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syphilis

An acute & chronic infection caused by Treponema pallidum, transmitted by direct contact, usually sexual intercourse. Etiology: - sexually transmitted disease - HIV1 infection is a risk factor* * diagnosis & management of syphilis are the same for people with & without HIV1 infection [28] Epidemiology: 1) increased incidence of 12.6% in 2002 a) increase restricted to non-hispanic white males [4] b) increase confined in large cities in west, northeast & midwest 2) 80% of USA counties reported no cases of syphilis in 2002 [4] 3) 90% of cases in 2013 in men, 80% of these in men who have sex with men [18] - RR = 106 homosexual men vs heterosexual men - RR = 167 homosexual men vs women [24 4) 2 clusters of ocular syphilis 2014-2015 in San Francisco & Seattle (10 of 12 coinfected with HIV1), majority in men who have sex with men [20] Clinical manifestations: 1) Incubation period: 12-30 days 2) Primary syphilis: a) chancre - single, painless 0.5-1.0 cm indurated genital ulcer - smooth base - multiple lesions can occur [2] b) minimal to mild fever c) non-tender bilateral genital inguinal lymphadenopathy d) lesions spontaneously heal in 3-6 weeks even without treatment 3) Secondary syphilis: a) skin eruptions, variable - mucous patches, erosions, surrounding erythema in oral cavity & in moist genital regions are highly infectious - whitish, wart-like lesions (condyloma latum) on mucous membranes - copper-colored, scaly papular eruption - diffuse rash; may include palms of hands & soles of feet - rash is never vesicular in adults (no vesicles) b) alopecia in some cases [25] c) generalized lymphadenopathy, non-tender d) in intertriginous areas papules may coalesce to form condyloma latum e) fever f) constitutional symptoms: malaise, fatigue g) headache, cranial nerve involvement, nuchal rididity, altered mental status h) coincident with primary chancre in 10% of cases i) spontaneous resolution in 3-6 weeks 4) Tertiary syphilis: a) formation of gummas b) ocular lesions - uveitis - Argyll-Robertson pupils - case with conjunctival erythema & photophobia [29] c) cardiovascular lesions d) CNS lesions e) atypical & accelerated neurosyphilis is seen in HIV1 infection 5) latent syphilis is tertiary syphylis in the absence of symptoms 6) General Paresis of the Insane (GPI) is an historical presentation of tertiary syphilis Laboratory: 1) serologic test for syphilis a) RPR or VDRL (nontreponemal serologic test for syphilis) - often negative in primary syphilis - present in high titers in secondary syphilis - present in low titers in tertiary syphilis - titers fall with treatment but rise again with reinfection [2] b) confirm positive RPR or VDRL with treponemal serologic test for syphilis - FTA-ABS, TPPA, TP-EIA - treponemal serologic tests for syphilis remain positive indefinitely [2] 2) dark field microscopy of scrapings from primary lesion 3) CSF analysis for latent disease or CNS symptoms: [2,14] a) CSF leukocytes > 5/uL b) elevated CSF protein c) positive CSF VDRL 4) HIV testing if genital ulceration [6]; all patients [2] 5) see ARUP consult [15] 6) CDC laboratory recommendations for syphilis testing [30] Differential diagnosis: - primary syphilis: see genital ulcer - papillomavirus causes genital warts, not ulcers - secondary syphilis: - target lesions of erythema multiforme due to Herpes simplex - tertiary syphilis: toxoplasmosis Management: 1) primary syphilis: bicillin L-A* 2.4 million units IM once - benzathine penicillin superior to cefixime in patients with HIV1 infection [27] 2) primary, secondary or early latent (asymptomatic) syphilis - bicillin L-A* 2.4 million units IM once [2,17] 3) late latent syphilis or syphilis of unknown duration - bicillin 2.4 million units IM weekly for 3 weeks (3x) 4) neurosyphilis (confirm with CSF analysis prior to treatment) a) 12-24 million units/day of penicillin G b) given as 2-4 million units IV every 4 hours c) alternative for penicillin allergy: ceftriaxone 2 g IV/IM QD d) duration for 10-14 days 5) neonatal syphilis of infant born to RPR+ mom - procaine penicillin G 50,000 units IM QD for 10 days 6) doxycycline or tetracycline for patients allergic to penicillin [7] - not pregnant [2] - pregnant patients allergic to penicillin must be desensitized & treated with penicillin [2] 7) azithromycin is an option a) not always effective [5,6] b) 2 grams once is effective for early primary syphilis [8] 8) amoxicillin 3 grams PO daily with probenecid for 2-4 weeks effective in HIV+ men [19] 8) pregnant women allergic to penicillin should be desensitized & treated with penicillin [2] 9) monitoring response to therapy a) follow-up at 2 weeks, 1, 2, 3, 6, 9 & 12 months (HIV+) b) > 4-fold decline in RPR titer is presumptive evidence of response to therapy 10) Jarisch-Herxheimer reaction may occur with initiation of therapy 11) partners of patients with primary, secondary or early latent syphilis should be treated for syphilis even if serologic test for syphylis is negative [2] * Bicillin C-R is sometimes given by mistake [5] Bicillin L-A is long-acting; Billicin C-R is not Screening: - high-risk patients [22] - HIV1 nfection - men who have sex with men

