Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 34-03: Syphilis + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ The spirochete can infect almost any organ or tissue in the body and cause protean clinical manifestations Transmission occurs most frequently during sexual contact +++ General Considerations ++ Caused by Treponema pallidum, a spirochete capable of infecting almost any organ or tissue in the body and of causing protean clinical manifestations (Table 34–1) The risk of syphilis after unprotected sex with an individual with infectious syphilis is ~30–50% Congenital syphilis: transplacental transmission occurs in infants of untreated or inadequately treated mothers Two major clinical stages Early (infectious) syphilis Late syphilis Stages are separated by a symptom-free latent period During early latency (within the first year after infection) the infectious stage may recur Early (infectious) syphilis Primary lesions (chancre and regional lymphadenopathy) Secondary lesions (commonly involving skin and mucous membranes, occasionally bone, CNS, or liver) Congenital lesions Late syphilis consists of So-called benign (gummatous) lesions involving skin, bones, and viscera Cardiovascular disease (principally aortitis) CNS and ocular syndromes ++Table Graphic Jump LocationTable 34–1.Stages of syphilis and common clinical manifestations.View Table||Download (.pdf) Table 34–1. Stages of syphilis and common clinical manifestations. Primary syphilis Chancre: painless ulcer with clean base and firm indurated borders Regional lymphadenopathy Secondary syphilis Skin and mucous membranes Rash: diffuse (may include palms and soles), macular, papular, pustular, and combinations Condylomata lata Mucous patches: painless, silvery ulcerations of mucous membrane with surrounding erythema Generalized lymphadenopathy Constitutional symptoms Fever, usually low-grade Malaise, anorexia Arthralgias and myalgias Central nervous system Asymptomatic Symptomatic Meningitis Cranial neuropathies (II–VIII) Other Ocular: iritis, iridocyclitis Renal: glomerulonephritis, nephrotic syndrome Hepatitis Musculoskeletal: arthritis, periostitis Tertiary (late) syphilis Late benign (gummatous): granulomatous lesion usually involving skin, mucous membranes, and bones but any organ can be involved Cardiovascular Aortic regurgitation Coronary ostial stenosis Aortic aneurysm Neurosyphilis Asymptomatic Meningovascular Tabes dorsalis General paresis Note: Central nervous system involvement may occur at any stage. +++ Demographics ++ In 2018, the number of primary and secondary syphilis cases in the United States was 35,063 and the rate of 10.8 per 100,000 people, which represents an increase of 14% over 2017 Most cases of syphilis in the United States continue to occur in men who have sex with men (MSM) However, despite the increase in primary and secondary syphilis in MSM, a concomitant increase in the incidence of HIV has not been observed + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs +++ Primary ++ Painless ulcer (chancre) on genitalia, perianal area, rectum, pharynx, tongue, lip, or elsewhere 2–6 weeks after exposure Nontender enlargement of regional lymph nodes +++ Secondary ++ Generalized maculopapular rash Mucous membrane lesions, which can be found on the lips, mouth, throat, genitalia, and anus Weeping papules (condylomata) in moist skin areas Generalized nontender lymphadenopathy Fever Meningitis, hepatitis, osteitis, arthritis, iritis +++ Early latent ++ No physical signs +++ Late latent ++ No physical signs +++ Late (tertiary) ++ Infiltrative tumors of skin, bones, liver (gummas) Aortitis, aneurysms, aortic regurgitation CNS disorders, including Meningovascular and degenerative changes Paresthesias Shooting pains Abnormal reflexes Dementia Psychosis +++ Differential Diagnosis ++ Chancroid (usually painful) Lymphogranuloma venereum Genital herpes Neoplasm Any lesion on genitalia should be considered possible primary syphilitic lesion + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ HIV test +++ Nontreponemal antibody tests ++ VDRL and rapid plasma reagin (RPR) Generally become positive 4–6 weeks after infection, or 1–3 weeks after a primary lesion Not highly specific False-positive reactions are frequent in Autoimmune or febrile diseases Infectious mononucleosis Malaria, leprosy Febrile diseases HIV Injection drug use Infective endocarditis Advanced age Hepatitis C Pregnancy False-negative results when very high antibody titers are present (prozone phenomenon) RPR titers are often higher than VDRL titers and thus are not comparable Titers are used to assess adequacy of therapy The time required for titers to decrease is variable. In general, patients with recurrent infection, high initial titers and later stages of disease, or those who are HIV infected have slower seroconversion and some may remain serofast +++ Treponemal