AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Syphilis is an infectious disease caused by the spirochete Treponema pallidum. It almost always is transmitted by sexual contact with infectious lesions, but it also can be transmitted in utero and via blood transfusion.

Syphilis has a myriad of presentations and can mimic many other infections and immune-mediated processes in advanced stages. Hence, it has earned the nickname "the great imposter." The complex and variable manifestations of the disease prompted Sir William Osler to remark that, "The physician who knows syphilis knows medicine."

Pathophysiology

T pallidum is a fragile spiral bacterium 6-15 micrometers long by 0.25 micrometers in diameter. It can survive only briefly outside of the body; thus transmission almost always requires direct contact with the infectious lesion(s).

T pallidum penetrates abraded skin or intact mucous membranes easily and disseminates rapidly, although asymptomatically, via the blood vessels and lymphatics.

The prominent histologic features of the human response to the presence of T pallidum are vascular changes with associated endarteritis and periarteritis. Additionally, chronic infection can result in granulomatous lesions called gummas.

The initial lesion of primary syphilis develops at the site of transmission after an incubation period of 10-90 days, with a mean of about 21-28 days, and then heals spontaneously in 3-7 weeks.

Secondary syphilis develops about 4-10 weeks after the appearance of the primary lesion and has a wide range of presentations. The most common systemic manifestations include malaise, fever, myalgias, and arthralgias with a generalized body rash and lymphadenopathy. These manifestations are termed the dermatitis-arthritis syndrome. During secondary infection, the immune reaction is at its peak and antibody titers are high.

Symptomatic secondary syphilis usually resolves without treatment. The disease then enters a latent stage that may be divided into early and late latent phases. Early latent syphilis is defined as follows: acquired syphilis within the preceding year, that is, (1) documented seroconversion; (2) unequivocal symptoms of primary or secondary syphilis; or (3) partner documented with primary, secondary, or early latent syphilis. Occasional relapses of active secondary lesions can occur. Late latent syphilis is defined as seroreactivity, in the absence of symptoms, greater than 2 years after inoculation. During the late latent stage, patients typically do not have infectious lesions. Tertiary syphilis is defined as seroreactivity greater than 2 years with symptoms. This can include all organ systems and, as alluded to earlier, manifests in many ways. As many as 40% of untreated infections can develop into tertiary disease.

Congenital syphilis is not addressed in this article.

Frequency

United States

Incidence of primary and secondary syphilis was about 100,000 cases in 1941 when reporting first began. Incidence declined steadily with the advent of antibiotic therapy to less than 10,000 cases by 1956. Over the next 25 years, the incidence of syphilis rose to about 35,000 by the early 1980s and then began to decrease again because of safer sexual practices associated with the AIDS epidemic of the 1980s. In 1990, 45,000 cases were reported. The incidence then declined to 16,500 in 1995 and went on to a brief nadir in 2000. Steadily, however, the incidence has increased, perhaps secondary to a nation wide effort by the Centers for Disease Control and Prevention (CDC) to irradicate the disease from the United States, which has led to better identification and reporting. In 2004, the overall incidence was 7,980 cases. The South continued to have the highest rates than any other region in the United States at 3.6 per 100,000.

Mortality/Morbidity

Mortality from syphilis can occur, but it is most likely due to complications of late disease. In this stage, death may result in approximately 20% of untreated patients.

Morbidity of primary and secondary syphilis ranges from the annoyance of the primary lesion to the more significant constitutional systemic symptoms of secondary syphilis. However, the progression to tertiary syphilis can result in serious permanent disability and sometimes death.

T pallidum is sensitive to penicillins and is easily treatable in the early stages.

Race

The disease still disproportionately affects black men, but the frequency of infections in blacks and whites has changed from, at one time 65:1 to currently 6:1 (black-to-white ratio).

The lowest incidence is among Native Americans.

Sex

Recent increases in incidence reflect new infections primarily among men. The ratio of male-to-female infections has risen from 1.2 in 1996 to 11.6 in 2004, suggesting that cases of men who have sex with men is primarily on the rise.

Some studies suggest that women with suspected sexually transmitted diseases (STDs) are screened for syphilis less often than men. This raises concerns about underdiagnosis in women.

