Genital Ulcer Disease Syphilis and Herpes:
Updates from 2021 CDC STI Guidelines
Katherine Hsu, MD, MPH, FAAP*
Medical Director, Div. of STD Prev., Mass. Dept. of Pub. Health Director, Ratelle STD/HIV Prevention Training Center
Professor of Pediatrics, Boston Univ. Med. Ctr.
Fall 2021
Disclosures
• In the past 12 months, Dr. Hsu has had no relevant financial interests or other relationships with manufacturer(s) of product(s) or provider(s) of service(s) that will be discussed in this presentation
• This presentation will NOT include discussion of pharmaceuticals or devices that have not been approved by the FDA
Talk Outline
• Review diagnosis, treatment, and management of syphilis and herpes
• Highlight differences between 2021 and 2015 CDC STI/STD Guidelines
• Summarize resources
H OW WE DIAGNOSE SYPHILIS AND HERPES HASN ’ T
CHANGED … MUCH
Syphilis Natural History
Incubation Period 3‐4 wks Range: 3‐90 days
Incubation Period 3‐4 wks Range: 3‐90 days
2‐6 wks Range: 1‐12 wks
2‐6 wks Range: 1‐12 wks
After 2‐8 weeks lesions disappear
spontaneously Range: up to 1 yr
After 2‐8 weeks lesions disappear
spontaneously Range: up to 1 yr
2‐20 years 2‐20 years 30‐50% 30%
Exposure 10 20 Latent Tertiary
Courtesy: Susan Philip, SF DPH And M. Urban, URochester Neurosyphilis can occur at any stage
25%
Overlap Between 1o and 2o can occur
More rapid progression or severe disease (multiple deep ulcers, simultaneous primary &secondary manifestations, lues maligna, neurologic involvement occurring at any stage) mostly described in HIV‐infected persons with advanced immunosuppression
W E DIAGNOSE GUD VISUALLY …
Primary Syphilis
Secondary Syphilis
Rash (acute HIV can look like this!)
Condyloma lata –
very infectious! Alopecia
Palmar and plantar rash
HSV: Multiple Genital Ulcerations
…
OR WE DIAGNOSEGUD
WITH SEROLOGIES,
SOMETIMESLESION CULTURE OR
PCR,
OR RARELY WITH DARKFIELD OR ON BIOPSY SPECIMENSMarrazzo, CDC-NNPTC Webinar: Sexual Health in MSM, June 7, 2012
1 : 1024 1 : 512 1 : 256 1 : 128 1 : 64 1 : 32 1 : 16 1 : 8
1 : 4 1 : 2
1 : 1
Dilutions of Non-specific Syphilis Tests (RPR/VDRL)
1 dilution 2 dilutions or “4 fold”
decline
Slide courtesy of M. Urban, MD
Causes of False Positive Syphilis Testing
• Non-treponemal tests – Viral infections
• Infectious mononucleosis
• Hepatitis
• Varicella
• Measles
– Lymphoma – TB
– Malaria – Endocarditis
– Connective tissue disease – Pregnancy
– Abuse of injection drugs
• Treponemal tests
– Other spirochetal illnesses (e.g. Lyme, leptospirosis, rat-bite fever, relapsing fever, yaws, pinta)
– But note, VDRL is non-reactive in Lyme!!!
AAP Red Book, 2012
Fakile Y, STD Prevention Conference, 2016 https://cdc.confex.com/cdc/std2016/webprogram/Paper38173.html
… but concerns about sensitivity & specificity abound
We often make the diagnosis of syphilis infection by serology.
We (generally) do NOT have a direct test for
the organism itself.
Why switch to EIA/CIA as first syphilis test?
