Back Again: Recurring Epidemics of Syphilis in the

U.S. – A Syphilis Management Update

Edward W. Hook III M. D.

University of Alabama at Birmingham

And

Jefferson County Depart. Of Health

Birmingham, Alabama

Treponema pallidum

Morphology Spiral, 8-13x0.15 m

Motility Corkscrew, Flexing

Division Time 33 hours - 5 days

In vitro Cultivation No

(Culture)

Principles of STD Management

Accurate Diagnosis

Effective TherapyDoseDurationCompliance

Concomitant Infections

Management of Partners

SYPHILIS MANAGEMENT GOALS

• Resolution of clinical signs/symptoms

• Prevention of disease progression

• Prevention of transmission to others

• Prevention of HIV transmission/acquisition

EPIDEMIOLOGICAL CHARACTERISTICS OF SYPHILIS

• Rates highest during social upheaval– War time– Economic stress– Most common in developing nations

• Disease most common in marginalized groups– Lower socio-economic classes– Racial / ethnic minorities– Limited access to health care– Commercial sex workers and drug users

Syphilis—Reported Cases by Stage of Infection, United States, 1941–

2011

2011-Fig 36. SR

Primary and Secondary Syphilis—by Sex and Sexual Behavior, 33 Areas*,

2007–2011

*32 states and Washington, DC reported sex of partner data for 70% of cases of P&S syphilis for each year during 2007-2011.†MSM=men who have sex with men; MSW=men who have sex with women only.

2011-Fig 37. SR

Primary and Secondary Syphilis—Rates by Age and Sex, United States,

2011

2011-Fig 42. SR

Selected STD Rates, 2007 – U.S., Canada, U.K. and Sweden

U.S.U.S. CanadaCanada U.K.U.K. SwedenSweden

N. GonorrhoeaeN. Gonorrhoeae 118.9118.9 36.136.1 30.630.6 7.07.0

C. TrachomatisC. Trachomatis 370.2370.2 224.4224.4 200.3200.3 458.4458.4

Early (P, S & EL Early (P, S & EL Syphilis)Syphilis)

7.47.4 3.73.7 4.34.3 2.62.6

1.1. CDC, STD SurveillanceCDC, STD Surveillance2.2. Public Health Agency of Canada, Reported cases of STIPublic Health Agency of Canada, Reported cases of STI3.3. WHO 2009WHO 20094.4. WHO 2009WHO 2009

SYPHILIS CONTROL

CURRENTLY AVAILABLE TOOLS HAVE BEEN USED WITH SUCCESS THROUGHOUT MOST OF THE

DEVELOPED WORLD

Features Favoring Syphilis Control

No animal reservoir

Reliable diagnostic tests

Safe, effective curable and preventative therapy

Relatively long, non-infectious incubation period

Low or declining disease rates

National Plan for Syphilis EliminationNational Plan for Syphilis Elimination

• Cross-Cutting Strategies

– Enhanced surveillance

– Strengthened community involvement and partnerships

• Intervention Strategies

– Rapid outbreak response

– Expanded clinical and laboratory services

– Enhanced health promotion

Progress on Syphilis Elimination(1997-2001)

Progress on Syphilis Elimination(1997-2001)

1998 1999 2000

Reduction

1997-2001

P&S syphilis cases

Congenital syphilis cases

Counties responsible for 50%

Black:White rate ratio

8,556

1,078

31

44:1

7,007

840

28

34:1

6,617

575

25

30:1

5,979

554

22

24:1

2001

6,103

441

21

16:1

29%

60%

32%

63%

1997

THE NEXT GREAT PLAGUE TO GO

Thomas Parran’s 5-Point Program For Syphilis Control – 1936

1. Case Finding – Serologic Screening Programs

2. Prompt Therapy

3. Contact Identification, Testing, and Therapy

4. Mandatory Serological Evaluations – Premarital and Early Pregnancy

5. Public Education = Symptoms, Complications, Treatment

Principles of STD Management

Accurate Diagnosis

Effective TherapyDoseDurationCompliance

Concomitant Infections

Management of Partners

NATURAL HISTORY OF SYPHILIS

2°

20-50%

Exposure … 1° Latent 3

33% 25% 33%

Parenthetical Comment: Rethinking Genital Herpes

Etiology of Genital Ulcers In 516 STD Clinic Patients

515 patients recruited from STD Clinics in 10 U.S Cities With High Syphilis Rates

