978;128(1):64-7 Int J STD AIDS. 2009;20(4): Int J STD AIDS. 2012;23(8):e4-6 Patient 2 continued 48 year old man with a history of Hepatitis C infection and alcohol abuse presents to ED with a pustular rash, decreased PO intake, and nausea Pustular rash on arms, back, and abdomen; no stigmata of chronic liver disease AST 52 U/L; ALT 58 U/L; AP 1260 U/L; t-bili 1.2 mg/dl Serum CIA reactive; RPR 1:128 BPG 2.4 MU IM X1 Sent to ultrasound for HCC screening and discharged after PCN therapy 12 cm mass in liver consistent with HCC Follow-up appointment with IR scheduled 1 week later for CT-guided biopsy At follow-up with IR, mass had disappeared 3

4 Liver Abscesses and Tumors Am J Surg Pathol 2014; 38 (12): Patient 3 58 y/o man R eye pain and redness X 4 days No medical care X 20 years Right eye: Panuveitis Serum CIA reactive; RPR 1:128 CSF Examination: 46 WBCs (mononuclear cells); VDRL 1:4; IV aqueous crystalline penicillin G 4,000,000 units IV q 4 hours + topical steroids Clinical Advisory: Ocular Syphilis in the United States Between December 2014 and March 2015, 12 cases of ocular syphilis were reported from two major cities, San Francisco and Seattle. Subsequent case finding indicated more than 200 cases reported over the past 2 years from 20 states. The majority of cases have been among HIV-infected MSM; a few cases have occurred among HIV-uninfected persons including heterosexual men and women. Several of the cases have resulted in significant sequelae including blindness. MMWR Morb Mortal Wkly Rep. 2015;64(40):

5 Prevalence of ocular syphilis No national estimates (passive reporting) Antibiotic era: Up to 8% of patients with secondary syphilis 3-51% of patients with neurosyphilis 7.9% of syphilis patients reported new onset of visual or hearing disturbances British Ocular Syphilis Study ( ): 0.3 per 1 million adults This compares to approximately 50 per 1 million cases of syphilis diagnosed annually in the United Kingdom health clinics during the same period Sex Transm Dis 1980; 7: Int J Dermatol 1987; 26: J Clin Neuroophthalmol 1983; 3: Sex Transm Dis 2015; 42: Invest Ophthalmol Vis Sci 2014;55: Arch Neurol 1993; 50:243-9 What stage(s) of syphilis involves the eye? What part(s) of the eye is/are involved? Every part of the eye can be involved during any stage of the infection Semin Ophthalmol 2005; 20: Majority of eye manifestations associated with syphilis are also associated with many other infectious and non-infectious diseases. AJO 1930; 13: Ocular Manifestations of Syphilis: Up to 50% Bilateral Lids Chancre Gumma Tarsitis Ulcerative blepharitis Conjunctiva Chancre Papular syphilides Gumma Orbit Periostitis Gumma Anterior Chamber Hypopyon Cornea Interstitial keratitis Ulcers Deep, punctate keratitis Keratitis profunda Keratitis punctate profunda Keratitis linearis migrans Gumma Sclera Episcleritis Scleritis Gumma Iris and Ciliary Body Roseolae Papules Gumma Iritis/Uveitis J.Clin Neuro-Ophthalmol. 3: , 1803 Lens Capsular rupture and necrotizing cortical inflammation (congenital syphilis Dislocation Retina and Vitreous Chorioretinitispseudoretinitis,pigmentosa, salt and pepper fundus Perivasculitis Central retinal artery/vein occlusion Cystoid macular edema Vitritis Optic Nerve Neuritis Perineuritis Neuroretinitis Gumma Motility Dysfunction Oculomotor, abducens, troclear paresis associated with basilar meningitis Periodic alternating nystagmus Pupils Light-near dissociation 5

6 How are ocular syphilis and neurosyphilis related? They are separate entities but there is overlap Embryologically, the neuroectoderm forms the posterior layers of the iris, retina, and optic nerves Sex Transm Infect pii: sextrans (published ahead of print) Diagnostic Criteria Ocular signs and symptoms in a person who has syphilis Most diagnoses are presumptive Most will have positive serological tests In patients with late ocular syphilis, up to 30% may have a nonreactive serum RPR/VDRL but will have a reactive serum treponemal test Implications of the RSA Rarely, with early primary syphilis, persons will have nonreactive syphilis serologies (both treponemal and RPR/VDRL) and eye symptoms 30% of persons with ocular syphilis will have a normal CSF examination A CSF examination is NOT necessary to make a diagnosis of ocular syphilis Role of CSF examination in the absence of neurological signs/symptoms Up to 70% of patients with ocular syphilis will have CSF abnormalities which need to be followed If the CSF VDRL is reactive (in up to 35% of patients with ocular syphilis), a DEFINITIVE diagnosis of ocular syphilis can be made Objective measure in persons with fluctuating symptoms The CDC recommends a CSF examination in all persons with syphilis and ocular signs/symptoms Arch Dermat Syph 1921; 3:272 6