180 tests per hour, no manual pipetting
CDC-
Recommended Algorithm for
Reverse Sequence Syphilis Screening
Radolf JD et al. MMWR, 2011
3%
57%
32%
Probable false positive EIA
•If high risk: repeat RPR in several weeks
Assess for hx of treated syphilis, sx/signs
•If treated, no further action
•If untreated, consider tx for latent syphilis
CDC Recommendations: Reverse
Sequence Syphilis Screening Algorithm
•All reactive EIA/CIAs should be reflexed to a
quantitative non-treponemal test (e.g. RPR, VDRL)
•Confirm reactive EIA/CIA
•Detect active infection
•Discordant specimens (e.g. EIA+/RPR-) should be confirmed with a 2nd treponemal test
•Confirmatory treponemal test should ideally be similarly sensitive and more specific than EIA/CIA
•TP-PA recommended
•FTA-ABS test not recommended (lower specificity than other treponemal tests and probably lower sensitivity; also requires trained personnel and a dedicated fluorescence microscope)
•Results of all 3 tests (EIA, RPR, TP-PA) should be reported simultaneously to provider
MMWR / February 11, 2011 / Vol. 60 / No. 5 Park et al., CID 2018
HSV Diagnosis
• Viral culture has variable sensitivity
– 95% vesicles – 70% ulcers
– 30% crusted lesions
• Serologic testing
– can differentiate between HSV-1 and-2
• Lesion PCR (amplified nucleic acid technology)
– lesions only, not for screening
– can differentiate between HSV-1 and-2
HSV Serology Testing Limitations
• Does not tell
– How long infected
– If person has had or will have symptoms
– How likely a person is to shed asymptomatically – Where infected (HSV-1)
• Cannot diagnose a lesion
• False positives
– Decreased PPV in low prevalence populations AND in patients with HSV-1 infection
• False negatives
– Only 77% of patients have antibodies by 6 weeks after HSV- 2 primary infection and 59% after HSV-2 non-primary
infection
Genital Ulcer Diseases 2021 Update
Khalil Ghanem, MD, PhD kghanem@jhmi.edu
HSV 2021 Update: Serological Diagnosis 2‐Step Testing
• The recommended serological tests for HSV‐1 and HSV‐2 are the Glycoprotein‐G‐based IgG EIAs [e.g., HerpeSelect HSV‐2 EIA]
• There are issues with the SPECIFICITY of the IgG‐2 EIAs with EIA index values
<3.0 [in one study, the specificity was 38%]
• Laboratories should provide index values for all HSV‐2 IgG EIA results
• If the index value <3.0, a second more specific test should be performed to confirm the original EIA result. There are two options for the second test:
• HSV‐2 Western Blot‐ only performed at the University of Washington
• https://depts.washington.edu/uwviro/
• HSV‐2 Biokit Rapid Test (Biokit USA, Lexington MA)
• NEVER IgM serologies‐ they are neither sensitive nor specific to diagnose a recent infection
Agyemang STD 2017 Slide courtesy of Khalil Ghanem
B ECAUSE THERE IS MORE DISEASE , WE WILL SEE MORE
COMPLICATIONS
Syphilis and Gonorrhea Over Time
*Infectious syphilis is defined as primary, secondary and early latent stages of syphilis within one year of infection.
Data Source: CDC. Sexually Transmitted Disease Surveillance 2017. Atlanta: U.S. Department of Health and Human Services; 2019.
Interpret 2014 STI data with caution due to a mid-year conversion to a new surveillance system.
Decreases in syphilis cases were due to BOTH behavior change AND to deaths occurring in HIV‐syphilis co‐infected individuals
?
G OALS OF EARLY TREATMENT ARE TO PREVENT
MORBIDITY FROM COMPLICATED SECONDARY , TERTIARY
AND CONGENITAL SYPHILIS
Manifestations:
• Conjunctivitis, scleritis, and episcleritis
• Uveitis: anterior and/or posterior
• Elevated intraocular pressure
• Chorioretinitis, retinitis
• Vasculitis Symptoms:
• Redness
• Eye pain
• Floaters
• Flashing lights
• Visual acuity loss
• Blindness Diagnosis:
• Ophthalmologic exam
• Serologies: RPR (if negative, rule out prozone, VDRL, treponemal tests
• Lumbar puncture
Ocular Syphilis
Wender, JD et al. How to Recognize Ocular Syphilis. Review of Ophthalmology. 2008.
Slide courtesy of Sarah Lewis, MD
Use screening tools to identify
patients who need
specialty care …
W HO [ DOES AND DOESN ’ T ] NEED LP IN 2021?
