Syphilis

Background

Syphilis is a sexually transmitted disease (STD) caused by the spirochete Treponema pallidum. It is a complex disease with protean variations that can mimic many common infections or illnesses. HIV infection may alter the natural history and management of syphilis, causing a more rapid course of illness, higher risk of neurologic complications, and potentially greater risk of treatment failure with standard regimens. Because many individuals with syphilis have no symptoms, or have symptoms that subside without treatment, sexually active individuals at risk of syphilis should receive regular screening for syphilis, as well as for other STDs. Many clinicians strongly recommend routine syphilis testing every 3-6 months for patients at risk of syphilis.

There has been a resurgence of syphilis in the United States, particularly among gay men and other men who have sex with men (MSM). Th is trend is concerning, because syphilis can have major health consequences if it is undetected and untreated, and because it is associated with increased risk of new HIV infections. Risk assessment should be conducted at each patient visit for unprotected sex (including oral, anal, and vaginal sex), multiple sex partners, and use of recreational drugs (methamphetamine and cocaine, in particular, are associated with high-risk sexual practices among MSM). Sexually active persons with HIV who are at risk of acquiring syphilis should be screened annually (with rapid plasma reagin [RPR] or Venereal Disease Research Laboratory [VDRL] testing, as discussed below). MSM with multiple partners should be tested every 3-6 months.

The natural history of untreated syphilis infection is divided into stages based on length of infection.

Primary Syphilis

Primary syphilis usually manifests after an incubation period of 1-3 weeks from exposure and is characterized by a painless self-limiting ulcer (chancre) at the site of sexual contact, although the organism disseminates shortly after exposure via the lymphatics to the bloodstream and beyond. HIV-infected individuals often have multiple or atypical syphilitic lesions that could be misidentified. Some patients have no primary lesion, or have a primary lesion that is not visible. Associated regional lymphadenopathy can occur. Without treatment, the primary lesion generally lasts a few days to a few weeks. Individuals sometimes have a resolving chancre concurrently with a rash of secondary syphilis.

Secondary Syphilis

Secondary syphilis usually develops 2-8 weeks after initial infection and is caused by ongoing replication of the spirochete at disseminated sites of infection that may involve multiple organ systems but most commonly involves the skin and mucous membranes. Rash is the most common presenting symptom; skin lesions may be macular, maculopapular, papular, or pustular, or they may appear as condyloma lata (which may look like condyloma acuminata caused by human papillomavirus). The rash often appears on the trunk and extremities and may involve the palms and soles of feet. Constitutional symptoms, lymphadenopathy, arthralgias, and myalgias are common and neurologic or other symptoms may occur. In the absence of treatment, the manifestations of secondary syphilis last days to weeks, then usually resolve to the latent stages.

Latent Syphilis

Latent syphilis follows resolution of secondary syphilis. As in HIV-uninfected individuals, latent syphilis is asymptomatic and the diagnosis is determined by positive serologic tests. Latent syphilis is further classified as "early latent" if the infection is known to be <1 year in duration, "late latent" if the infection is known to be >1 year in duration, or "latent syphilis of unknown duration" if the duration of infection is not known.

Late or Tertiary Syphilis

Late or tertiary syphilis is caused by chronic infection with progressive disease in any system causing serious illness and death in untreated patients. The most common manifestations include cardiovascular syphilis, gummatous syphilis, and the late forms of neurosyphilis (tabes dorsalis and general paresis) (see the "Neurosyphilis" section, below).

Neurosyphilis

Neurosyphilis can occur at any time after initial infection, owing to early spread of the spirochete to the central nervous system (CNS) in approximately 30% to 40% of patients. The vast majority of these patients have no neurologic signs or symptoms and clear this site of infection. The early forms of neurosyphilis occur within weeks to a few years after infection, including during the secondary stage of syphilis. The earliest form is syphilitic meningitis, which causes cranial nerve abnormalities (particularly extraocular or facial muscle palsies causing visual changes and facial weakness, tinnitus, and hearing loss) and/or mild meningitis symptoms. The second form of early neurosyphilis is meningovascular syphilis, which presents with stuttering stroke symptoms owing to increasing inflammation of the cerebral arteries causing intermittent occlusion. Ocular syphilis (uveitis, retinitis, retinal detachment, and other eye abnormalities) may occur early after infection with or without the early forms of neurosyphilis. Although these early forms of neurosyphilis, including ocular syphilis, occur in patients without HIV, they may be more common in HIV-infected individuals.