antibody tests ++ Newer screening algorithms begin with an automated treponemal test, the EIA (enzyme immunoassay), or CLIA (chemiluminescence assay) and then follow up with a nontreponemal test (RPR or VDRL) if the treponemal test is positive Compared with traditional treponemal-specific tests, the EIAs have sensitivities of 95–100% and specificities of 99–100% A positive treponemal test with a negative RPR or VDRL may represent prior, treated syphilis, untreated latent syphilis, or a false-positive treponemal test; it should be evaluated with a second treponemal test, but interpretation of discordant results is not yet standardized Rapid treponemal tests Single test has been approved by FDA Used worldwide, particularly in limited resource settings Sensitivity ranges from 62% to 100% and specificity from 83% to 95% Polymerase chain reaction (PCR) In the United States, there are no FDA-approved PCR kits for T pallidum However, it is available as a laboratory developed test in select research, referral, and public health laboratories Has the highest yield in primary and secondary lesions There are no standards for these tests, but PCR has many advantages as a tool for direct detection, including high sensitivity and ability to use a wide range of clinical specimen types, including cerebrospinal fluid Testing of blood has low sensitivity and is not recommended; the exception is for evaluation of congenital syphilis The TPPA test has traditionally been one of the most commonly used treponemal tests, along with the fluorescent treponemal antibody absorption test (FTA-ABS). These tests help determine whether a positive nontreponemal antibody test is false-positive or is indicative of syphilis Results are positive in most patients with primary syphilis and in almost all patients with secondary syphilis False-positive tests occur rarely in systemic lupus erythematosus and in other disorders associated with increased levels of γ-globulins Lyme disease may cause a false-positive treponemal test but rarely causes a false-positive nontreponemal test +++ Diagnostic Procedures ++ Darkfield microscopic examination May show T pallidum in fresh exudate from moist lesions or aspirated material from regional lymph nodes in primary or secondary syphilis Not recommended for oral lesions due to presence of non-pathogenic treponemes in the mouth Immunofluorescent staining for T pallidum of dried smears of fluid taken from early lesions has replaced darkfield microscopy in most laboratories because of its simplicity and convenience Cerebrospinal fluid (CSF) findings in neurosyphilis include Elevated total protein Positive CSF VDRL However, CSF may be normal and VDRL may be negative CSF FTA-ABS is sometimes used It is a highly sensitive test but lacks specificity A high serum titer of FTA-ABS may result in a positive CSF titer in the absence of neurosyphilis + Treatment Download Section PDF Listen +++ +++ Medications ++ See Table 34–3 Ceftriaxone Limited data available Optimum dose and duration not well defined Azithromycin has been shown to be effective, but should be used with caution and not at all in MSM due to demonstrated resistance ++Table Graphic Jump LocationTable 34–3.Recommended treatment for syphilis.1View Table||Download (.pdf) Table 34–3. Recommended treatment for syphilis.1 Stage of Syphilis Treatment Alternative2 Comment Early Primary, secondary, or early latent Benzathine penicillin G 2.4 million units intramuscularly once Doxycycline 100 mg orally twice daily for 14 days or Tetracycline 500 mg orally four times daily for 14 days or Ceftriaxone 1 g intramuscularly or intravenously daily for 8–10 days3 Late Late latent or uncertain duration Benzathine penicillin G 2.4 million units intramuscularly weekly for 3 weeks Doxycycline 100 mg orally twice daily for 28 days or Tetracycline 500 mg orally four times daily for 28 days No routine CSF evaluation unless neurologic, otologic, or ocular changes Tertiary without neurosyphilis Benzathine penicillin G 2.4 million units intramuscularly weekly for 3 weeks Doxycycline 100 mg orally twice daily for 28 days or Tetracycline 500 mg orally four times daily for 28 days CSF evaluation recommended in all patients Neurosyphilis Aqueous penicillin G 18–24 million units intravenously daily, given every 3–4 hours or as continuous infusion for 10–14 days Procaine penicillin, 2.4 million units intramuscularly daily with probenecid 500 mg orally four times daily for 10–14 days or Ceftriaxone 2 g intramuscularly or intravenously daily for 10–14 days Follow treatment with benzathine penicillin G 2.4 million units intramuscularly weekly for up to 3 weeks 1Penicillin is the only documented effective treatment in pregnancy; pregnant patients with true allergy should be desensitized and treated with penicillin according to stage of disease as above.2Patients treated with alternative therapies require close