7 Role of adjunctive corticosteroid therapy No clear evidence for benefit or harm Topical corticosteroids have been used as treatment adjuncts for syphilitic interstitial keratitis and anterior uveitis Oral and intravenous corticosteroids have been used as treatment adjuncts for posterior uveitis, scleritis, and optic neuritis Intravitreal injections of triamcinolone may be harmful Retina 2012; 32: Complications Incidence of visual impairment 0.29/eye year for HIV uninfected 0.21/eye year for HIV infected Incidence of permanent blindness 0.07/eye year for HIV uninfected 0.06/eye year for HIV infected Risk factors for poor visual outcomes: longer duration of untreated infection; macular chorioretinitis Long-term complications: glaucoma, cataract, epiretinal membrane and macular edema, choroidal neovascularization, widespread chorioretinal scarring Am J Ophthalmol 2015; 159: Lancet Infect Dis 2004; 4(7): Is there evidence for T. pallidum oculotropism? Evidence for neurotropism: In Seattle, a specific strain type (14d/f) was associated with neurosyphilis J Infect Dis 2010; 202: Sex Transm Dis. 2016;43(8):

8 Explaining the increasing numbers Increasing rates of syphilis Increasing use of the RSA Increasing awareness**** Ophthalmology 1990; 97: Sex Transm Dis. 2015;42(6):347-9 Part 2 EPIDEMIOLOGY & THE CHALLENGE OF CONTROL 8

9 Syphilis in the U.S. 2015: The rate increased 19% from 2014 and 66% from 2011 During , the P&S syphilis rate among women increased 27.3%. 49.8% of cases among MSM were HIV-positive, compared with 10.0% of cases among MSW, and 3.9% of cases among women CDC. Sexually Transmitted Disease Surveillance Atlanta: U.S. Department of Health and Human Services;

10 The Infection/Reinfection Cycle 493 early syphilis cases in 2010 and 2011 were reported among 460 MSM in Baltimore, MD: One in five MSM with syphilis had repeat infection 26% of repeat syphilis infections occurred 12m apart (median 18m) Repeat infections: 5% primary; 40% secondary; 53% early latent 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% MSM with single syphilis MMWR (32); MSM with repeat syphilis No HIV dx (as of 2 wks after syphilis dx date) HIV dx on (or within 2 wks after) syphilis dx date HIV dx before syphilis Complex Factors Influence Transmission Fenton. Infect Dis Clin N Am 2005; 19:

11 Syphilis Control 1. Case finding through serological screening 2. Prompt effective therapy 3. Identification of exposed partners 4. Mandatory serological evaluation of people who may transmit infection to others 5. Public education R o = ß c D (R ) = # of contacts/time x transmission probability/contact x duration of infectiousness Education Education might work if there is a knowledge deficit. It s unlikely to work if there is a behavior deficit or a reasoning deficit. DAVID ASCH Behavioral Interventions Mathematical models suggest that changes in behaviors and condom use, particularly short-term ones (and even long-term ones if they were only modest) would not impact syphilis rates Gray. STD 2011;38: Behaviors (no matter how irrational they appear to us) are always emotionally rational to the person committing them Linda Hellmann 11

12 Serological Screening Every 3-month screenings among highly active MSM is very high-yield and cost efficient. Gray. STD 2010; 37: ; Lewis J Publ Health Management Practice 2011; 17: Tuite. BMC Public Health 2013, 13:606 Annual screening of 62% of a population can lead to local syphilis elimination Q 3mos screening of 23% of a population can lead to local syphilis elimination Tuite. Sex Transm Inf 2015, 10:1-6 Among 1268 HIV uninfected MSM from Baltimore (part of National HIV Behavioral Surveillance System): - 54% received an HIV test in previous 12 months - 31% had received a syphilis test - 72% had seen a healthcare provider Said. AIDS Behav 2015 The Ambiguity & Inconsistency of Serological Screening Messages Strategies to Increase Screening Opt-In and Opt-Out vs. risk-based strategies Opt-in and opt-out strategies increased testing 2X Opt-out > Opt-in Although increased screening failed to meet quarterly testing guidelines Guy. PLOS One 2013, 8(8):e71436; Callander. STD 2013, 40(4):338 Social marketing campaigns Check Yourself campaign: Confirmed awareness was strongly associated with syphilis screening Plant. STD 2014; 41(1):