High-risk groups include men having sex with men, inmates in correctional facilities, and those engaging in high-risk sexual activity.

Age

Syphilis is most common during the years of peak sexual activity. However, increased numbers of elderly persons are being diagnosed, presumably because of drugs that enable sexual activity among this age group.

• Most new cases occur in both men and women aged 15-39 years, with the highest infection rates in persons aged 20-29 years.
• Since latent syphilis can persist for years or decades, the manifestations of tertiary syphilis often occur much later in life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Since the manifestations of syphilis (particularly advanced syphilis) are nonspecific and may masquerade as many other diseases, the physician must keep a high index of suspicion regarding the possible diagnosis of syphilis during the workup.

The clinician should carefully reconstruct the time course and description of all symptoms and lesions and obtain a complete sexual history, including information about condom use and the number and symptomatology of all partners.

The United States Preventive Services Task Force (USPSTF) issued screening guidelines to include all pregnant women and people at risk of acquiring syphilis.

• Primary syphilis
• • Genital chancre - "Painless" until examined, then may be tender
  • Frequently solitary, may be multiple (Sometimes seen as "kissing" lesions on opposing skin surfaces, for example the labia.)
• Patchy alopecia
• Secondary syphilis
• • Rash - Bilaterally symmetric
  • Asymptomatic
  • Positive serology
• Tertiary syphilis
• • Mental status may be altered.
  • Patients may have symptoms related to the cardiovascular, musculoskeletal, or central nervous systems.
  • Serologic findings are often negative.

Physical

Conduct the physical examination with the manifestations of primary, secondary, and tertiary syphilis in mind. The lesions and exanthem of primary and secondary syphilis are infectious, thus, gloves must be worn.

• Primary syphilis
• • The chancre of primary syphilis usually begins as a single, painless papule that rapidly becomes eroded and indurated. The ulcer has a cartilaginous consistency at the edge and base.
  • Chancres usually are located on the penis in heterosexual men, but in homosexual men may be found in the anal canal, mouth, or external genitalia. Common primary sites in women include the cervix and labia.
  • Atypical primary lesions are common and may manifest as a papular lesion without subsequent ulceration or induration.
  • The primary lesion usually is associated with regional lymphadenopathy that may be unilateral or bilateral. Inguinal adenitis is usually discrete, firm, mobile, and painless, without overlying skin changes.
• Secondary syphilis
• • Secondary syphilis may present in many different ways but usually includes a localized or diffuse mucocutaneous rash and generalized nontender lymphadenopathy. The exanthem may be macular, papular, pustular, or mixed.
  • Typical early lesions are usually less than 20, round, discrete, nonpruritic, and symmetric macules distributed on the trunk and proximal extremities. Red papular lesions also may appear on the palms, soles, face, and scalp and may become necrotic. Patchy and nonpatchy alopecia may occur. In intertriginous areas, papules may coalesce to form highly infectious lesions called condylomata lata. Lesions usually progress from red, painful, and vesicular to "gun metal grey" as the rash resolves.
  • Mucous patches are superficial mucosal erosions, usually painless, that may develop on the tongue, oral mucosa, lips, vulva, vagina, and penis.
  • Constitutional symptoms of secondary syphilis include malaise, sore throat, headache, fever, anorexia, and, rarely, meningismus.
  • Other, less common, manifestations of secondary syphilis include gastrointestinal involvement, hepatitis, nephropathy, proctitis, arthritis, and optic neuritis.
• Symptomatic tertiary syphilis is the result of a chronic, progressive inflammatory process that eventually produces clinical symptoms years to decades after the initial infection.
• Gummatous syphilis manifests as coalescent granulomatous lesions that usually affect skin, bone, and mucous membranes, but may involve any organ system. The lesions often cause local destruction of the affected organ system.
• Cardiovascular syphilis results from endarteritis of the aorta, subsequent medial necrosis, aortitis, and aneurysm formation. Other large arteries may be affected as well.
• Neurosyphilis may be asymptomatic or symptomatic. In asymptomatic neurosyphilis, no signs or symptoms are present, but cerebral spinal fluid (CSF) abnormalities are demonstrable, including possible pleocytosis, elevated protein, decreased glucose, or a reactive CSF Venereal Disease Research Laboratory (VDRL) test.
• • Symptomatic neurosyphilis may manifest as syphilitic meningitis, meningovascular syphilis, or parenchymatous neurosyphilis.
  • Syphilitic meningitis usually develops within several years of initial infection, and patients present with typical symptoms of meningitis, including headache, nausea and vomiting, and photophobia, but are typically afebrile. Patients may exhibit cranial nerve abnormalities.
  • Meningovascular syphilis manifests 5-10 years after infection and is the result of endarteritis, which affects small blood vessels of the meninges, brain, and spinal cord. Patients may present with CNS vascular insufficiency or outright stroke.
  • Parenchymatous neurosyphilis results from direct parenchymal CNS invasion by T pallidum and is usually a late development (15-20 years after primary infection).
  • Patients present with ataxia, incontinence, paresthesias, and loss of position, vibratory, pain, and temperature sensations. Paresis and dementia, with changes in personality and intellect, may develop.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Primary genital syphilitic lesion
Herpes simplex (primary and recurrent infection)
Chancroid
Traumatic superinfected lesions
Carcinoma
Mycotic infection
Granuloma inguinale
Lichen planus
Psoriasis
Fungal infection
Venereal chlamydial infections