S: Subjective

Symptoms depend on the site of initial infection, the stage of disease, and whether neurosyphilis is present. Symptoms are not present in most patients.

If symptoms are present, the patient may experience the following:

• Painless sore(s), ulcer(s), or abnormal lesions in the genital area, vagina, anus, or oral cavity
• New rash, usually on the trunk, often on extremities, soles of the feet, or palms
• Wart-like growths, mucus patches, or patchy hair loss
• Fever, malaise, swollen glands, arthralgias, myalgias
• Neurosyphilis: vision changes, eye pain, tinnitus, hearing loss, headaches, dizziness, facial weakness, motor or sensory loss, altered mental status, changes in personality or affect, lightning-rod pains in the lower extremities

Conduct a targeted history of patients at risk of syphilis, those who are contacts to a case, or those with positive syphilis serologies, asking about symptoms listed above, including duration; inquire about other or associated symptoms. Ascertain the following:

• Previous diagnosis of syphilis, stage, treatment, and last titer result
• New sex partners in past 90 days (for primary or secondary syphilis)
• Date of last negative syphilis test, and where obtained
• Pregnancy status

O: Objective

Check for fever, document other vital signs.

Perform a complete examination including the following:

• Skin and mucosal areas (including the palms and soles, genitals, perianal area): chancre/ulcers, abnormal lesions, rash, condyloma lata, patchy hair loss
• Oropharynx: chancres, mucus patches, condyloma lata
• Lymph nodes
• Heart: murmurs
• Ophthalmic examination (including slit-lamp examination for persons with ocular complaints; uveitis, retinitis, retinal detachment)
• Neurologic examination (mental status, cranial nerves [including visual acuity], sensory, motor, reflexes, coordination, gait): abnormal mental status, visual acuity changes, extraocular movement abnormalities, neurosensory hearing loss, facial palsy, paraesthesias, sensory motor loss, hyperactive reflexes, ataxia

A: Assessment

Because syphilis has a wide range of manifestations, the differential diagnosis is broad. It is important to consider syphilis as a possible cause of many presenting illnesses. A partial differential diagnosis includes the following:

• Other causes of maculopapular rashes: pityriasis, tinea versicolor, drug eruption, folliculitis, scabies, psoriasis, acute HIV infection
• Other causes of genital ulcerative disease: herpes simplex virus (HSV), chancroid, trauma, other skin infections (e.g., those caused by Staphylococcus or Candida)
• Other causes of ocular disease; cytomegalovirus (CMV) retinitis, CMV immune reconstitution uveitis, HSV keratitis
• Other causes of neurologic disease: Bell palsy, CNS lymphoma, toxoplasmosis, other causes of meningitis, stroke
• Other causes of systemic symptoms (e.g., fever, malaise, adenopathy): acute HIV infection, acute hepatitis, other infections or malignancies

P: Plan

Diagnostic Evaluation

Darkfield examination and direct fluorescent antibody

Darkfield examination, direct fluorescent antibody (DFA), or polymerase chain reaction (PCR) testing of a sample from suspicious genital or anal chancres or moist dermatologic lesions (not oral lesions) are definitive tests for syphilis, although these are not available in most clinic settings.