Related

Jarisch-Herxheimer reaction serologic test for syphilis Treponema pallidum

Specific

bejel (endemic syphilis) condyloma latum congenital syphilis neurosyphilis (dementia paralytica, syphilitic paresis) pinta secondary syphilis yaws (frambesia)

General

spirochete infection sexually-transmitted disease; sexually-transmitted infection; venereal disease (STD, STI) granulomatous disease

References

  1. Stedman's Medical Dictionary 26th ed, Williams & Wilkins, Baltimore, 1995
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 92
  4. Journal Watch 24(1):2-3, 2004 MMWR Morb Mortal Wkly Rep 52:1117, 2003 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5246a1.htm
  5. Prescriber's Letter 11(5):26 2004 Detail-Document#: 200513 (subscription needed) http://www.prescribersletter.com
  6. Riedner G, Rusizoka M, Todd J, Maboko L, Hoelscher M, Mmbando D, Samky E, Lyamuya E, Mabey D, Grosskurth H, Hayes R. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med. 2005 Sep 22;353(12):1236-44. PMID: 16177249 - Holmes KK. Azithromycin versus penicillin G benzathine for early syphilis. N Engl J Med. 2005 Sep 22;353(12):1291-3. No abstract available. PMID: 16177256
  7. Wong T et al. Primary syphilis: Serological treatment response to doxycycline/tetracycline versus benzathine penicillin. Am J Med 2008 Oct; 121:903. PMID: 18823862
  8. Hook EW III et al. A phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis. J Infect Dis 2010 Jun 1; 201:1729. PMID: 20402591
  9. Karp G et al. Syphilis and HIV co-infection. Eur J Intern Med 2009 Jan; 20:9. PMID: 19237085)
  10. Nakashima AK et al. Epidemiology of syphilis in the United States, 1941-1993. Sex Transm Dis 1996 Jan/Feb; 23:16. PMID: 8801638
  11. Grassly NC et al. Host immunity and synchronized epidemics of syphilis across the United States. Nature 2005 Jan 27; 433:417. PMID: 15674292
  12. Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases surveillance, 2008. Nov 2009. http://www.cdc.gov/std/stats08/syphilis.htm
  13. French P. Syphilis. BMJ 2007 Jan 20; 334:143. PMID: 17235095
  14. Libois A et al. HIV and syphilis: When to perform a lumbar puncture. Sex Transm Dis 2007 Mar; 34:141. PMID: 16865051
  15. Su JR, Beltrami JF, Zaidi AA, Weinstock HS. Primary and secondary syphilis among black and Hispanic men who have sex with men: case report data from 27 States. Ann Intern Med. 2011 Aug 2;155(3):145-51 PMID: 21810707
  16. ARUP Consult: Treponema pallidum - Syphilis The Physician's Guide to Laboratory Test Selection & Interpretation https://arupconsult.com/content/treponema-pallidum - Syphilis Testing Algorithm https://arupconsult.com/algorithm/syphilis-testing-algorithm
  17. Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010 Dec 17;59(RR-12):1-110. PMID: 21160459 - many of these guidelines withdrawn from NGC Jan 2016
  18. Patton ME et al Primary and Secondary Syphilis - United States, 2005-2013 MMWR Weekly. May 9, 2014 / 63(18);402-406 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6318a4.htm