Cutaneous eruption of secondary syphilis
Drug eruptions
Pityriasis rosea
Psoriasis
Lichen planus
Viral exanthem

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• T pallidum cannot be cultivated in vitro and is too small to be seen under the light microscope. Therefore, direct visualization of the organism by darkfield microscopy, immunofluorescent staining, or serologic testing is necessary for diagnosis of syphilis.
• • Darkfield microscopic diagnosis of oral lesions should be avoided because of the difficulty in distinguishing T pallidum morphologically from Treponema macrodentium and Treponema microdentium, 2 nonpathologic treponemes found in the mouths of healthy individuals.
  • A positive darkfield examination is the only means of making an absolute diagnosis of syphilis.
• A negative darkfield examination does not rule out the diagnosis, and the lesion should be reexamined the following day.
• The nontreponemal tests, VDRL and rapid plasma reagent (RPR), are antilipoidal antibodies seen in other disease states, pregnancy, and occasionally after vaccination. They are nonspecific and cannot rule in disease. These tests have sensitivities approaching 80% in patients with symptomatic primary syphilis and virtually 100% in patients with secondary syphilis.
• • A positive VDRL should be quantified and titers followed at regular intervals after treatment. As such, its value is in response to treatment. However, it does not correlate with symptom resolution.
  • Most patients have nonreactive nontreponemal tests within several years after successful treatment for syphilis, but a significant number have persistently positive tests, the so-called serofast reaction.
  • False-positive results may result, and no one test alone should be relied upon to make the diagnosis of syphilis.
  • Patients with a reactive VDRL or RPR should have the result confirmed by specific treponemal testing. These tests include the fluorescent treponemal antibody absorption (FTA-ABS) and the microhemagglutination assay for T pallidum (MHA-TP). These tests detect antibodies to treponemes, but other treponemal antibodies are separated from Tp antibodies during the washing phase of the reaction.
• Primary syphilis
• • Serology and darkfield microscopy or immunofluorescent staining confirms the diagnosis of syphilis.
  • Little indication exists for other routine laboratory studies in the evaluation of the lesion of primary syphilis.
• Secondary syphilis
• • The manifestations of secondary syphilis may mimic many other diseases, and laboratory evaluation should reflect the particular presentation and the concerns of the physician.
  • A complete blood count (CBC), electrolytes, erythrocyte sedimentation rate (ESR), blood cultures, and other laboratory studies may be appropriate, depending on the presentation of the patient.
• Tertiary syphilis
• • Serology and darkfield microscopy are used in diagnosis.
  • Evaluation of neurosyphilis requires a lumbar puncture (LP) and evaluation of the CSF. Obtain routine laboratory studies as necessary. The CDC currently recommends LP only if the patient is seroreactive and HIV positive, has symptoms of neurosyphilis, or is receiving treatment for neurosyphilis.

