1. A 46 year old male with a rash Primary Care Conference June 28th, 2006 Bev Grooms Thom, PA-C

2. 2 Case Presentation: 46 y/o male with a rash 46 y/o single international executive presented for evaluation of a 1 month hx of a non pruritic, non tender trunkal and upper extremity rash. “Occasionally scaly” Pt had been in South America x 10 days; rash began soon after return. Tanned several times before trip Had Yellow Fever vaccine prior to trip Travels to Asia > 2x per year New med: Lipitor x 2 months prior to onset rash

3. 3 Case Presentation: 46 y/o male with a rash Unusual “herald patch” Pt admitted to non healing penile lesion x 6 weeks Penile lesion described as “whitish”, non tender. Denies fever, chills, sore throat, weight loss, fatigue, alopecia and lymphadenopathy

4. 4 Case Presentation: 46 y/o male with a rash Homosexual male Condom use: –“Always” with anal insertive or receptive intercourse –“Most of the time” with insertive or receptive oral sex Number of partners: –15 in past year –2 in last 6 months

5. 5 Case Presentation: 46 y/o male with a rash: PE VS … normal ENT: No oral lesions Skin: Maculopapular faint erythematous rash, irregular shaped and sized (0.5-1.5 cm) over chest, back, arms and abdomen. Palms and plantar aspect feet not involved.

6. 6 Trunkal rash

7. 7 Case Presentation: 46 y/o male with a rash: PE Genitalia: Single 1.5 cm oval shaped ulcerated lesion on penile shaft with smooth, whitish border. Non tender. Scattered maculopapular erythematous lesions elsewhere on penile shaft. No urethral discharge Testicular exam: Normal

8. 8 Penile ulcer

9. 9 Case Presentation: 46 y/o male with a rash: Differential Non pruritic trunkal/extremity rash secondary to ??? –pityriasis rosea –photosensitivity reaction –medication reaction –syphilis

10. 10 Case Presentation: 46 y/o male with a rash: Diagnostics CBC with diff (normal) HIV.. Non reactive RPR … reactive at 1:32 dilution, confirmed on TPPA Pt informed, directed to inform partners.

11. 11 Case Presentation: 46 y/o male with a rash: Management Returned to clinic six days after initial visit Rash spread to lower extremities and buttock, no palmar/plantar involvement. At time of rx, pt c/o sore throat. No other c/o. –Strep and GC culture negative Rx … 2.4 million units IM Benzathine Penicillin G

12. 12 Case Presentation: 46 y/o male with a rash: Follow up RTC 2 1/2 months post treatment … ST cleared immediately, rash resolved 2 weeks post treatment. Patient’s partner recently became HIV positive but is RPR negative. Patient’s repeat 3 month HIV negative Follow up RPR within 6 months

13. 13 Case Presentation: 46 y/o male with a rash: Learning Objectives Awareness of the differential diagnosis of a diffuse maculopapular rash Have knowledge of the signs, symptoms and stages of syphilis Understand the ramifications of co-infection of syphilis and HIV Attain knowledge of the diagnosis and treatment of syphilis Raise consciousness regarding syphilis as a re- emerging entity

14. 14 Syphilis: Definition A chronic infection caused by the bacterium treponema pallidum (Tp) Non Tp treponemes may exist elsewhere The manifestations of disease are quite varied, occurring in any one individual in different stages over time Primarily sexually transmitted Recognized for centuries, origin unknown

15. 15 Syphilis: Epidemiology Reportable disease, therefore allows a relatively accurate # of early cases Late 1980s/early 1990s … mini epidemic of early syphilis led to rates higher than any time since introduction of penicillin 2000 … incidence falls to all time low, raising hopes for eradication. Targeted groups had been women (decline incidence by 35%) and African- Americans (similar decline)

16. 16 Syphilis: Epidemiology Since 2001, early syphilis rates have increased and this trend continues This increase has occurred mainly among men who have sex with men (MSM) Relatively high rate of HIV co-infection in persons with syphilis –25% co-infection rate in 2002 among 6862 pts with primary and secondary syphilis

17. 17 Syphilis: Epidemiology: HIV associations Strong association between both diseases –Both primarily sexually transmitted –Increased HIV transmission in setting of genital ulcer disease Little evidence syphilis more severe in HIV disease but interaction between the two may alter some of the manifestations of syphilis. –More likely to present with secondary syphilis and those pts more likely to have persistent chancres –More likely to have multiple and persistent chancres

18. 18 Syphilis: Epidemiology: HIV associations Pts with untreated syphilis may have higher HIV RNA load and lower CD4 counts that respond favorably to effective treponemal therapy. Fulminant presentation, rapid progression and treatment failures are rare –Some reports state risk of treatment failure may depend on degree of immunosuppression induced by HIV

19. 19 Geographic features in the U.S.

