DISCLOSURES LEARNING OBJECTIVES 10/17/2018. NPA Conference Saratoga Srings NY, October Sexually Transmitted Infections: New and Not so New Bugs

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1 Sexually Transmitted Infections: New and Not so New Bugs Melinda S Godfrey MBA, MS, NP University of Rochester Infectious Disease Division Monroe County STD Clinic New York State, STD Center of Excellence DISCLOSURES I have no disclosures. I will mention some testing methodologies and treatments that are not FDA approved but are CDC recommended LEARNING OBJECTIVES 1. Describe current epidemiology of common & new Sexually Transmitted Infections. 2. Identify the clinical manifestations and diagnosis of STIs 3. List the current treatment recommendations of common STIs 1

2 STDs Organisms and Syndromes N. gonorrheae HBV Epididymitis Vulvitis C. trachomatis HSV Molluscum contagiosum Vaginitis M. genitalium HPV Viral Hepatitis Vaginosis U. urealyticum CMV Proctitis Cervicitis T. pallidum HTLV-I & - II AIDS PID G. lambria HTLV-11 Urethritis Neoplasia H. ducreyi HHV-8 Arthritis Infertility C. granulomatis HIV Conjunctivitis Iritis T. vaginalis S. scabiei Neonatal Diseases Warts E. histolytica P. pubis Adverse Pregnancy Outcomes Recent - Ebola virus, Zika virus, meningococcus Principles of STD Management Screen all recommended regardless of symptoms (2/3 have no symptoms) Presumptive treatment of STD syndromes Partner management Epidemiological treatment of known contacts of curable STDs Expedited Partner Therapy (EPT) in NYS for uncomplicated CT in heterosexuals only Evaluation for concurrent STDs Including HIV (co-infections are common) STIs and STDs - in general: 1/3 of those infected with an STI: have no clinical signs and no symptoms 1/3 have no symptoms: but have clinical signs on examination 1/3 of those infected with an STI: have clinical signs on exam and complaints of symptoms 2

3 Syphilis

4 Syphilis: What s new New cases still on the rise Newer testing algorithms widely utilized Health alert for eye diseases "New rapid CLIA waived test Congenital syphilis (NYS Alert 7/2018) Primary and Secondary Syphilis Rates of Reported Cases by State, United States and Outlying Areas 2017 STD Surveillance Report 2017 NOTE: The total rate of reported cases of primary and secondary syphilis for the United States and outlying areas (including Guam, Puerto Rico, and the Virgin Islands) was 9.5 per 100,000 population. See Section A1.11 in the Appendix for more information on interpreting reported rates in the outlying areas. ACRONYMS: GU = Guam; PR = Puerto Rico; VI = Virgin Islands. Primary and Secondary Syphilis Rates of Reported Cases by County, United States and Outlying Areas, 2017 STD Surveillance Report 2017 * In 2017, 1,562 (49.7%) of 3,140 counties in the United States reported no cases of primary and secondary syphilis. 4

5 Primary and Secondary Syphilis Reported Cases by Sex and Sexual Behavior, 37 States*, STD Surveillance Report 2017 * 37 states were able to classify 70% of reported cases of primary and secondary syphilis as either MSM, MSW, or women for each year during Primary and Secondary Syphilis Rates of Reported Cases by Sex and Male-to-Female Rate Ratios, United States, STD Surveillance Report 2017 Primary and Secondary Syphilis Reported Cases by Sex, Sexual Behavior, and HIV Status, 2017 STD Surveillance Report

6 Congenital Syphilis Reported Cases by Year of Birth and Rates of Reported Cases of Primary and Secondary Syphilis Among Women Aged Years, United States, STD Surveillance Report

