russell waddell: syphilis presentation and treatment

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STD Services Royal Adelaide Hospital Joy Copland Sexually Transmitted Diseases Services Dr. Russell Waddell Internal Medicine Service Royal Adelaide Hospital Syphilis Presentation Manifestations PLHIV Treatment

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Dr. Russell Waddell of Royal Adelaide Hospital discusses the clinical presentation and treatment of syphilis in people with HIV. This presentation was given at AFAO's syphilis forum in May 2009.

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Page 1: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Sexually Transmitted Diseases Services

Dr. Russell Waddell

Internal Medicine Service

Royal Adelaide Hospital

SyphilisPresentation

Manifestations PLHIVTreatment

Page 2: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

How Syphilis Causes Disease(Pathophysiology)

Treponema pallidum penetrates intact mucous membranes or microscopic dermal abrasions and within hours enters lymphatics and blood to spread throughout the body.

It attaches to the endothelial lining of blood vessels causing inflammation - endarteritis.

Later there can be a hyper-sensitivity response to the organism resulting in gummatous lesions and necrosis

Page 3: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Primary Syphilis - Clinical Manifestations

• Incubation: 9 - 90 days (average 21 days)• Chancre

– Early: macule/papule erodes – Late: clean based, painless, indurated ulcer with

smooth firm borders – Unnoticed in 15-30% of patients – Resolves in 1-5 weeks – HIGHLY INFECTIOUS

Page 4: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Primary Syphilis Chancre

Source: Florida STD/HIV Prevention Training Center

Page 5: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Page 6: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Secondary Syphilis - Clinical Manifestations

• Represents haematogenous dissemination of spirochetes that occurs at the time of initial infection

• Usually 2-8 weeks after chancre appears • Findings:

– rash - whole body (includes palms/soles) – mucous patches – condylomata lata –lumps in moist areas of the genitals

HIGHLY INFECTIOUS – constitutional symptoms – fever, swollen lymph nodes,

enlarged liver & spleen

• Sn/Sx resolve in 2-10 weeks

Page 7: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Secondary Syphilis Rash

Source: Florida STD/HIV Prevention Training Center

Page 8: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Secondary Syphilis

Source: Diepgen TL, Yihune G et al. Dermatology Online Atlas

Page 9: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Secondary Syphilis –Condylomata Lata

Source: Florida STD/HIV Prevention Training Center

Page 10: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Tertiary Syphilis

• Cardiovascular– Spirochete targets the small blood vessels supplying the

aorta – scarring causes thinning and oarta balloons out and the aortic valve is damaged

• Gummatous– hyper-sensitivity reaction to old Treponemes or new

infection – Can occur in any organ - often skin, bone, brain.– Hard lump, central portion dies (necrosis) and ulcer can

develop if on skin or mucous membrane

Page 11: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Tertiary Syphilis

• Neuro-syphilis– Spirochete targets the small blood vessels supplying the

brain or the meninges – meningitis or stroke in region of middle cerebral artery

– Cranial nerves (nerves to eye and hearing commonly affected)

– Spinal cord damage -walking affected, loss of reflexes and sensation (touch, pain and temperature) in legs.

Page 12: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Clinical History of Syphilis

1o 1- 6 weeks

2o weeks to months

3y

Early latent

Early latent

Late latent2 years

Incubation 9 – 90 days

Neuro syphilis

Gumma

Cardiovascular

Page 13: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Primary Syphilis in HIV infected

• Chancre usually single but multiple may occur in ~ 25% and more common in HIV infected(~70% in one study)

• Transient increase in Viral load and decrease in CD4-

• ? Long term effects on HIV progression

Rolfs 1997, Rompalo 2001

Page 14: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Secondary Syphilis in HIV infected

• Condylomata lata reportedly more common in HIV but conflicting reports

• Primary and secondary can occur together more commonly?– 1/3 cases even in HIV -ve

Rolfs 1997, Rompalo 2001

Page 15: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Syphilis in HIV infected

• Rapid progression from primary chancre to gummatous lesions has been observed ( Freidman-Kien 1996)

• Cases of rapidly developing aortitis • Despite appropriate treatment

progression to neuro-syphilis within 2 years of diagnosis of syphilis (Malone 1995)

Page 16: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Syphilis in HIV infected

• Some evidence for increased frequency of Neuro-syphilis. – Note 1/3 of all cases of syphilis with or without

symptomatic neuro-syphilis or HIVhave detectable T. pallidum in CSF regardless of HIV status (Rolfs 1997 NEJM)

• Most is seen at initial presentation cf HIV-ve• Is it increased invasion or inability to control

infection in CNS?