  19. Tanizaki R et al. High-dose oral amoxicillin plus probenecid is highly effective for syphilis in patients with HIV infection. Clin Infect Dis 2015 Jul 15; 61:177 PMID: 25829004 http://cid.oxfordjournals.org/content/61/2/177
  20. Woolston S et al Notes from the Field: A Cluster of Ocular Syphilis Cases - Seattle, Washington, and San Francisco, California, 2014-2015. MMWR Weekly. October 16, 2015 / 64(40);1150-1 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6440a6.htm
  21. Militz H, Hungerer C IMAGES IN CLINICAL MEDICINE. Treponema pallidum - The Great Imitator. N Engl J Med. 2015 Nov 19;373(21):2069 PMID: 26580999 http://www.nejm.org/doi/full/10.1056/NEJMicm1501265
  22. U.S. Preventive Services Task Force. Draft Recommendation Statement. Dec 2015. Syphilis Infection in Nonpregnant Adults and Adolescents: Screening. http://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement146/syphilis-infection-in-nonpregnant-adults-and-adolescents
  23. World Health Organization (WHO) WHO Guidelines for the treatment of Treponema pallidum (syphilis). 2016. apps.who.int/iris/bitstream/10665/249572/1/9789241549806-eng.pdf
  24. de Voux A, Kidd S, Grey JA, et al. State-Specific Rates of Primary and Secondary Syphilis Among Men Who Have Sex with Men - United States, 2015. MMWR Morb Mortal Wkly Rep 2017;66:349-354 https://www.cdc.gov/mmwr/volumes/66/wr/mm6613a1.htm
  25. Moshiri AS, Moxam A Syphilitic Alopecia N Engl J Med 2018; 379:1657 PMID: 30354954 https://www.nejm.org/doi/full/10.1056/NEJMicm1804118
  26. Ghanem KG, Ram S, Rice PA The Modern Epidemic of Syphilis. N Engl J Med 2020; 382:845-854 PMID: 32101666 https://www.nejm.org/doi/full/10.1056/NEJMra1901593
  27. Stafylis C et al. Clinical efficacy of cefixime for the treatment of early syphilis. Clin Infect Dis 2021 Feb 26; PMID: 33640982 https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab187/6152217
  28. DHHS Panel. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: Syphilis. Department of Health and Human Services 2023 Sep 7; [e-pub] https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/whats-new
  29. NEJM Knowledge+ - Tuddenham S, Ghanem KG. Neurosyphilis: Knowledge Gaps and Controversies. Sex Transm Dis. 2018 Mar;45(3):147-151. PMID: 29420441 PMCID: PMC5808573 Free PMC article. Review.
  30. Papp JR, Park IU, Fakile Y, Pereira L, Pillay A, Bolan GA. CDC Laboratory Recommendations for Syphilis Testing, United States, 2024. MMWR Recomm Rep 2024;73(No. RR-1):1-32 https://www.cdc.gov/mmwr/volumes/73/rr/rr7301a1.htm
  31. National Center for Emerging and Zoonotic Infectious Diseases (U.S.). Division of High-Consequence Pathogens and Pathology. Division of High-Consequence Pathogens and Pathology - Laboratory Recommendations for Syphilis Testing in the United States - Supplementary Material MMWR 2024. Jan https://stacks.cdc.gov/view/cdc/138288