7 Syphilis - Diagnosis & Management Diagnostic Tests Clinical Presentation Treatment Follow-up & Response to Therapy 7

8 Diagnosis of Syphilis Recognize Clinical Syndrome Clinical Diagnosis of Syphilis often tough to know syphilis is to know medicine Wide spectrum of illness chancre, rash most often identified Long periods of latency Identify organism T. pallidum cannot be easily cultured Use specimens from lesions to allow visualization of organism Available in specialized settings only Serology (antibody testing) cornerstone of diagnosis Essential even when making a clinical diagnosis Syphilis Serology Tests Two types of serological tests: 1. Non-specific, non-treponemal antibody (e.g. RPR, VDRL, TRUST) quantitative result (1:256) may be negative when chancre develops 2. Specific, treponemal antibody (FTA-ABS, MHA-TP, TPPA, EIAs, CLIAs, MBIAs) qualitative result only (+ or - ) does not distinguish past and present infection positive earlier than non-specific antibody Need both types of tests to make an accurate diagnosis of syphilis Test performance characteristics vary by stage and activity of disease Syphilis Diagnostic Tests: Non-treponemal tests (e.g. RPR, VDRL, TRUST) Non-specific antibody - must confirm with a specific antibody test Reactive ~3-4 weeks after exposure May be falsely negative with early chancre (primary syphilis) May have prozone phenomenon needs further dilution Reported as a reciprocal dilution (e.g. 1:256) Generally declines with treatment Used for follow-up after treatment May revert to negative over time, even without treatment 8

9 Syphilis Diagnostic Tests: Treponemal antibody tests (e.g. FTA-ab, TPPA, ELISA, CIA) Specific tests for antibody to T. pallidum Still some false positive tests Usually are positive sooner after exposure Remain positive for life in majority of patients Causes of False-Positive Reactions in Serologic Tests for Syphilis Disease RPR/VDRL FTA-ABS Age Autoimmune Diseases Cardiovascular Disease Dermatologic Diseases Drug Abuse Febrile Illness Glucosamine/chondroitin sulfate Possibly Hepatitis B S ag,?hepatitis C ab No No Lyme disease Malaria No Pinta, Yaws Pregnancy* * Recent Immunizations -- STD other than Syphilis * May cause increase in titer in women previously successfully treated for syphilis ELISA Adapted from Syphilis Reference Guide, CDC/National Center for Infectious Diseases, 2002 Syphilis Rapid Test Now CLIA-waived 12/2014, the FDA issued a CLIA waiver for a rapid syphilis screening antibody test (whole blood, serum, or plasma) This waiver allows the test to be performed by nonlaboratory staff in a variety of settings, e.g., Medical offices, emergency departments/urgent care centers, outreach sites, community-based organizations Studies leading to FDA approval reported 95-99% sensitivity & 91-98% specificity respectively Recent reports at NCSD conference 45% false positive Negative predictive value high 9

10 Syphilis Primary (10-90 days) chancre (painless ulcer) with non-tender adenopathy resolves spontaneously Secondary (6-9 weeks later; may recur if untreated) chancre still present ~15%; classic rash (palms and soles), condylomata lata, patchy alopecia, mucus patches, hepatitis Tertiary (years later) end organ damage, cardiovascular (thoracic aneurysm), gumma, CNS (meningitis, eye dx, CN defects, paresis, tabes dorsalis) The Stages and Symptoms of Syphilis No Signs or Symptoms Exposure Early Latent Late Latent Primary Secondary days 6 months 12 months.years Chancre Rash, Nodes, lesions Infectious Period via Sex Tertiary Gumma, heart & central nervous system Perinatal Transmission Primary Syphilis Develops ~ 3 weeks after infection (10-90 days) Lesion begins with painless erythema that subsequently ulcerates Ulcer (chancre) has clean base and clear exudate Indurated (can t press the edges together) May have painless unilateral inguinal lymphadenopathy RPR may be negative when chancre develops. Specific tests positive earlier. 10

11 Primary syphilis - chancre Primary syphilis-chancre Primary syphilis-chancre Visual Dx Visual Dx 11

12 Primary syphilis - chancre Primary syphilis - chancre Syphilis Staging: PRIMARY Diagnosis requires a mucocutaneous ulcer Typical clinical appearance Induration most reliable sign Positive lesion tests Darkfield, DFA, or PCR, biopsy In first 7-10 days Antibody tests may be false negative Specific TP tests are positive earlier than nonspecific Order specific test (EIA, TPPA, FTA-abs) even if RPR negative Conventional wisdom FTA-abs is earliest to be + If RPR positive (after 7-10 days) titer usually 1:1-1:8 12