13 Partners & the Internet MSM who used the internet had ~2-fold higher odds of engaging in unprotected anal intercourse, a 3.4 higher odds of having anonymous sex, and a higher average number of partners in the past 6 months (10 vs 5) Liau. Sex Transm Dis 2006;33: Taylor. Sex Transm Dis 2004;31:552 6 Ng. m J Public Health2013; 103: Beymer. Sex Transm Infect 2014;90: Targeting at-risk populations was complicated as many sexual encounters involved anonymous partners. Outbreaks among MSM were influenced by the use of geospatial realtime networking applications that allow users to locate other MSM within close proximity. Simms. Euro Surveill. 2014;19(24):pii=20833 The Challenges of Partner Notification for MSM The current data for MSM suggest DIS-assisted notification as typically practiced results in a lower proportion of cases found per index case than has historically been the norm for (predominantly) heterosexual cases. Hogben. Sexually Transmitted Diseases 2005; 32(10):S43 S47 Van Aar. BMC Infect Dis 2012; 12: 114. BUT THERE IS ANOTHER SIGNIFICANT CHALLENGE 13

14 PrEP is a FANTASTIC intervention that may have unintended consequences IF WE CAN CONTROL HIV TRANSMISSION AMONG MSM, WHY SHOULD WE CARE ABOUT SYPHILIS? HIV Prevention / STD Prevention HIV group was on board because the messages were similar and STDs increased risks of HIV acquisition and transmission STD group was on board because the messages were similar and there was HIV $$$ PrEP Treatment as Prevention 14

15 THERE IS A NEED FOR NOVEL INTERVENTIONS TO COMBAT STDs Syphilis Control: Doxycycline? PrEP 30 MSM who had syphilis twice or more since their HIV diagnosis randomized to daily DOXY 100 mg or placebo F/U at weeks 12, 24, 36, and 48 Outcomes: CT, NG, TP OR 0.28 (95%CI: ) Bolan et al. Sex Transm Dis. 2015;42(2): PEP 232 MSM in IPERGAY TDF/FTC PrEP Study Randomized 1:1: Two 100 mg tablets of DOXY to be taken within 72 hours of condomless sex (on-demand) 8.7 months F/U Median 7 pills/month HR for syphilis: 0.27 (95%CI: ) Molina et al. CROI 2017 Abstract 91LB Summary Syphilis rates are increasing- particularly among MSM but now among women and infants Limited $ for control It s becoming more challenging to implement Thomas Parran s approach to STD control in the internet era Be aware of the less common clinical manifestations of syphilis Novel approaches are needed 15

16 References AIDS 2016, 30 : AJO 1930; 13: Am J Ophthalmol 2015; 159: Arch Dermat Syph 1921; 3:272 Arch Neurol 1993; 50:243-9 Bolan et al. Sex Transm Dis. 2015;42(2): CDC. Sexually Transmitted Disease Surveillance Atlanta: U.S. Department of Health and Human Services; Fenton. Infect Dis Clin N Am 2005; 19: Int J Dermatol 1987; 26: Invest Ophthalmol Vis Sci 2014;55: J Clin Neuroophthalmol 1983; 3: J.Clin Neuro-Ophthalmol. 3: , 1803 Lancet Infect Dis 2004; 4(7): Liau. Sex Transm Dis 2006;33: References - 2 MMWR (32); MMWR Morb Mortal Wkly Rep. 2015;64(40): Molina et al. CROI 2017 Abstract 91LB Ng. m J Public Health2013; 103: Ophthalmology 1990; 97: Plant. STD 2014; 41(1):50-57 Retina 2012; 32: Sex Transm Dis. 2015;42(6):347-9 Sex Transm Dis 1980; 7: Sex Transm Dis. 2015;42(6):347-9 Sex Transm Dis 2015; 42: Sex Transm Dis. 2016;43(8):524-7 Sex Transm Infect pii: sextrans (published ahead of print) Simms. Euro Surveill. 2014;19(24):pii=20833 Taylor. Sex Transm Dis 2004;31:552 6 Van Aar. BMC Infect Dis 2012; 12: