AUTHOR INFORMATION

Section 1 of 11

Authored by Muhammad Waseem, MD, Assistant Professor of Emergency Medicine in Clinical Pediatrics, Weill Medical College of Cornell University; Consulting Staff, Department of Pediatrics, Bronx Lebanon Hospital; Consulting Staff, Department of Emergency Medicine, Lincoln Medical & Mental Health Ctr

Muhammad Waseem, MD, is a member of the following medical societies: American Academy of Pediatrics, and American Medical Association

Edited by Robert W Tolan, Jr, MD, Chief of Allergy, Immunology and Infectious Diseases, The Children's Hospital at St Peter's University Hospital, Clinical Associate Professor of Pediatrics, Drexel University College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Leslie L Barton, MD, Professor, Program Director, Department of Pediatrics, University of Arizona School of Medicine; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Russell W Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of Infectious Diseases, Louisiana State University Health Sciences Center

Author's Email:	Muhammad Waseem, MD
Editor's Email:	Robert W Tolan, Jr, MD

eMedicine Journal, February 21 2006, VOLUME 7, Number 2

INTRODUCTION

Section 2 of 11

Background: Syphilis is a communicable disease caused by Treponema pallidum, which belongs to the Spirochaetaceae family. The genus name, Treponema, is derived from the Greek term for "turning thread." Pathogenic members of this genus include T pallidum, Treponema pertenue, and Treponema carateum.

Between 1905 and 1910, Schaudinn and Hoffman identified T pallidum as the cause of syphilis, and Wasserman described a diagnostic test for the long-recognized infection. Pathogenic treponemes are associated with the following 4 diseases:

• Venereal syphilis, caused by T pallidum pallidum

• Yaws, caused by T pallidum pertenue

• Endemic syphilis (bejel), caused by T pallidum endemicum

• Pinta, caused by T carateum

The treponemes responsible for these diseases cannot be distinguished serologically, morphologically, or by genome analysis, and they have not been cultivated successfully on artificial media.

Pathophysiology: When untreated, syphilis is a lifelong infection that progresses in 3 clear, characteristic stages. After initial invasion through mucous membranes or skin, the organism multiplies rapidly and disseminates widely. The organism spreads through the perivascular lymphatics and then the systemic circulation before clinical development of the primary lesion. The primary lesion, containing infectious treponemes, arises within hours after infection and persists throughout primary and secondary disease.

Secondary lesions develop when spirochetal invasion of tissues of ectodermal origin (eg, skin, mucous membranes, CNS) precipitates an inflammatory response. These lesions develop 6-12 weeks after infection. This stage of rapid spirochete multiplication and dissemination may bring invasion of the entire body. Thus, tertiary syphilis may involve any organ system.

Secondary infection becomes latent within 1-2 months after the rash onset. Relapses with secondary manifestations can be seen during the first year of latency, a period referred to as the early latent period. Early latent syphilis (ie, duration <1 y) is when the recurrent lesions of secondary syphilis are most likely to occur. No relapses occur after the first year; what follows is late syphilis, which may be either asymptomatic (ie, late latent) or symptomatic (ie, tertiary). Late latent syphilis is associated with resistance to both reinfection and relapse.

Tertiary neurosyphilis can manifest in various ways. Meningeal syphilis rarely occurs and presents a few years following the original infection. Late neurosyphilis may present with focal ischemia of the CNS or stroke as a result of endarteritis of small blood vessels of the brain. Meningovascular syphilis can affect any part of the CNS. Actual destruction of the nerve cells in the cerebral cortex leads to a combination of psychiatric manifestations and neurologic findings.

Congenital syphilis is caused by transplacental transmission of spirochetes; the transmission rate approaches 100%. Perinatal death may result from congenital infection in more than 40% of affected, untreated pregnancies. Among survivors, manifestations traditionally have been divided into early and late stages. Manifestations are defined as early if they appear in the first 2 years of life and late if they develop after age 2 years.

Because inflammatory changes do not occur in the fetus until after the first trimester of pregnancy, organogenesis is unaffected. Nevertheless, all organ systems may be involved. With early-onset disease, manifestations result from transplacental spirochetemia and are analogous to the secondary stage of acquired syphilis. Congenital syphilis does not have a primary stage. Late-onset disease is seen in patients older than 2 years and is not considered contagious.

Frequency:

• In the US: From 1985-1990, overall syphilis incidence increased 75%. This resurgence was due primarily to increased illegal drug use (particularly crack cocaine) that was associated with an exchange of sex for drugs. Concomitant infection with human immunodeficiency virus (HIV) is also common because HIV and syphilis affect similar patient groups.

• Internationally: The disease occurs worldwide, predominantly in large cities. With the exception of the United States, syphilis is less common in developed nations.

Mortality/Morbidity: Syphilis causes untold morbidity and remains a significant cause of mortality if left untreated.

Race: Syphilis has no racial predilection, although its incidence appears to correlate with the socioeconomic factors that contribute to disease prevalence among the poor, the urban, and the overcrowded, in whom drug use and the exchange of sex for drugs may be more common.

Sex: Historically, men were more commonly infected than women; however, a study involving high-risk adolescents has reported 69% of cases involved young women, indicating that the gender distribution of syphilis is in flux.

Age: Adolescent and young adults are most at risk due to sexual and other risk-taking behaviors (eg, drug use).

CLINICAL

Section 3 of 11

History: Most recognized syphilitic disease in children is congenital. A pregnant woman with syphilis who has not received therapy or who has received inadequate therapy may transmit the infection to the fetus at any clinical stage of the disease. Assume children with acquired syphilis have been infected through sexual abuse, unless another method of transmission is identified. Syphilis, previously known as the great imitator, can have numerous and complex manifestations.

• Primary syphilis: The primary lesion, called a chancre, is painless but slightly tender. It usually develops at the site of the infection an average of 3 weeks after exposure to T pallidum. Patients may ignore a visible lesion because it is painless unless it becomes secondarily infected.



• Secondary syphilis


• • Because of the widespread dissemination of spirochetes, frequent constitutional symptoms include fever, malaise, pharyngitis, rash, anorexia, arthralgias, and generalized painless lymphadenopathy.
  
  
  
  • Renal, hepatic, and ophthalmologic manifestations may be present.
  
  
  
  • Meningitis occurs in 30% of patients with secondary syphilis but may cause no symptoms. Symptomatic aseptic meningitis occurs in 1-2% of affected patients and is characterized by headache, stiff neck, nausea, and vomiting.
  
  
  
• Tertiary syphilis


• • Tertiary neurosyphilis presents with symptoms of meningitis or with focal deficits consistent with stroke. The mnemonic device "PARESIS" is an aid to recall the following types of symptoms:
    • Personality

    • Affect

    • Reflexes (eg, hyperactive)

    • Eye (eg, Argyll Robertson pupils)

    • Sensorium (eg, illusions, delusions, hallucinations)

    • Intellect (eg, decreased recent memory, orientation, judgment, insight)

    • Speech abnormalities
  
  
  
  • Syphilis at any stage can affect ears and eyes. Such involvement may be the only presentation, and, therefore, any patient with unexplained hearing loss, vestibular abnormalities, or ocular inflammation should be tested for treponemal antibodies.
  
  
  
• Early-onset congenital syphilis


• • Most affected infants are asymptomatic at birth and are identified only by routine prenatal screening. If untreated, symptoms develop within weeks or months. The typical stillborn or highly symptomatic newborn is born prematurely with an enlarged liver and spleen, skeletal involvement, and often pneumonia and bullous skin lesions.
  
  
  
  • The earliest signs of congenital syphilis may be poor feeding and snuffles (ie, syphilitic rhinitis).
  
  
  

Physical:

• Primary syphilis


• • Primary syphilis is characterized by a painless papule at the site of inoculation that quickly erodes, leaving an ulcer (the chancre). The base of the ulcer is smooth, without exudate, and the borders are raised and firm.

  • Painless nonsuppurative enlargement of local lymph nodes accompanies the chancre and can persist for months.

  • Primary chancres heal within 3-6 weeks.
  
  
  
• Secondary syphilis


• • Mucocutaneous lesions are the most frequent signs of disease and strongly suggest the diagnosis. Discrete, macular, pink-to-red lesions are 3-10 mm in diameter and may spread to involve the entire body, including the palms, soles, and other locations.

  • Unlike the primary lesions, secondary lesions do not ulcerate. These lesions often evolve from macules into red papules and, in a few patients, finally progress to pustules.

  • Vesicular lesions conspicuously are absent.

  • Painless generalized lymphadenopathy is found in 85% of patients.

  • Broad grayish plaques called condyloma lata may be found in warm, moist, intertriginous areas.

  • Mucous patches are superficial, silver-gray erosions that occur on mucous membranes.
  
  
  
• Tertiary syphilis manifestations are divided into the following subgroups:


• • In benign tertiary syphilis, gummatous lesions are found in skin and bones but rarely in other organs. Gummas are considered benign because they rarely involve vital body structures.

  • Cardiovascular syphilis refers to aortic dilatation due to medial necrosis of the aorta; the essential signs are aortic insufficiency or saccular aneurysm of the aorta.
  
  
  
  • Meningitic tertiary neurosyphilis manifests with signs of meningitis and is differentiated from other causes of aseptic meningitis by a reactive result on a Venereal Disease Research Laboratory (VDRL) test of cerebrospinal fluid (CSF); this test is termed a CSF VDRL.
  