13 Secondary Syphilis Occurs ~ 6-9 weeks after primary; may have clinical recurrence for ~ 1 year if untreated Disseminated infection - many clinical signs Classical sign is rash: progresses from macular to papular, then to papulosquamous (may itch then), resolves over 3-4 weeks Palmar, plantar lesions, nickel & dime lesions Generalized lymphadenopathy, mucous patches, condylomata lata, alopecia Hepatitis, nephritis, iritis Any itis is possible Early systemic manifestations of secondary syphilis Sore throat 53% Malaise 42% Headache 24% Weight loss 18% Fever 14% Meningismus 8% Abd discomfort 7% Arthralgias 7% Vaginal discharge 3% Secondary Syphilis 13

14 Secondary syphilis - papulosquamous rash Pityriasis like rash in secondary syphilis 14

15 Secondary Syphilis 15

16 16

17 Secondary syphilis: condylomata lata PE no ulcer no rash RPR 1: 256 HIV negative Syphilis Staging: Secondary Based on presence of secondary signs and positive specific and non specific tests Lesion tests may also be positive (condylomata lata, mucous patches) RPR very sensitive for screening in Secondary RPR titers generally 1:16-1:

18 Syphilis - Diagnosis Clinical Diagnosis poor Direct visualization of organism (very specialized) Culture - not available Serology cornerstone of diagnosis Non-Treponemal (non-specific tests) e.g. RPR Treponemal Tests (specific confirmatory tests) e.g. FTAab, ELISA need both specific and non-specific tests to accurately diagnose and stage syphilis Decline in RPR in follow up used to assess response to treatment Syphilis Staging: Early Latent No signs or symptoms Staging based on reactive specific and non-specific antibody tests 1. History of signs/symptoms of syphilis within the prior year OR 2. Negative syphilis tests within the previous year (seroconversion) OR 3. Sexual contact to another Early Syphilis case within the prior year RPR titer usually 1:32-1:8 Syphilis Staging: Late Latent Syphilis No signs or symptoms Staging based on positive specific and non-specific tests None of the 3 conditions needed to diagnose Early Latent RPR titer usually 1:4 or lower RPR may become non-reactive in Late Latent, without treatment 18

19 Management of Syphilis All patients with syphilis should be tested for HIV infection In areas with high HIV prevalence, retest for HIV after 3 months, if first HIV result negative. Penicillin is drug of choice Sexual partners of patients with infectious syphilis need to be evaluated and treated Syphilis Treatment by Stage Primary, Secondary, Early Latent Syphilis* LA Benzathine Penicillin 2.4 million units IM x 1** Doxycycline 100 mg bid po x 2 weeks Late Latent Syphilis LA Benzathine PCN 2.4 million units IM x 3 weekly Doxycycline 100 mg po bid x 4 weeks *Sexual partners from last 90 days need evaluation and treatment **Penicillin is the only recommended treatment in pregnancy 19

20 Gonorrhea Gonorrhea - What s new Resistance Worries Cephalosporin resistance coming (soon?) single case in North America so far (Quebec) Azithromycin resistance reported in US NAATs for Extra-genital testing Gonorrhea Rates of Reported Cases, United States, STD Surveillance Report

21 Gonorrhea Rates of Reported Cases by State, United States and Outlying Areas 2017 STD Surveillance Report 2017 Gonorrhea Rates of Reported Cases by County, United States and Outlying Areas, 2017 STD Surveillance Report 2017 Gonorrhea Rates of Reported Cases by Sex, United States, STD Surveillance Report

22 GC Urethritis Males Incubation Typically 3-7 days asymptomatic infection may occur (10%) Symptoms Dysuria, purulent or mucopurulent discharge Signs Yellow purulent discharge may be mucoid or mucopurulent (10%) Source: CDC/NCHSTP/Division of STD Prevention, STD Clinical Slides GC Cervicitis Incubation Unknown but S/S generally develop by 10 days Symptoms Present in 50% of cases and are non-specific vaginal discharge, dysuria, cervical bleeding Signs Exam is highly variablenormal to frank purulent discharge Source: CDC/NCHSTP/Division of STD Prevention, STD Clinical Slides 22