PCR Result Number (%)

HSV 320 (62%)

Syphilis 51 (10%)

HSV and Syphilis 13 (3%)

Chancroid 16 (3%)

PCR Negative 116 (22%)

Mertz K et al JID 1998: 178: 1795-9

Back To Syphilis

NATURAL HISTORY OF SYPHILIS

2°

20-50%

Exposure … 1° Latent 3

33% 25% 33%

Secondary syphilis

NATURAL HISTORY OF SYPHILIS

2°

20-50%

Exposure … 1° Latent 3

33% 25% 33%

Serologic Tests for Syphilis

Nontreponemal Tests (VDRL, RPR)Antigen -cardiolipin-lecithin-cholesterolQuantitative

Treponemal Tests (FTA-ABS, MHA-TP, EIAs)Treponemal AntigensQualitative

Interpretation of Changing STS Titers

Error of RPR VDRL Tests - + 1 dilution

Meaningful change is 2 dilution (or 4-fold) change in titere.g. 1:2 1:4 or 1:1, no meaningful change

1:2 1:8, meaningful change

Quantitative RPR or VDRL test, results are not interchangeable

Two dilution decline in titer indicates response to therapy however, failure to decline > 2 dilutions does not necessarily mean patient has failed treatment

SYPHILIS SERODIAGNOSIS:Why Use Confirmatory Tests?

Imagine the results of false positive tests (BFPs) when 100,000 people without syphilis are tested. Assume BFP rates of 1.5% for the non-treponemal and 1% for treponemal tests used

ScreeningNon-treponemal Test Treponemal Test 100,000 100,000 x .015 x 01 1500 1000

Confirmatory TestingTreponemal Test Non-treponemal Test 1,500 1,000 x .01 x 015 15 15

PITFALLS ENCOUNTERED IN SYPHILIS SERODIAGNOSIS AND FOLLOW-UP

Biologic False Positives

False Negative or Delayed STS Reactivity

Delayed or Partial Response to Therapy

Interpretation of Test Results in Pregnant Patients

Interpretation of Test Results in Patients with Prior Syphilis

EIA Serologic Tests for Syphilis

EIA= Enzyme Immuno- Assay

Pro’sCloned Treponemal AntigensEasy to do in large numbers.Inexpensive

Con’sLimited data on specificityPositives need quantitative test to assess response to therapy and perhaps for confirmation

EIA (ELISA) Serologic Tests for SyphilisSuggested Evaluation of Positive Tests

Clinical Evaluation and Record Search. Significance of positive test unknown in persons with prior syphilis.

Confirm result with RPR/VDRL.

If positive, use for monitoring response to therapy.

If negative- ?? Possible longstanding infection vs.. false positive. Clinical evaluation/correlation required

HIV/STDPotential Interactions

1. STDs as markers for HIV risk

2. STDs as risk factors for HIV/acquisition transmission

3. Alterations of clinical +/or laboratory manifestations of STDs due to coexistent HIV infection

4. Decreases susceptibility to STD therapy due to coexistent HIV infection

5. Acceleration of HIV natural history due to coexistent or intercurrent STDs

Syphilis Therapy: Goals

1. Cure of disease: improvement of clinical signs and symptoms; prevention of disease progression

2. Prevention of disease transmission

3. Reduction of risk for HIV acquisition

NATURAL HISTORY OF SYPHILIS

2°

20-50%

Exposure … 1° Latent 3

33% 25% 33%

Recommend Treatment For Gonorrhea and Syphilis, 1935 - 2006

Gonorrhea Syphilis

SulfonilamidePenicillin PenicillinAmpicillinTetracyclineSpectinomycinCeftriaxoneFluoroquinolonesCefixime