Serologic tests

Nontreponemal tests (RPR or VDRL) may yet to be reactive in primary and secondary syphilis; treponemal tests may be slightly more sensitive and should be ordered if the nontreponemal test result is negative in a patient with signs or symptoms suggestive of primary or secondary syphilis. Because false-positive results may occur, particularly in the setting of HIV infection, positive nontreponemal test results must be confirmed with a treponemal test. Titers on the day of treatment should be used to follow response to treatment; a fourfold change in titer is considered a significant change. Although fluctuating titers after treatment in HIV-infected patients have been seen, a sustained (>2 weeks) fourfold increase in titer raises concerns about reinfection or treatment failure. Note that the same nontreponemal test should be used consistently for a single patient; RPR titers cannot be compared with VDRL titers.

Treponemal antibody tests (TP-PA [T. pallidum particle agglutination], EIA [enzyme immunoassay], or CIA [chemiluminescence immunoassay]) confirm a positive nontreponemal test. Many high-volume laboratories have begun to use a treponemal test as an initial screen for syphilis infection, followed by a quantitative nontreponemal test, to reduce the workload from the titration required for nontreponemal titers. The FTA-ABS (fluorescent treponemal antibody absorption) may lack specificity and is no longer recommended as the gold standard treponemal test.

A false-negative RPR or VDRL result may occur, usually when the test is performed in early infection, before a sufficient antibody response has developed. Another possible cause of a false-negative nontreponemal result is the prozone phenomenon, seen when antibody concentrations are very high (usually in secondary syphilis) and the specimen is not diluted sufficiently. If serologic test results are negative and suspicion of syphilis is high, request that the laboratory perform additional dilutions on nontreponemal test specimens; if the diluted sera is nonreactive, then perform other diagnostic tests (e.g., biopsy).

Cerebrospinal fluid evaluation

HIV-infected patients with neurologic or ocular signs or symptoms of syphilis or tertiary syphilis should undergo lumbar puncture (LP) and cerebrospinal fluid (CSF) analysis. CSF evaluation also is indicated for patients in whom treatment for early syphilis fails (see below). Routine CSF evaluation is not indicated for HIV-infected patients who have syphilis without neurologic or ophthalmic signs or symptoms. CSF analysis should include the following:

• CSF-VDRL: This test is specific but not very sensitive; a positive result is diagnostic but a negative result does not rule out neurosyphilis.
• Leukocytes: Elevated white blood cell count (>10 cells/µL) is suggestive but not specific. Note that mononuclear pleocytosis (up to 5-20 cells/µL) is not uncommon in patients with HIV infection, particularly those with higher CD4 cell counts; a threshhold of >20 cells/µL may improve the specificity of the neurosyphilis diagnosis.
• Some recommend checking CSF FTA-ABS. This is very sensitive but not very specific; a negative result indicates that neurosyphilis is highly unlikely.

Other testing

All patients who test positive for syphilis should be tested for gonorrhea and chlamydia, with sampling sites based on sexual practices and exposures (oropharyngeal, urethral, cervical or vaginal, or anorectal testing). Patients not known to be HIV infected also should be tested for HIV.

Treatment

Treatment of syphilis in HIV-infected individuals essentially is the same as in HIV-uninfected individuals, and depends on stage and the presence or absence of neurosyphilis. It is important to follow patients closely to assure the success of treatment. For further information, see the Centers for Disease Control and Prevention (CDC) Sexually Transmitted Diseases Treatment Guidelines (see "References," below).

An RPR or VDRL test should be sent on the day of treatment; the titer will be the reference point for assessing treatment efficacy (see "Follow-Up," below).

Early syphilis

(<1 year in duration [i.e., primary, secondary, and early latent]; no neurologic signs or symptoms)

• Recommended: benzathine penicillin G, 2.4 million units IM (single dose)
• Alternatives: note that penicillin is strongly preferred; consider allergy testing and desensitization to penicillin; in penicillin-allergic, nonpregnant patients, consider the following; note that these therapies are not as well proven in HIV-infected individuals; close monitoring for treatment response is recommended
  • Doxycycline, 100 mg PO BID for 14 days
  • Tetracycline, 500 mg PO QID for 14 days
  • Ceftriaxone, 1 g IM or IV once daily for 10-14 days
• Treatment failures have been reported in patients treated with azithromycin (2 g, single dose); this regimen is not recommended in MSM or pregnant women, and treatment efficacy has not been studied in HIV-infected individuals.