23 Antimicrobial Susceptibility of N. gonorrhoeae Quinolone resistance: widespread in US/worldwide (~ 1/3) PCN/TCN resistance: widespread (~1/4) Azithro: emerging - ~ 0.5% of isolates with decreased susceptibility Cephalosporins. Sporadic cases of decreased susceptibility to ceftriaxone & cefixime reported internationally Clinical failures with cephalosporins have occurred in Japan, Western Europe. Cefixime failure more widely reported than ceftriaxone failures Most patients have been MSM Updates: CDC STD Prevention Conference /1/16 5/10/16 Hawaii DOH identified 8 GC isolates with Azithromycin resistance (MIC >1:16) All also resistant to PCN, TCN, Cipro 5/8 with elevated increased CTX MIC -.125ug/ml Likely clonal expansion from single clade Isolates from 7 patients 6M, 1F All heterosexual and with typical symptoms All successfully treated - CTXone 250 mg IM plus Azithro 1 gm 8 partners identified 1 male with GC dx by NAAT and successfully treated before investigation. Remainder tested negative for GC 23

24 Heterosexual male female partner in SE Asia, UK +GC with R to Azithromycin, CTXone (urethral and pharyngeal) Failed 1 gm IV Ceftriaxone/ Spectinomycin (throat still +) Now being treated with Ertapenem 2015 Recommended Rx for Uncomplicated GC Infections of Cervix, Urethra, Rectum Ceftriaxone 250 mg IM x 1 dose plus Azithromycin 1 gram po X 1 dose Ideally dispensed at the same time Doxycycline 100 mg po bid x 7 days acceptable in place of azithro in allergic patients 24

25 Chlamydia Chlamydia: What s new Rates remain very high NAATS are gold standard Extragenital testing for MSM population Chlamydia Rates of Reported Cases by State, United States and Outlying Areas 2017 STD Surveillance Report

26 Chlamydia Rates of Reported Cases by County, United States and Outlying Areas, 2017 STD Surveillance Report 2017 Chlamydia Rates of Reported Cases by Age and Sex, United States, 2017 STD Surveillance Report 2017 CT Urethritis Incubation Unknown 5-10 days in symptomatic > 50% asymptomatic Symptoms Urethral discharge, dysuria Signs None or Clear, mucoid, or mucopurulent discharge Source: CDC/NCHSTP/Division of STD Prevention, STD Clinical Slides 26

27 CT Cervicitis Incubation Unknown; > 80% asymptomatic Symptoms Non-specific, including vaginal discharge or spotting, dyspareunia Signs Variable from normal to 30-50% with cervicitis endocervical discharge, edematous cervical ectopy, cervical friability* Source: CDC/NCHSTP/Division of STD Prevention, STD Clinical Slides Complications of GC/CT Untreated GC/CT infection may result in ascending infection and PID/Epididymitis ~15% of untreated CT results in PID (CDC) 25% of women with a single episode of symptomatic PID will experience sequelae, including ectopic pregnancy, infertility, or chronic pelvic pain. Risk of ectopic pregnancy increased 6-10 fold after PID. Tubal infertility post PID: 8% of women after one episode 20% of women after two episodes 50% of women after three episodes 2015 Rx for Uncomplicated Chlamydial Infections of Cervix, Urethra, Rectum Azithromycin 1 gram po X 1 dose or Doxycycline 100 mg po bid x 7 days Alternatives: Levofloxacin 500 q d x 7 days Oflaxacin 300 bid x 7 days Erythromycin 500 qid x 7 days 27

28 Urethritis New Diagnostic Criteria Diagnostic Considerations: Discharge on examination (mucoid, mucopurulent, or purulent) Gram stain > 2 WBCs/oil immersion, methylene blue or gentian violet on urethral secretions + leukocyte esterase on first void urine If Gram stain not available: IF least one diagnostic criteria: Test and treat for gonorrhea AND chlamydia IF Symptoms without signs Chlamydia/gonorrhea testing Empiric treatment for high risk or unlikely follow-up 3/14/14 MMWR Updated Recommendations for Laboratory Based Detection of Chlamydia trachomatis and Neisseria gonorrhoeae The performance of NAATs with respect to overall sensitivity, specificity and ease of specimen transport is better than any other tests available for the diagnosis of chlamydial and gonococcal infections. Preferred specimens (FDA approved): Males urine (equivalent to urethra) Females vaginal (equivalent to cervical; superior to urine) Laboratories should use NAATs to detect chlamydia and gonorrhea except in cases of: Child sexual assault involving boys Rectal and oropharyngeal infections in prepubescent girls Potential gonorrhea treatment failure ( need culture for antibiotic susceptibility testing) Extragenital Testing 28