  
  
  • Late neurosyphilis may present with focal neurological findings suggestive of a stroke.
  
  
  
• Early-onset congenital syphilis


• • Early manifestations of congenital infection are varied and involve multiple organ systems. The most striking lesions affect the mucocutaneous tissues and bones. Mucous patches, rhinitis, and condylomatous lesions are highly characteristic features of mucous membrane involvement in congenital syphilis.
  
  
  
  • Nasal fluid is highly infectious. Snuffles are followed quickly by a diffuse maculopapular desquamative rash that involves extensive sloughing of the epithelium, particularly on the palms and soles and about the mouth and anus. In contrast to acquired syphilis, a vesicular rash and bullae may develop. These lesions are highly infectious.
  
  
  
  • Hepatomegaly is reported in almost 100% of cases, and biochemical evidence of liver dysfunction usually is observed.
  
  
  
• Late-onset congenital syphilis


• • Scarring from the early systemic disease causes late manifestations of congenital syphilis.
  
  
  
  • Manifestations include neurosyphilis and involvement of the teeth, bones, eyes, and the eighth cranial nerve.
  
  
  

Causes: Syphilis transmission usually occurs transplacentally or by sexual contact. Vertical transmission of early syphilis during pregnancy results in a congenital infection in at least 50-80% of exposed neonates. Other modes of transmission include contact with contaminated blood or infected tissues. Children encounter 2 forms of syphilis: acquired syphilis, transmitted almost exclusively by sexual contact, and congenital syphilis, which results from transplacental transmission of spirochetes.

DIFFERENTIALS

Section 4 of 11

Acropustulosis
Afebrile Pneumonia Syndrome
Atypical Mycobacterial Infection
Bacteremia
Candidiasis
Cervicitis
Child Abuse & Neglect: Sexual Abuse
Chlamydial Infections
Chorioretinitis
Enteroviral Infections
Erythema Toxicum
Fulminant Hepatic Failure
Gonorrhea
Herpes Simplex Virus Infection
Human Immunodeficiency Virus Infection
Jaundice, Neonatal
Leptospirosis
Listeria Infection
Lyme Disease
Lymphadenopathy
Measles
Meningitis, Aseptic
Meningitis, Bacterial
Myocarditis, Nonviral
Myocarditis, Viral
Parvovirus B19 Infection
Pharyngitis
Pneumonia
Rhinovirus Infection
Rubella
Splenomegaly
Sporotrichosis
Streptococcal Infection, Group A
Thrush
Tuberculosis
Tularemia
Varicella

Other Problems to be Considered:

Anthrax
Bejel
Granuloma inguinale
Lymphogranuloma venereum
Pinta
Rat-bite fever
Relapsing fever
Sepsis
Venereal warts
Yaws

WORKUP

Section 5 of 11

Lab Studies:

• Serologic testing is commonly used to confirm a diagnosis of syphilis. Direct examination for spirochetes is definitive, when positive, and histopathology may also be useful. Ancillary testing is generally required, depending on the clinical circumstance.



• Because the organism cannot be cultured on artificial media, simple laboratory stains fail to demonstrate the spirochetes. Clinical manifestations of infection are protean. Serology has the primary role in confirming the diagnosis. The 2 types of serologic tests for syphilis are nontreponemal reaginic tests and treponema-specific tests.


• • Nontreponemal reaginic serologic tests
    • A positive nontreponemal reaginic test must be confirmed by a treponema-specific test. Depending on the clinical circumstance, treatment can begin before confirmation is received.

    • Nontreponemal reaginic tests include the rapid plasma reagin (RPR), the VDRL, and the automated reagin test (ART), all of which are useful in routine screening and are equally sensitive, inexpensive, simple to perform, and rapid. These tests are also useful for ongoing measurement of disease activity (eg, measuring response to treatment or testing for reinfection).

    • These tests measure antibody directed against a lipoidal antigen that results from the interaction of host tissues with T pallidum or to the spirochete itself. Nonspecific antibodies develop 4-8 weeks following infection.

    • Seroreactivity occurs in 70% of patients within 2 weeks of developing a chancre and in 100% of patients with secondary and latent disease. The tests may be falsely negative in early primary syphilis, latent acquired syphilis of long duration, and late congenital syphilis.

    • Quantitative results of these tests tend to correlate with disease activity, so they are very helpful for screening. A 4-fold or greater rise in titer may be seen during the evolution of early syphilis. In secondary syphilis, test results always are positive and often at a high titer (ie, at least 1:32).