RecommendedBenzathine Penicillin G, 2.4 Mu IM

Penicillin AllergyDoxycyline 100 mg PO, BID x 14d

Limited DataCeftriaxone 1.0 g IM or IV x 8-10d

Azithromycin 2.0g PO

2010 CDC STD TREATMENT GUIDELINESEarly Syphilis

SYPHILIS THERAPY:RESPONSE TO THERAPY

• Primary or Secondary Syphilis – Fourfold (2 dilution) or greater decline in RPR or VDRL titers by time of 3 month follow-up

• Early Latent Syphilis – Fourfold (2 dilution) or greater decline in RPR or VDRL titers by time of 6 month follow-up

MANIFESTATIONS OF SYPHILIS TREATMENT FAILURE

Clinical Relapse (Recurrent or New Signs)

Serologic Failurea) Relapse following initial responseb) Serologic progression despite therapyc) Serologic non-response

N.B. Treatment failure must be differentiated from reinfection

TREATMENT OF EARLY SYPHILIS IN HIV-INFECTED AND UNINFECTED PERSONS

3 Mo. 6 Mo. 12 Mo.

Treatment Group

Usual 25% (175) 24% (157) 18% (137)

Enhanced 29% (189) 19% (172) 17% (144)

Rolfs et al, NEJM

Proportion of Subjects with RPR Decline <2 Dilutions

2010 STD TREATMENT GUIDELINESSyphilis in Pregnant Patients

Serological Screening for All Women in Early Pregnancy; Repeat Screening at 28-32 Weeks and at Delivery in High Risk Patients or High

Prevalence Communities

Treat as Recommended for Non-Pregnant Patients

No Infant Should Leave the Hospital Without Maternal Serologic Status having Been

Determined at Least Once During Pregnancy

HIV/STDPotential Interactions

1. STDs as markers for HIV risk

2. STDs as risk factors for HIV/acquisition transmission

3. Alterations of clinical +/or laboratory manifestations of STDs due to coexistent HIV infection

4. Decreases susceptibility to STD therapy due to coexistent HIV infection

TREATMENT OF EARLY SYPHILIS IN HIV-INFECTED AND UNINFECTED PERSONS

3 Mo. 6 Mo. 12 Mo.

Treatment Group

Usual 25% (175) 24% (157) 18% (137)

Enhanced 29% (189) 19% (172) 17% (144)

HIV-Status

Positive 38% (76)* 28% (69) 21% (61)

Negative 24% (287) 19% (259) 16% (219)

Proportion of Subjects with RPR Decline <2 Dilutions

*P < 0.05

Rolfs et al, NEJM

2010 STD TREATMENT GUIDELINESSyphilis in HIV Infected Patients

Treat as Recommended for Patients Without HIV Infection

Closer Follow-up

(3, 6, 9, 12, and 24 mos)

2010 STD TREATMENT GUIDELINESEarly vs. Late Latent Syphilis

Early Latent SyphilisDocumented Seroconversion Past Year Unequivocal

history of 1°, 2° syphilis symptoms, past yearSex partner with 1°, 2°, or EL syphilis, past year

Late Latent SyphilisAll others

(STD Titers Do Not Differentiate Early vs. Late Latent Syphilis)

Benzathine Penicillin G 2.4 Mu IM weekly x 3

Penicillin Allergy

Doxycycline 100 mg PO, BID x 28

2010 CDC STD TREATMENT GUIDELINESLate Latent and Tertiary Syphilis

Syphilis Therapy:Response To Therapy

Late Latent or Tertiary Syphilis Other Than Neurosyphilis – Follow-up at 6 and 12 months. If titers increase fourfold, if an initially high (> 1:32) fails to decrease, or if signs or symptoms progress or develop, re-evaluate for neurosyphilis and re-treat.

Latent Syphilis:Response To Therapy

SYPHILIS MANAGEMENT GOALS

• Resolution of clinical signs/symptoms

• Prevention of disease progression

• Prevention of transmission to others

• Prevention of HIV transmission/acquisition