29 Proportion of extragenital gonorrhea and chlamydia infections associated with concurrent negative urethral tests. Monica E. Patton et al. Clin Infect Dis. 2014;cid.ciu184 Published by Oxford University Press on behalf of the Infectious Diseases Society of America This work is written by (a) US Government employee(s) and is in the public domain in the US. Figure 1. Genital and extragenital GC (top) and CT (bottom) in women. Figure 1 Neisseria gonorrhoeae and Chlamydia trachomatis Among Women Reporting Extragenital Exposures. Trebach, Joshua; Chaulk, C; Page, Kathleen; Tuddenham, Susan; MD, MPH; Ghanem, Khalil; MD, PhD Sexually Transmitted Diseases. 42(5): , May DOI: /OLQ % GC cases missed if extragenital tests not done 13.8% CT cases missed if extragenital tests not done Copyright 2015 American Sexually Transmitted Diseases Association. Published by Lippincott Williams & Wilkins, Inc. Extragenital GC and CT Infections NAATs test of choice. Need laboratory validation given no FDA approval CDC recommends pharyngeal GC and rectal CT & GC screening for MSM and HIV + persons at least annually and Q 3-6 months if risk Untreated pharyngeal GC associated with: transmission to male partners acquisition of resistance (GC more difficult to cure in pharynx) Untreated rectal GC and CT often asymptomatic but less known about transmission? associated with increased HIV transmission/acquisition 29

30 What about Partners? CT and GC Sex Partner Management Sex partners should be evaluated, tested, & treated if they had sexual contact with the patient during the 60 days preceding the onset of symptoms or diagnosis of GC or Chlamydia The most recent sex partner should be evaluated & treated even if the time of the last sexual contact was > 60 days before symptom onset or diagnosis 2015 STD Treatment Guidelines: Unless prohibited by law or other regulations, medical providers should routinely offer EPT to heterosexual patients w/ chlamydia or gonorrhea infection when the provider cannot confidently ensure that all of a patient s sex partners from the prior 60 days will be treated. 30

31 NYS EPT Recommended treatment for EPT for Ct infection Azithromycin* 1 gram po x 1 dose *If the patient's sex partner is allergic to azithromycin or related drugs, EPT should not be used and the partner should be referred for care. "EPT" must be written in the body of the prescription form EPT law overrides the requirement that prescriptions include a patient s name, address, and age If known, the name, address, and date of birth of the sex partner should be included If unknown, the name, address, and date of birth of the sex partner should be left blank and the EPT designation will be sufficient to fill the prescription Lymphogranuloma venereum (LGV) The Other Chlamydia: LGV Caused by C. trachomatis L1-L3 serovars Infects monocytes not columnar cells Manifests as transient ulcer, large adenopathy(buboes), proctocolitis Most common in tropical/subtropical climates Africa, SE Asia, Latin America, Caribbean Since 2003, increasing reports in Europe, N. America Outbreaks in MSM communities with high rates of HIV co-infection Clinically presenting as proctitis/proctocolitis Occasional heterosexual cases seen 31

32 Clinical Manifestations Primary Infection: Incubation: 3-30 days Localized inflammation often described as papule that evolves to pustule or small ulcer Self limited 2-3 days usually Often not noticed due to short duration Source: CDC Division of STD Prevention Clinical Slides Clinical Manifestations Regional dissemination 2-6 weeks after primary lesion Manifests with regional LN involvement Inguinal/femoral for genital primary lesions Retroperitoneal/intraabdominal for rectal primary lesions May have systemic symptoms: fevers, malaise, arthralgias Source: CDC Division of STD Prevention Clinical Slides MSM outbreaks present Largely due to serovar L2, L2b, L2c Proctitis/Proctocolitis most common clinical manifestation Anorectal syndrome: rectal pain, tenesmus, mucoid or bloody discharge, abdominal or back pain, fever HIV coinfection common (50%- 87%) Asymptomatic cases reported ~ 40% in some reports, < 1% in others 32