Syphilis 2021 Update:
What to do with RPR Titers that Don’t Respond Appropriately
• Lack of a fourfold decline in titers after waiting a full 12m following
therapy for early syphilis and a full 24m following therapy for late syphilis:
• Any neurological signs/symptoms? If yes, perform immediate LP
• Could the patient have been reinfected? If yes, treat
• If both of the above are negative, you can either follow the patient carefully or you can give additional antibiotics. Several observational studies suggest that there are NO short/intermediate‐term benefits to additional antibiotics
• A four‐fold increase in titers after appropriate therapy:
• Any neurological signs/symptoms? If yes, perform immediate LP
• Could the patient have been reinfected? If yes, treat
• If the patient denies the possibility of reinfection, and the titer continues to be elevated when repeated two weeks later, consider performing a LP
Slide courtesy of Khalil Ghanem
Syphilis 2021 Update:
CSF Examination
• Perform a lumbar puncture (LP) in persons who:
• Have neurological signs and symptoms
• Are diagnosed with tertiary syphilis (cardiovascular, gummas)
• Consider in those who are asymptomatic but whose serological titers increase four‐fold after stage‐appropriate therapy and in whom the likelihood of
reinfection is low
• No data to support routine LP in asymptomatic PWH
• No need for follow‐up LP 6 months after the diagnosis and treatment of neurosyphilis in HIV uninfected or PWH who are on ART if they
improve clinically, and their serological titers are responding appropriately
Slide courtesy of Khalil Ghanem
2021 Update: Otic and Ocular Syphilis
Otosyphilis
• Clinical manifestations:
cochleovestibular dysfunction and syphilis infection without an alternate diagnosis; ~50% bilateral
• Symptoms: Hearing loss, vertigo, and/or tinnitus (ringing in the ears)
• Diagnosis is presumptive; CSF examination is normal in 90% of cases and is NOT
recommended if patient only has otic signs and symptoms
• Immediate referral for evaluation
• Therapy: IV penicillin (+/‐ corticosteroids)
Ocular Syphilis
• Clinical manifestations: any portion of the eye; any ocular manifestation;
• Symptoms: Redness, pain, floaters, flashing lights, visual acuity loss
• Diagnosis is presumptive; CSF
examination is normal in 40% of cases and is NOT recommended if patient only has ocular signs and symptoms
• Immediate ophthalmological examination
• Therapy: IV penicillin (+ corticosteroids)
Slide courtesy of Khalil Ghanem
DON’T FORGET IMPACT OF SYPHILIS AND HERPES ON PREGNANT WOMEN
Two‐for‐One Deal
2021 Syphilis Update: Syphilis During Pregnancy
• Maternal risk factors for syphilis during pregnancy include sex with
multiple partners, sex in conjunction with drug use or transactional sex, late entry to prenatal care (i.e., first visit during the second trimester or later) or no prenatal care, methamphetamine or heroin use, incarceration of the woman or her partner, and unstable housing or homelessness
• Certain evidence indicates that additional therapy is beneficial for
pregnant women to prevent congenital syphilis. For women who have primary, secondary, or early latent syphilis, a second dose of benzathine penicillin G 2.4 million units IM can be administered 1 week after the initial dose
• Missed doses >9 days between doses are not acceptable for pregnant women receiving therapy for late latent syphilis
Slide courtesy of Khalil Ghanem
• Two stillbirths with syphilis and a congenital syphilis case exhibiting symptoms of rash, jaundice and hepatosplenomegaly at birth have been reported to MDPH in 2020.
• One stillbirth occurred in woman with limited prenatal care who delivered at 28 wks gestation.
• Other stillbirth occurred in a woman who delivered at 33 wks with negative 1sttrimester syphilis screening, no history of risk to prompt 3rdtrimester re‐screening, but in retrospect had a rash compatible with secondary syphilis at 27 wks.
• Symptomatic congenital syphilis case was born at 37 wks to a woman with negative 1sttrimester syphilis screening, no history of syphilis symptoms, and no history of risk to prompt 3rdtrimester re‐
screening.
• Massachusetts now recommend universals syphilis screening early in 3rd trimester (~27‐28 weeks gestation), in addition to routine syphilis screening performed at first prenatal visit
MA Congenital Syphilis Stillbirth Alert
HSV 2021 Update: HIV & Pregnancy
• In PWH with a CD4 < 200 cells/mm3 and a history of genital herpes, consider 6 months of HSV suppressive therapy when initiating ART to decrease reactivation of genital herpes
• During pregnancy: At the onset of labor, all women should be
questioned thoroughly about symptoms of genital herpes, including prodromal symptoms (e.g., pain or burning at site before appearance of lesion), and all women should be examined thoroughly for herpetic lesions. Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally.