Page 17: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Syphilis in HIV infected

• Detection of T pallidum in CSF is common in early syphilis (HIV+ & HIV -) and does not predict symptomatic neuro-syphilis

• Detection of T pallidum in CSF is not more common in HIV infected and is not predictive of symptomatic neuro-syphilis.

• Early aggressive evaluation of CSF in HIV infected persons may not be a useful guide to therapy

• HIV positive with or without neuro-syphilis are likely to have higher CSF WBC counts and CSF protein levels

Rolfs 1997

Page 18: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Syphilis Serology and HIV infection

• In a minority of cases, serology may be unreliable: – HIV can cause false positive RPR/VDRL (1-6%

Rusnak J JID 1994)– False-negative RPR/VDRL have been occasionally

reported.– RPR/VDRL titre tends to be lower in primary syphilis– RPR/VDRL titres are statistically significantly higher

in secondary syphilis, – Titres decline more slowly with treatment

Page 19: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Treatment

• Host immune response important – 60-70% of untreated individuals go through life

without developing late complications– 1/3 RPR becomes negative after 20+ years

without treatment • Asymptomatic neuro-syphilis: response to near

useless treatment (CSF-Kohlmer WR became non reactive)

– 5-25 cells 85% responded to treatment– 25-100 cells 65% responded to treatment– 100+ cells 45% responded to treatment

Page 20: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Treatment (USA, Clinic275)

• Early syphilis (epidemiologic, primary, secondary and early latent)

– (1) Benzathine penicillin G 2.4 MU i.m. single dose

• Late latent, cardiovascular and gummatous syphilis and treatment failures

– (1) Benzathine penicillin 2.4 MU i.m. weekly for two weeks (three doses)

• Neurosyphilis (early or late)

– Aqueous crystalline penicillin G 18–24 million units per day, administered as 3–4 million units IV every 4 hours or continuous infusion, for 10–14 days

Page 21: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Treatment• Penicillin allergy – desensitize and treat as above

• Missed doses in course of weekly therapy – the appropriate course of action is unclear.

– Pharmacologic considerations suggest that an interval of 10–14 days between doses of benzathine penicillin might be acceptable before restarting the sequence of injections.

Page 22: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Syphilis Treatment and HIV

• JARISCH-HERXHEIMER REACTION– Fever and muscle aches following

penicillin therapy for syphilis. – Cause not clear often attributed to sudden

release of toxins from the dying and dead treponemes?

• Reported more frequently in HIV infected patients (26%v12%)

Page 23: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Early syphilis: Alternative Treatment regimens

– (1) Procaine penicillin G• 600 000 units i.m. daily for 10 days (III, B)

– (2) Doxycycline• 100 mg PO b.d. 14 days (III, B)

– (3) Azithromycin • 2 g PO stat (1b, B)

– (4)Azithromycin • 500 mg daily 10 days (II, B)

– (5) Erythromycin• 500 mg PO q.d.s. 14 days (III, B)

– (6) Ceftriaxone• 500 mg i.m. daily 10 days

– (7) Amoxycillin • 500 mg PO q.d.s. plus Probenecid 500 mg q.d.s. 14 days (III, B)

Page 24: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Alternative Treatment

• Late latent, cardiovascular and gummatous syphilis– (1) Procaine penicillin

• 600,000 units i.m. o.d. for 17 days (III, B)

– (2) Doxycycline • 100 mg PO b.d. for 28 days (IV, C)

– (3) Amoxycillin• 2 g PO t.d.s. plus probenecid 500 mg q.d.s. for

28 days. (III, C)

Page 25: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Alternative Treatment

• Neurosyphilis – (1) Procaine penicillin

• 1.8–2.4 MU i.m. o.d. plus probenecid 500 mg PO q.d.s. for 17 days– (2) Benzyl penicillin

• 18–24 MU daily, given as 3–4 MU i.m. every four hours for 17 days (III, C)

– (3) Doxycycline• 200 mg PO b.d. for 28 days (IV, C)

– (4) Amoxycillin• 2 g PO t.d.s. plus probenecid 500 mg PO q.d.s. for 28 days (IV, C)

– (5) Ceftriaxone • 2 g i.m. (with lidocaine as diluent) or i.v. (with water for injection as

diluent) for 10–14 days (IV, C)

Page 26: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Symptomatic neurosyphilis

• Conventional therapy is effective for the vast majority of immuno-competent patients with asymptomatic CNS involvement in primary and secondary syphilis.