33 Lymphogranuloma Venereum: An Increasingly Common Anorectal Infection Among Men Who Have Sex with Men Attending New York City STD Clinics, Pathella, P, et al CDC STD Prevention Conference, 2016 Screen CT isolates from male rectal specimens for LGV serovar % % Correlation: Black, age > 30, HIV+, partner to HIV, h/o syphilis No correlation: GC, CT, condom use, # partners LGV cases: 86% with rectal symptoms Rectal CT (not LGV): 60% with symptoms Diagnosis of LGV Not easy no FDA approved test Historically diagnosed through serology no longer recommended CT NAATs (most) include LGV & non LGV serovars but don t distinguish the two In house NAAT assays to distinguish specific LGV serovars available in some labs Treatment of LGV Standard recommendation: Doxycycline 100 mg po bid x 21 days?? Azithromycin 1 gm po q week x 3 Cure rates appear superior with Doxycycline Empiric treatment if no diagnostic testing available in setting of CT + rectal specimen from MSM with rectal symptoms 33

34 Mycoplasma genitalium Mycoplasma genitalium Emerging Issue M. genitalium first identified in the early 1980 s Cause of male urethritis looks like NGU 15 20% of non gonococcal urethritis (NGU) 20 25% of non chlamydial NGU 30% of persistent or recurrent urethritis More common than GC but less than CT NAAT preferred method to detect M. genitalium Research settings/in house PCR assays None FDA approved yet* Mycoplasma genitalium: Treatment 7 day doxycycline regimen - largely ineffective median cure rate of approximately 31% 1 gram single dose azithromycin more effective against M. genitalium than doxycycline in two randomized trials Resistance to azithromycin emerging Median cure rate ~ 85% initially but 39% in the most recent trial (4/15/15) Moxifloxacin 400 q d 7, 14 and 21 day regimens in case reports 34

35 Neisseria meningitidis Case 45 yo AA male with thick purulent green urethral discharge 3 female sexual partners in past month Urethral gram stain: Diagnosis: GC urethritis TX: CTX 250 IM plus Azithromycin 1 gram po Labs: GC/CT NAAT negative Background Neisseria meningitidis (Nm) Gram negative diplococci Serogroups categorized by polysaccharide capsular antigens (13 total) Most disease caused by: A, B, C, Y and W135 NP carriage may result in invasive meningococcal disease usually meningitis, bacteremia Vaccine available for A,C,Y, W 135 and B Some meningococci don t express capsular antigens 35

36 Large Cluster of Neisseria meningitidis Urethritis in Columbus, Ohio, 2015 Bazan, JA, et al CID 2017CID 2017:65 (1 July) 1/1/15-11/18/15: 76 possible cases identified 75/76 confirmed as Nm 1/76 confirmed as GC by culture Hx - 0 cases 1/14-11/14 3 cases from 12/14 not included 297 culture + GC. All also gram stain +/ urine NAAT + 75/373 (20%) gram stain positive for GNID confirmed as Nm Co-infections: not different except pharyngeal GC urethral CT 15% Nm / 24% GC GC pharynx Nm 0 / GC 9% (p =.05) Large Cluster of Neisseria meningitidis Urethritis in Columbus, Ohio, 2015 Patient Characteristics: similar race, ethnicity, age Median Age: Nm 31 (IQR 24-38) / GC 28 (IQR 23-38) Black: Nm 81% / GC 71% Non Hispanic: Nm 91% / GC 92% Heterosexual - Nm 99% / GC 78% (p <.01) Sexual behavior: no differences in condom use, relationship status, sex w ETOH/drug use, anon partners, exchange sex for $/drugs Oral Sex with female partner total - Nm 99% / GC 73% (p <.01) Oral Sex with female partner of MSW - Nm 99% / GC 80% (p =.02) Symptoms: 99% Nm / 96% GC No of days with symptoms: 4 Nm / 4 GC No partners (90 d): Nm 2 (IQR 1-3) / 2 GC (IQR 2-4) Bazan, JA, et al CID 2017CID 2017:65 (1 July) Summary: N. meningitidis Urethritis Be aware of classic GC with negative NAAT tests as possible Nm CDC - Treat as usual GC CDC - Treat partners c/w GC partner therapy Not reportable but CDC requesting notification if noticeable increase nmurethritis@cdc.gov Remove from GC surveillance report if your organization reports + GS as diagnostic Further research needed re: women, other sites, effects of vaccination 36

37 QUESTIONS? 37