A 46 year old male with a rash

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

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. 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. 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. 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. Trunkal rash

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. Penile ulcer

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Geographic features in the U.S.

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

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

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

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. 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. 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. 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. Dark Field Microscopy

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. 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. 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. 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. 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. 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. 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. 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. 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. 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