Imaging Studies

• Imaging studies should be performed depending on the organ system involved. For example, granulomatous disease can be seen on CT scan of the brain.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Emergency Department Care

Base ED care on the symptoms of the individual patient. Most patients need only supportive care in the ED; however, a patient presenting with advanced neurosyphilis may require emergent intervention, including possible intubation. The current treatment for syphilis, from the Centers for Disease Control and Prevention 1993 STD treatment guidelines, is as follows; for dosage information, see Medication section.

• Primary, secondary, and early latent syphilis ( <1 y duration)
• • Recommended treatment - Single dose of benzathine penicillin G, 2.4 million U IM
  • Alternative treatments (only for nonpregnant, penicillin-allergic patients) - 2-week course of doxycycline 100 mg PO bid, tetracycline 500 mg PO qid, or erythromycin base 500 mg PO qid. Azithromycin has been used as an alternative, but recently resistance has been reported in San Francisco. It has been suggested that penicillin-allergic patients be desensitized in order to receive standard drug therapy.
• Late latent syphilis (>1 y duration), syphilis of undetermined duration, and late syphilis
• • Recommended treatment - Benzathine penicillin G, 2.4 million U IM once weekly for 3 consecutive weeks
  • Alternative treatment - Doxycycline 100 mg PO bid or tetracycline 500 mg PO qid daily for 4 weeks
• Neurosyphilis
• • Recommended treatment - Aqueous crystalline penicillin G, 2-4 million U IV q4h for 10-14 days
  • Alternative treatment - Procaine penicillin, 2.4 million U IM qd, plus probenecid 500 mg PO qid for 10-14 days
• Inform the patient of the possibility of a Jarisch-Herxheimer reaction that may occur at the outset of treatment.
• • Patients may develop transient fever and symptoms such as malaise, chills, headache, and myalgias.
  • Existing lesions may intensify temporarily.
  • The reaction is quite common, develops within several hours after beginning antibiotic treatment, and usually clears within 24 hours.

Consultations

If the ED physician has concerns or questions about the patient's presentation or course, an infectious disease consultation is a reasonable course of action. Additionally, the CDC, WHO, and MMWR are an excellent updated references.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goal of pharmacotherapy is to eradicate the causative organism of syphilis, T pallidum. The drug of choice is parenteral penicillin G for all stages of syphilis. Since the dividing time of Tp is slow (days), penicillin G benzathine is the only penicillin effective for single-dose therapy because it is in depo form and levels remain therapeutic in the blood for up to 30 days. Avoiding Bicillin C-R (combination procaine and benzathine), which remains in blood for only 7 days, is essential.

Since T pallidum resistance to penicillin has not emerged, the primary need for alternative drugs in treating syphilis is reserved for penicillin-allergic patients. Alternative regimens recommended for penicillin-allergic patients are doxycycline, tetracycline, and erythromycin.

Although neither the tetracyclines nor erythromycin has been evaluated as extensively as penicillin G in the treatment of syphilis, some evidence suggests higher treatment failure rates in erythromycin-treated patients. Alternative treatment regimens should be used only in cases of documented penicillin allergy.

In a randomized controlled trial of 328 subjects with primary, secondary, or latent syphilis, the efficacy of a single, 2 g oral dose of azithromycin was compared to 2.4 million units of penicillin G benzathine intramuscularly. Although 52% of the study population were HIV seropositive, the cure rates were equivalent between the two drugs. Although encouraging, these results should not encourage the use of macrolides as a first-line agent because of increasing reports of macrolide resistance.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Patients treated for primary and secondary syphilis should have follow-up VDRL at 3, 6, and 12 months after treatment. Patients with HIV should be monitored closely as they are known to have more rapid progression of disease.
• • Most patients with primary syphilis who are treated adequately have a nonreactive VDRL within 1 year, and almost all patients treated for secondary syphilis have a negative VDRL result within 2 years.
  • A small minority of patients remain seropositive in spite of successful treatment.
  • Therapy is considered a failure if the signs and symptoms of syphilis return.
  • This occurs when the titer of the nontreponemal test increases 4-fold or a 4-fold decrease from the initial VDRL titer does not occur within 1 year.
• Patients with neurosyphilis should have follow-up at 6-month intervals for at least 3 years with physical examinations and CSF and serologic testing.
• Pregnant women treated for syphilis should have monthly VDRL testing for the duration of their pregnancy.