Slide courtesy of Khalil Ghanem
H OW WE TREAT AND MANAGE SYPHILIS AND HERPES
HASN ’ T CHANGED MUCH EITHER …
SYPHILIS – CDC TREATMENT RECS
Primary, secondary and early latent syphilis Benzathine PCN 2.4 million units IM x 1 dose
(Jarisch-Herxheimer reaction can occur during tx of early syphilis, 30-70% of the time)
PCN allergy – If compliance can’t be assured, consider desensitization, then treat with PCN (instructions in CDC STI guidelines)
– Doxycycline 100 mg PO bid or tetracycline 500 mg PO qid for 14 days – Ceftriaxone 1 g IM or IV daily for 10 days
Late latent disease
Benzathine PCN 2.4 million units IM once a week x 3 doses Neurologic/ocular syphilis
Aqueous crystalline penicillin G 18–24 million units per day for 10–14 days
Consider benzathine PCN 2.4 million units IM once a week for up to 3 weeks as chaser
PENICILLIN
Follow titers q3-6 mths for a year
• All patients should be tested for HIV co-infection
– HIV PrEP recommended for all who are not already infected
• Quantitative non-treponemal serologic tests should be repeated
– 6 and 12 months after primary and secondary syphilis – 6, 12, and 24 months after latent syphilis
• In HIV-coinfected individuals, quantitative non-
treponemal serologic tests should be repeated MORE FREQUENTLY
– 3, 6, 9, 12, and 24 months after primary and secondary syphilis – 6, 12, 18, and 24 months after latent syphilis
SYPHILIS – FOLLOW-UP OF TITERS
CONSIDER HIV PREP
*Tenofovir/emtricitabine now licensed for HIV PrEP in adolescents weighing ≥35kg
Guidance for Youth HIV PrEP Use
Sexually Active Youth Youth Who Inject Drugs Indicators of
substantial risk of acquiring HIV
HIV positive sexual partner
High HIV prevalence area
High HIV prevalence sexual network
High number of sexual partners
Recent bacterial STI
Inconsistent or no condom use
Exchanging sex for drugs or money
HIV positive injecting partner
Sharing injection equipment
Eligible for PrEP Documented negative HIV test result before prescribing PrEP
No signs/symptoms of acute HIV infection
Documented hepatitis B infection and vaccination status
Normal renal function
No medications contraindicated for use with TDF/FTC Prescription Daily continuing oral doses of TDF/FTC, ≤90 day supply Follow‐up Every three months:
Repeat HIV test
Adherence counseling
Side effect assessment
Risk reduction counseling and support
STI symptom assessment and testing1
Renal function reassessment2
Pregnancy intention reassessment and testing for females
For youth who inject drugs or use other substances, support access to clean needles/syringes and treatment services
[1]Includes oral/rectal STI testing for MSM and other eligible youth.
[2]At 3 months and every 6 months thereafter.
Adapted from:
CDC & USPHS:
Preexposure prophylaxis for the prevention of HIV infection in the United States—
2017 Update: a clinical practice guideline.
Published March 2018.
*Tenofovir/emtricitabine now licensed for HIV PrEP in adolescents weighing ≥35kg
• Exposed within 90 days to primary, secondary or early latent syphilis
– Treat, even if seronegative
• Exposed >90 days to primary, secondary or early latent syphilis
– Treat, if serologic test results not available immediately and follow-up is uncertain
• Exposed to late latent syphilis or syphilis of unknown duration
– Evaluate clinically and serologically, treat if syphilis suspected
• Discuss with your public health colleagues!
SYPHILIS – PARTNER MANAGEMENT
• Lots of counseling points, now divided into HSV- 1 and HSV-2 counseling
– Decreased risk for recurrences and shedding with HSV-1 vs.
HSV-2
• Review new CDC 2021 STI Guidelines!
– https://www.cdc.gov/std/treatment- guidelines/herpes.htm
HSV – TREATMENT and
PARTNER MANAGEMENT
Talk Summary
• Review diagnosis, treatment, and management of syphilis and herpes
• Highlight differences between 2021 and 2015 CDC STI/STD Guidelines
• Summarize resources
CDC STD T REATMENT G UIDELINES :
A ROSE BY ANY OTHER NAME …
CDC STI Guidelines Development
• Evidence-based on principal outcomes of STD therapy 1. Microbiologic eradication
2. Alleviation of signs & symptoms 3. Prevention of sequelae
4. Prevention of transmission
• Recommended regimens preferred over alternative regimens
• Alphabetized unless there is a priority of choice
• Reviewed June 2019; published July 2021
• www.cdc.gov/std/treatment
• Pocket guides, teaching slides, charts, app
Misnomer!
• Prevention
• Screening
• Counseling
• Management AND
• Treatment Guidelines https://www.cdc.gov/std/treatment‐guidelines/default.htm
Want to know more about STDs?
There’s an app for that.
CDC STD Treatment
Guidelines App for Apple and Android
Available now SOON, FREE!
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