clinical and serologic monitoring.3Fewer data for ceftriaxone treatment; optimal dose or duration not known.CSF, cerebrospinal fluid +++ Primary, secondary, or early latent ++ Benzathine penicillin G 2.4 million units intramuscularly once; only option for pregnant women Alternatives Doxycycline, 100 mg orally twice daily for 14 days Tetracycline, 500 mg orally four times daily for 28 days Ceftriaxone 1 g intramuscularly daily for 8–10 days +++ Late latent or uncertain duration ++ Benzathine penicillin G 2.4 million units intramuscularly weekly for 3 weeks Alternatives Doxycycline, 100 mg orally twice daily for 28 days Tetracycline, 500 mg orally four times a day for 28 days +++ Tertiary without neurosyphilis ++ Benzathine penicillin G 2.4 million units intramuscularly weekly for 3 weeks Alternatives Doxycycline, 100 mg orally twice daily for 28 days Tetracycline, 500 mg orally four times a day for 28 days +++ Neurosyphilis ++ Table 34–3 Aqueous penicillin G 18–24 million units intravenously daily, given every 3–4 hours or as continuous infusion for 10–14 days 2.4 million units of benzathine penicillin G intramuscularly once weekly for 1–3 weeks at the conclusion of the intravenous treatment is recommended, since the 10- to 14-day treatment course for neurosyphilis is less than the 21 days Alternatives Procaine penicillin, 2.4 million units intramuscularly daily with probenecid 500 mg orally four times a day for 10–14 days Ceftriaxone 2 g intramuscularly daily for 10–14 days + Outcome Download Section PDF Listen +++ +++ Follow-Up ++ Counsel patients to abstain from sexual activity until rendered noninfectious by antibiotic therapy +++ Primary, secondary, early latent syphilis ++ Reexamine clinically and serologically at 6-month intervals In HIV-uninfected patients, a repeat HIV test should be obtained (all patients with syphilis who are not known to be HIV-infected should have an HIV test at the time of diagnosis) Consider lumbar puncture If careful follow-up cannot be ensured, repeat treatment with benzathine penicillin G 2.4 million units intramuscularly weekly for 3 weeks +++ Latent syphilis ++ Repeat serologies at 6, 12, and 24 months +++ Neurosyphilis ++ Repeat lumbar puncture every 6 months If CSF cell count has not decreased by 6 months or is not normal at 2 years, give second course of treatment +++ Complications ++ Jarisch-Herxheimer reaction Manifests as fever and aggravation of the clinical picture Usually begins within first 24 h of treatment and subsides within next 24 h Treatment should not be discontinued unless symptoms become severe or threaten to be fatal or syphilitic laryngitis, auditory neuritis, or labyrinthitis is present May be blunted by simultaneous administration of antipyretics, although no proved method exists +++ Prevention ++ MSM should be screened every 6–12 months; high-risk individuals should be screened as often as every 3 months Pregnant women should be screened at the first prenatal visit and again in the third trimester; a third screen at delivery should be performed if there are risk indicators Patients treated for other sexually transmitted diseases should also be tested for syphilis Persons who have known or suspected sexual contact with patients who have syphilis should be evaluated and presumptively treated to abort development of infectious syphilis +++ Prognosis ++ The lesions associated with primary and secondary syphilis are self-limiting, even without treatment, and resolve with few or no residua Ocular and otologic syphilis has been associated with permanent vision and hearing loss Tertiary and congenital syphilis may be highly destructive, permanently disabling, and may lead to death +++ When to Refer ++ If uncertain about interpretation of serologic tests, need for lumbar puncture, or optimal therapy, or if patient has severe penicillin allergy Early (infectious) syphilis cases may be contacted for partner notification and treatment by local public health authorities +++ When to Admit ++ Admit for complications (eg, stroke, meningoencephalitis, dementia) or for observation for Jarisch-Herxheimer reaction + References Download Section PDF Listen +++ + +Hook EW 3rd. Syphilis. Lancet. 2017 Apr 15;389(10078):1550–7. [PubMed: 27993382] + +Molina JM et al. Post-exposure prophylaxis with doxycycline to prevent sexually transmitted infections in men who have sex with men: an open-label randomised substudy of the ANRS IPERGAY trial. Lancet Infect Dis. 2018 Mar;18(3):308–17. [PubMed: 29229440] + +Ropper AH. Neurosyphilis. N Engl J Med. 2019 Oct 3;381(14):1358–63. [PubMed: 31577877] + +Workowski KA et al; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015 Jun 5;64(RR-03):1–137. Erratum in: MMWR Recomm Rep. 2015 Aug 28;64(33):924. [PubMed: 26042815] + +World Health Organization (WHO). WHO guidelines for the treatment of Treponema pallidum (syphilis). Geneva; 2016. [PubMed: 27631046]