Late latent syphilis

(>1 year in duration or of unknown duration; no neurologic signs or symptoms)

• Recommended: benzathine penicillin G, 2.4 million units IM weekly for 3 consecutive weeks (7.2 million units in total)
• In penicillin-allergic clients, refer for desensitization to penicillin. As an alternative, some specialists consider doxycycline 100 mg PO BID for 28 days, although efficacy in HIV-infected individuals is not proven. Referral to infectious disease specialist and close clinical monitoring are required.

Tertiary syphilis

Consult with specialists.

Neurosyphilis

(syphilis at any stage with neurologic or ocular symptoms, or CSF abnormalities consistent with neurosyphilis in patients who fail treatment)

Ideally, patients should be hospitalized and given 2 weeks of penicillin IV under close observation. Penicillin-allergic patients should be referred for desensitization, if possible.

• Recommended: aqueous crystalline penicillin G, 18-24 million units IV per day (3-4 million units Q4H [or continuous infusion] for 10-14 days).
• Alternatives (require strict adherence with therapy):
  • Procaine penicillin 2.4 million units IM per day, plus probenecid 500 mg PO QID, both for 10-14 days
  • Some experts consider use of ceftriaxone 2 g IM or IV once daily for 10-14 days with close clinical monitoring
• Most experts recommend administration of benzathine penicillin, 2.4 million units IM weekly for 3 weeks, after completion of the standard 10- to 14-day course of therapy for neurosyphilis.
• Recheck CSF leukocyte count every 6 months until the cell count normalizes (if CSF pleocytosis was present at initial evaluation). If the leukocyte count is not lower at 6 months, consider retreatment (consult with a specialist). Normalization of serum RPR may predict normalization of CSF parameters.

Note that a Jarisch-Herxheimer reaction may occur after initial syphilis treatment, especially in primary, secondary, or even latent syphilis. This self-limited treatment effect should not be confused with an allergic reaction to penicillin. It usually begins 2-8 hours after the first dose of penicillin and consists of fever, chills, arthralgias, malaise, tender lymphadenopathy, and intensification of rash. It resolves within 24 hours and is best treated with rest and acetaminophen. Patients should be warned about the possibility of a Jarisch-Herxheimer reaction.

Pregnancy

Pregnant women should be treated with penicillin, using a regimen appropriate for the stage of infection (see above). Additional treatment may be indicated in early syphilis; consult with a specialist. Penicillin-allergic pregnant women should be referred for desensitization to penicillin. Doxycycline and tetracycline may cause fetal toxicity and should not be used during pregnancy. Azithromycin and erythromycin do not have adequate efficacy in treating pregnant women or their fetuses and should not be used. The efficacy of ceftriaxone during pregnancy has not been studied adequately.

Women treated during the second half of pregnancy are at risk of contractions, early labor, and fetal distress if they develop a Jarisch-Herxheimer reaction; thus, they should be advised to seek obstetric attention if they develop fever or contractions, or note a decrease in fetal movement.

Sex partners

Syphilis is transmitted sexually only when mucocutaneous lesions of syphilis are present; this is uncommon after the first year of infection. Nevertheless, sex partners of a patient who has syphilis in any stage should be evaluated. For patients with primary syphilis, that means partners within the previous 3 months plus the duration of the lesion; for patients with secondary syphilis, partners within the previous 6 months plus the duration of signs; for patients with early latent syphilis, partners within the past 1 year.

• Persons exposed within 90 days preceding the diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, as they may be infected with syphilis even if they are seronegative.
• Persons exposed more than 90 days before the diagnosis of primary, secondary, or early latent syphilis should be treated presumptively if serologic test results are not available immediately and their follow-up is in doubt. Otherwise, they should receive serologic testing and be treated appropriately if the test result is positive.