Deterrence/Prevention

• Safe sex practices
• Use of condoms

Complications

• Cardiovascular disease
• CNS disease
• Membranous glomerulonephritis
• Paroxysmal cold hemoglobinemia
• Irreversible end-organ damage
• Jarisch-Herxheimer reaction

Prognosis

• The prognosis in primary and secondary syphilis is excellent. T pallidum remains highly responsive to the penicillins and cure is likely.
• The prognosis in tertiary syphilis is less sanguine, although a significant number of patients demonstrate cure with antibiotic therapy.
• The course of untreated syphilis was investigated in the Oslo study in which 2000 patients were enrolled and over 1000 were monitored during the period from 1891-1951.
• • The mortality rate as a direct result of syphilis was about 20% in this group, with most of those deaths resulting from cardiovascular syphilis.
  • More than 60% of the subjects went through their lives with no apparent ill effects of advanced disease.
• In the 1930s, the US public health service conducted the Tuskegee study, which monitored nearly 400 African American males with syphilis over several decades and showed similar results. (This study is notorious for the moral and ethical lapses that occurred when these subjects were not treated after the development of antibiotic therapy in the early 1940s.)

Patient Education

• As with all STDs, patient education must stress the importance of safer sexual practices and the need for prompt medical evaluation of chancres and other symptoms of STDs. All patients diagnosed with an STD should be screened for HIV.
• For excellent patient education resources, visit eMedicine's Sexually Transmitted Diseases Center and Pregnancy and Reproduction Center. Also, see eMedicine's patient education articles Sexually Transmitted Diseases, Syphilis, Birth Control Overview, and Birth Control FAQs.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to conduct testing for syphilis because the lesion or rash is suggestive of another entity is the major potential pitfall in patients with syphilis.
• • Given the ability of syphilis to masquerade as a number of illnesses, routine serologic testing for syphilis is prudent when rendering a diagnosis of pityriasis rosea or another generalized rash. Similar logic applies to genital lesions.
  • If the alternative diagnosis is an STD, such as chancroid, good medical care includes testing for syphilis.
  • Regardless of the symptoms, testing for coexisting syphilis is recommended when diagnosing other STDs, such as urethritis or cervicitis. An increase in attention to this issue in women with suspected STDs is needed.

Special Concerns

• Pregnancy
• • The penicillin regimen appropriate to the stage of disease is the only treatment recommended.
  • Do not administer tetracycline or doxycycline during pregnancy.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Brillman JC, Quenzer RW. Infectious Disease in Emergency Medicine. 2nd ed. Lippincott-Raven;1998:686-92.
• CDC. Inadvertent use of Bicillin C-R to treat syphilis infection--Los Angeles, California, 1999-2004. MMWR Morb Mortal Wkly Rep. Mar 11 2005;54(9):217-9. [Medline]. [Full Text].
• Calonge N. Screening for syphilis infection: recommendation statement. Ann Fam Med. Jul-Aug 2004;2(4):362-5. [Medline]. [Full Text].
• Clinical Effectiveness Group. National guidelines for the management of early syphilis. Sex Transm Dis. 1999;75:29-33.
• Csonka GW, Oates JK. Sexually Transmitted Diseases. WB Saunders;1990:227-76.
• Department of Health and Human Services. Sexually Transmitted Diseases Surveillance 2004 Report. Syphilius Surveillance Report. 2005. [Full Text].
• Garfinkel M, Blumstein H. Gender differences in testing for syphilis in emergency department patients diagnosed with sexually transmitted diseases. J Emerg Med. Nov-Dec 1999;17(6):937-40. [Medline].
• Hoeprich PD, Jordan MC. Infectious Diseases. 4th ed. Lippincott-Raven;1989:666-83.
• Isselbacher KJ, Braunwald E, Wilson JD. Harrison's Principles of Internal Medicine. 13th ed. McGraw-Hill;1994:726-37.
• Riedner G, Rusizoka M, Todd J, et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med. Sep 22 2005;353(12):1236-44. [Medline].

Article Last Updated: Apr 24, 2006