20. 20 Syphilis: Epidemiology In addition to US, syphilis an important problem elsewhere in the world. In 1999 WHO estimated new cases –North America.. 100,000 –Western Europe.. 140,000 –Eastern Europe and Central Asia.. 100,000 –North Africa and Middle East.. 370,000 –Latin America and Caribbean, sub-Saharan Africa, south and southeast Asia … 3-4 million each!

21. 21 Syphilis: Etiology Transmission primarily via sexual contact between infected and uninfected partners Portal of entry via small abrasions. Replication locally with spread to regional lymph nodes Early lesions very infectious; chancres, mucous patches and condyloma lata –Transmission occurs in 1/3 patients exposed to these lesions

22. 22 Syphilis: Etiology May be transmitted by kissing or touching active lesions on the lips, oral cavity, breasts or genitals In MSM, transmission documented in those individuals who only have had oral sex as their only risk factor for acquisition

23. 23 Syphilis: Etiology Other modes include transplacental, non- sexual contact with infections lesions, laboratory accidents and contaminated blood products (rare because donors are screened and Tp cannot survive >24-48 hrs under current blood bank storage conditions)

24. 24 Syphilis: Etiology Risk factors in MSM and bisexual men: –HIV infection –Combined use of methamphetamine and sildenafil –Recent sexual partners from the Internet

25. 25 Syphilis: Clinical Manifestations: Early or primary After 2-3 week incubation period, a papule appears at site of inoculation. May be as long as 3 months due to inoculation load and previous infection with syphilis Usually painless, soon ulcerates to produce classic chancre Multiple chancres may occur, but not common. Increased in HIV infected persons 1-2 cm ulcer with raised, indurated margin Usually non-exudative base, associated with mild to moderate regional bilateral lymphadenopathy

26. 26 Syphilis: Clinical Manifestations: Early or primary Spontaneous healing of chancres within 2-8 weeks, potentially longer in immunocompromised patients, even in absence of treatment. Mechanism of healing not known, but thought secondary local immune responses. Systemic spread occurs quickly Spirochetes disseminate during the primary stage of infection

27. 27 Syphilis: Differential Diagnosis: Early or primary Syphilis Chancroid Genital Herpes Behcet’s disease Drug eruptions

28. 28 Syphilis: Clinical Manifestations: Secondary In untreated primary infection, within weeks to months, 25-30% patients will develop illness due to secondary syphilis Fever, malaise, diffuse lymphadenopathy Patchy alopecia, HA, ST and weight loss Classic hyperpigmented, scaly maculopapular rash on trunk, extremities, including palms and soles Condylomata lata (raised, grey to white lesions involving warm, moist areas) may develop in some patients

29. 29 Syphilis: Clinical Manifestations: Secondary The findings of enlarged epitrochlear lymph nodes in the absence of upper extremity pathology is considered to be highly suspicious for syphilis. Skeletal manifestations: Osteitis, arthritis, bursitis GI: Hepatitis, hepatomegaly, elevated alk phos, gastritis GU: Nephropathy (glomerulonephritis and nephrotic syndrome)

30. 30 Syphilis: Clinical Manifestations: Secondary Visual: Anterior and posterior uveitis –May be asymptomatic or have altered vision … –Syphilis may be correctly diagnosed after failure to respond to or worsening following steroid treatment.

31. 31 Syphilis: Clinical Manifestations: Secondary: Neurologic Neurologic abnormalities may occur within the first few weeks after initial infection or for up to 25 years without treatment (causing diagnostic confusion - different forms may coexist and overlap). Manifestations may include headache, stiff neck, N&V, photophobia, cranial neuropathies associated with ocular and otic deficits, facial nerve palsies, papilledema and encephalopathy.

32. 32 Syphilis: Clinical Manifestations: Secondary: Neurologic Most patients do not have the rash of secondary syphilis by the time significant neurologic findings are present. Occasionally neurologic (and other) manifestations of secondary syphilis can occur for up to 5 years in the untreated patient. A common clinical problem is when lumbar puncture should be performed in patients with early syphilis

33. 33 Syphilis: Clinical Manifestations: Secondary: Neurologic No evidence that treatment failures more common in pts with early syphilis and abnl CSF analysis after rx with benzathine PCN The primary indications for lumbar puncture are symptoms of meningitis or other focal neurologic findings A serum RPR > 1:32 is associated with a > 10 fold increase risk of neurosyphilis Therefore, the decision to do an LP rests on both symptoms and RPR titer

34. 34 Syphilis: Clinical Manifestations: Secondary Similar to primary disease, acute manifestations of secondary syphilis typically resolve spontaneously, even in the absence of treatment

35. 35 Syphilis: Clinical Manifestations: Latent Latent syphilis is defined as the period during which patients have no symptoms but have infection demonstrable by serologic testing There are two periods of latent syphilis –Early latent … secondary syphilis may recur (mucocutaneous relapses … potentially infectious) –Late latent … no clinical manifestations, transmission no longer probable.