Follow-Up

All HIV-infected patients treated for early syphilis should be evaluated clinically and serologically at 3, 6, 9, 12, and 24 months (at 6, 12, 18, and 24 months for latent syphilis) to rule out treatment failure. Treatment success is determined by a fourfold decrease in RPR or VDRL titer by 6-12 months (for primary and secondary syphilis) or 12-24 months (for latent syphilis) of treatment. Patients whose titers do not decrease appropriately could have experienced treatment failure or may have been reinfected. Any patient with apparent treatment failure should undergo an LP for CSF analysis and be re-treated as appropriate.

Some patients retain reactive (low-titer) nontreponemal test results after successful treatment for syphilis. In these "serofast" individuals, reinfection with syphilis is indicated by a rise in test titer of at least fourfold. If, at any time, a sustained fourfold increase (lasting >2 weeks) in nontreponemal test titers occurs and reinfection is unlikely, CSF examination should be performed and appropriate treatment should be given. For patients with persistently high or fluctuating titers after CSF examination and appropriate re-treatment, consult with a specialist.

Risk-reduction counseling

All patients with syphilis should receive risk evaluation and risk-reduction counseling. Evaluate each patient's sexual practices with regard to risk of acquiring STDs and of transmitting HIV. Work with the patient to reduce sexual risks.

Patient Education

• Instruct patients to go to clinic for treatment at the intervals recommended. If patients are given oral antibiotics (penicillin-allergic individuals), instruct them to take their medications exactly as prescribed.
• Warn patients about the possibility of a Jarisch-Herxheimer reaction and advise them about self-management of associated symptoms (e.g., acetaminophen or aspirin at usual doses, fluids, and rest).
• Instruct patients about the required follow-up laboratory and clinical evaluations necessary to document adequate treatment. Emphasize the need for regular evaluation of treatment efficacy.
• Sex partners from the previous 3-6 months (sometimes longer, depending on the stage of syphilis) need to be evaluated and treated as soon as possible, even if they have no symptoms. Advise patients to inform their partners that they need to be tested and treated. Ask patients whether they would like assistance with partner notification and refer to the local health department for partner services, if available.
• Syphilis is a reportable communicable disease in the United States. Inform patients that they may be contacted to verify adequate treatment and assist with partner notification and treatment.
• Provide education about sexual risk reduction. Review sexual practices and support patients in using condoms with every sexual contact to prevent becoming reinfected with syphilis or infected with other STDs, and to prevent passing HIV to sex partners.

References

• Centers for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. April 10, 2009.
• Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2010. MMWR 2010 Dec 17; 59 (No. RR-12):1-110.
• Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA. 2003 Sep 17;290(11):1510-4.
• Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis. 2004 Feb 1;189(3):369-76.
• Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis. 2004 Apr 1;38(7):1001-6.
• Mitchell SJ, Engelman J, Kent CK, et al. Azithromycin-resistant syphilis infection: San Francisco, California, 2000-2004. Clin Infect Dis. 2006 Feb 1;42(3):337-45.
• Paz-Bailey G, Meyers A, Blank S, et al. A case-control study of syphilis among men who have sex with men in New York City: association with HIV infection. Sex Transm Dis. 2004 Oct;31(10):581-7.
• Peterman TA, Heffelfinger JD, Swint EB, et al. The changing epidemiology of syphilis. Sex Transm Dis. 2005 Oct;32(10 Suppl):S4-10.
• Pope V. Use of treponemal tests to screen for syphilis. Infect Med. 2004 21(8); 399-404.
• Stolte IG, Dukers NH, de Wit JB, et al. Increase in sexually transmitted infections among homosexual men in Amsterdam in relation to HAART. Sex Transm Infect. 2001 Jun;77(3):184-6.
• Torian LV, Makki HA, Menzies IB, et al. HIV infection in men who have sex with men, New York City Department of Health sexually transmitted disease clinics, 1990-1999: a decade of serosurveillance finds that racial disparities and associations between HIV and gonorrhea persist. Sex Transm Dis. 2002 Feb;29(2):73-8.