Page 27: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Syphilis the great mimic

You cannot keep a good disease

down

Page 28: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Epidemiological Treatment

• Epidemiological Treatment Defined as

– treatment for early syphilis • after

– Clinical examination and assessment of level of risk

(contact primary:- 46–60% infected) • and

– collection of diagnostic tests (serology, swabs PCR, fluid for darkfield)

• but – before the results are available

Page 29: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Epidemiological Treatment

Sexual transmission of T. pallidum – occurs only when muco-cutaneous syphilitic

lesions are present– uncommon after the first year of infection– For identification of at-risk sexual partners, the

periods before treatment are (USA)1) 3 months plus duration of symptoms for primary syphilis,

2) 6 months plus duration of symptoms for secondary syphilis,

3) 1 year for early latent syphilis

Page 30: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Monitor for Treatment failure• Treatment failure

– No four-fold decrease within 6 –12 months of therapy – ≥Four-fold increase in non-treponemal test titre– Recurrence of signs or symptoms– Re-infection excluded

• 15% of early syphilis do not reach 4 fold decrease in titre after 12 months.

• CSF examination and re-treatment is indicated• Re-treat as per late latent regimen if CSF normal

Page 31: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Follow up• Early syphilis,

– clinical and serological – (VDRL or RPR) follow-up at months 1, 2, 3, 6 and 12, – then six monthly until VDRL/RPR negative or serofast.

• Late syphilis – minimum serological follow-up is three monthly until sero-fast.

Must perform VDRL/RPR titre at commencement of therapy

• Response to treatment:– Resolution of clinical lesions– A four-fold or greater titre decrease in the VDRL/RPR within 3-6 months– Neurosyphilis

• CSF cell count decreased by six months and the CSF VDRL/RPR normal by two years

• In rare instances, despite a negative CSF examination and a repeated course of therapy, serologic titres might still not decline.

• In these circumstances, the need for additional therapy or repeated CSF examinations is unclear.

Russell Waddell
1,3,6,12 months
Page 32: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Syphilis and HIV infection

• Some experts believe that HIV patients with syphilis should be treated as for neurosyphilis to prevent the development of neurological involvement,

• CSF abnormalities ( mononuclear pleocytosis and elevated protein levels) are common in patients with early syphilis and in persons with HIV infection

• Therefore, some specialists recommend CSF examination before treatment of HIV-infected persons with early syphilis, with follow-up CSF examination conducted after treatment in persons with initial abnormalities.

• Hard evidence for this policy is lacking.

Page 33: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Disease RPR/VDRL FTA-ABS TP-PA

Age Yes

Autoimmune Diseases Yes Yes

Cardiovascular Disease Yes Yes

Dermatologic Diseases Yes Yes --

Drug Abuse Yes Yes

Febrile Illness Yes

Glucosamine/chondroitin sulfate Possibly

Leprosy Yes No --

Lyme disease Yes

Malaria Yes No

Pinta, Yaws Yes Yes Yes

Pregnancy Yes*

Recent Immunizations Yes -- --

STD other than Syphilis Yes

Source: Syphilis Reference Guide, CDC/National Center for Infectious Diseases, 2002

*May cause increase in titer in women previously successfully treated for syphilis

Causes of False Positives

Page 34: Russell Waddell: Syphilis Presentation and Treatment

STD ServicesRoyal Adelaide Hospital

Joy Copland

Serological Tests in Untreated Syphilis

Stage of Disease (Percent Positive [Range])

Test Primary Secondary Latent Tertiary

VDRL 78 (74-87) 100 95 (88-100) 71 (37-94)

RPR 86 (77-99) 100 98 (95-100) 73

FTA-ABS* 84 (70-100) 100 100 96

TPPA* 76 (69-90) 100 97 (97-100) 94

EIA 93 100 100

*FTA-ABS and TP-PA are generally considered equally sensitive in the primary stage of disease.