36. 36 Syphilis: Clinical Manifestations: Latent USPHS has modified the definition by categorizing early latent syphilis as infection of one year’s duration or less All other cases referred to as late latent or latent syphilis of unknown duration In late latent disease, the organisms dividing time is probably longer and treatment may need to be more prolonged

37. 37 Syphilis: Clinical Manifestations: Late or tertiary Defined as stages of syphilis that occur after early (primary or secondary) or latent syphilis May arise within a year of initial infection or up to 30 years later. –Occurs in uncertain proportion of infected patients. Remains to be seen how many cases of late syphilis will occur given the recent resurgence of early syphilis Typically involves CNS, cardiovascular, skin or subcutaneous tissues

38. 38 Syphilis: Diagnosis: Primary syphilis Complicated by fact that organism can not be cultivated in vitro Dark field microscopy of lesion exudate –Spirochetes manifesting corkscrew morphology of treponemes showing white organisms against a black background Obtain from base of chancre after cleaning with saline and applying gentle pressure

39. 39 Dark Field Microscopy

40. 40 Syphilis: Diagnosis: Primary syphilis DFA test on exudate may be done when immediate processing of specimen not possible PCR of exudate possible (relatively new) –PCR combined probe for syphilis, chancroid and HSV available –Available at UW as a “send out” test

41. 41 Syphilis: Diagnosis: Serologic testing RPR is screening test done at UW core lab –If positive, core lab reflexly obtains a TPPA Early syphilis –Screening tests (non treponemal, e.g RPR) 78-86% sensitive in primary syphilis Secondary syphilis –Likelihood of false negative RPR remote –Usually high antibody titers by this time Latent syphilis –Titers decline. Not uncommon to see 1:1 to 1:16 levels –Diagnosis of late or tertiary depends on clinical findings and not serologic testing

42. 42 Syphilis: Treatment of early or secondary disease All manifestations of primary and secondary syphilis will resolve without therapy Therapy must be prolonged since Tp divides slowly, averaging one doubling per day in vivo Long acting penicillin preparations are the mainstay of treatment

43. 43 Syphilis: Treatment of early or secondary disease Benzathine penicillin G, 2.4 million units x one dose remains treatment of choice per CDC and WHO Only long acting penicillin should be used since low, continuous levels are necessary to eliminate treponemes Use of CR Bicillin (= concentrations of procaine and benzathine PCN G) results in detectable serum levels for only 7 days!!

44. 44 Syphilis: Treatment of early or secondary disease IM only route; IV has been associated with cardiopulmonary arrest and death No resistance has been reported to date despite several decades of use Potential complication: Jarisch-Herxheimer reaction –Release of pyrogenic endotoxins from rapid kill of treponemes. –Occurs within first few hours of rx of syphilis, usually secondary.

45. 45 Syphilis: Treatment of early or secondary disease Penicillin allergic patients –Azithromycin, single 2 gram dose shown to be effective (98% cure vs. 95% PCN Rx), but increasing reports of macrolide resistance –Doxycycline, 100mg bid x 14 days or TCN, 500mg qid x 14 days Settings where penicillin must be used –Congenital syphilis –Syphilis in pregnancy Rx late in pregnancy carries > risk for congenital syphilis than rx in early pregnancy –Neurosyphilis

46. 46 Syphilis: Treatment of latent disease Single dose treatment only appropriate if –There is documentation of a non reactive syphilis serology in the past year or … –If there is documentation of a seropositivity and chancre within the past year In the absence of above, treatment should be for “latent syphilis of unknown duration” … 3 doses of 2.4 mu benzathine PCN at weekly intervals Rx issues in HIV patients

47. 47 Treatment issues in HIV patients Primary and secondary syphilis: Single dose benzathine penicillin G, 2.4 mu IM unless patient presents with abnormal neurologic signs or symptoms Early latent patients can be managed the same as primary or secondary syphilis

48. 48 Treatment issues in HIV patients Syphilis of unknown duration or late latent should have a CSF exam before treatment –Normal CSF.. Rx with benzathine PCN G, 2.4 mu x 3 consecutive weeks –Abnormal CSF, i.e. neurosyphilis … aqueous crystalline PCN G, 3-4 million units IV q 4hr or continuous infusion total 18-24 million units per day x 10-14 days. PCN allergic patients may receive ceftriaxone or be desensitized to PCN

49. 49 Syphilis: Treatment followup RPR should fall four fold in 6 to 12 months Some serologic non-responders may be due to reinfection … therefore treatment with a second course required Be sure all sexual partners are treated CDC suggests LP if patients do not see 4 fold decrease in RPR titers