    • A prozone phenomenon occurs in approximately 2% of patients, especially in those with secondary syphilis and those who are pregnant. High levels of antibody in undiluted serum cause an obscured positive test result. When clinical findings strongly suggest syphilis (eg, an infant with the appearance of congenital syphilis, despite negative maternal serology), perform appropriate dilutions to exclude this phenomenon.

    • The quantitative RPR, VDRL, or ART tests should become nonreactive 1 year after successful therapy in primary syphilis, 2 years after successful treatment in secondary or congenital syphilis, and 5 years after successful therapy in late syphilis. Meanwhile, a sustained 4-fold decrease in titer demonstrates adequate therapy.

    • Similarly, a 4-fold increase in titer following therapy suggests reinfection or relapse and necessitates reevaluation.

    • False-positive test results are caused when the antigen recognized in the nontreponemal tests is found in other tissues. Those becoming negative within 6 months are termed acute, while those that persist longer are termed chronic. Acute false-positive tests may result from an acute immunologic stimulus (eg, acute bacterial or viral infection, vaccination, early HIV infection). Chronic false-positive test results occur with parenteral drug use, autoimmune or connective tissue diseases (especially systemic lupus erythematosus), aging, and hypergammaglobulinemic states. A false-positive nontreponemal test usually can be identified by using treponema-specific tests.
  
  
  
  • Treponema-specific tests
    • These tests, which measure antibodies specific for T pallidum, include T pallidum immobilization (TPI), fluorescent treponemal antibody absorption (FTA-ABS), and microhemagglutination assay for antibodies to T pallidum (MHA-TP).

    • Use these tests in all cases to confirm a positive nontreponemal reaginic test.

    • Treponema-specific tests are not completely specific for syphilis because false-positive reactions can occur with other spirochetal diseases (eg, yaws, pinta, leptospirosis, rat-bite fever, relapsing fever, Lyme disease [which causes a negative VDRL test result]).

    • These tests become positive soon after infection and typically remain positive for life, despite adequate treatment. Test results do not correlate with disease activity and tests are not quantified.

    • The immunoglobulin M (IgM) FTA-ABS measures antibody specific to the infant born to an infected mother. This test, however, is less specific than once thought and is available only at the Centers for Disease Control and Prevention (CDC) in Atlanta, so its general usefulness is questionable.
  
  
  
• Direct examination for spirochetes


• • An uncommon method to achieve definitive diagnosis is to identify spirochetes by microscopic darkfield examination or by direct fluorescent antibody tests on exudate or tissue. Examination of a serous transudate from moist lesions (eg, the primary chancre, condyloma latum, mucous patch, placenta) is most productive because these lesions have the largest numbers of treponemes.
  
  
  
  • Darkfield microscopy is particularly helpful early in the disease, prior to development of seroreactivity.
  
  
  
  • Consider a suspicious lesion nonsyphilitic only after 3 competent examinations with negative findings have been performed.
  
  
  
  • Specimens from the oral cavity cannot be used because nonpathogenic treponemes are part of the normal oropharyngeal flora.
  
  
  
• The organism's presence can be demonstrated by histopathology (see Histologic Findings) and by the following ancillary tests:


• • Cerebrospinal fluid (CSF) analysis
    • The CNS becomes involved in as many as 40% of patients as a result of seeding during the inevitable spirochetemia. Asymptomatic involvement can be detected only by CSF analysis for pleocytosis, increased protein concentration, and a VDRL test. A CSF white blood cell count greater than 10 per mm³ (10 × 10⁶ per L), or a CSF protein level greater than 50 mg per dL (0.50 g per L) indicates possible neurosyphilis.

    • CSF examination is essential to evaluate any seropositive patient with neurologic signs and/or symptoms and is recommended for all untreated patients who have had syphilis more than 1 year or when duration is unknown.

    • Although the only specific diagnostic test for CNS disease in congenital syphilis is a reactive CSF VDRL test result, newborns may have a negative CSF VDRL test result and still develop signs of neurosyphilis. Therefore, all those with presumptive congenital syphilis should be treated for neurosyphilis.

    • A nonquantitative VDRL test is the only serologic test that should be performed on CSF. Because this test is highly specific, but relatively insensitive, a negative result does not exclude neurosyphilis.
  
  
  
  • CBC
    • Anemia, thrombocytopenia, and either leukopenia or leukocytosis characterize congenital syphilis.

    • Monocytosis is common.

    • Evidence of Coombs-negative hemolytic anemia or a leukemoid reaction may be present.
  
  
  
  • LFT
    • Syphilitic hepatitis is characterized by a disproportionately high alkaline phosphatase level and a normal or moderately elevated serum bilirubin level but no cholestasis.

    • Aspartate aminotransferase and alanine aminotransferase levels often are elevated.

    • Prothrombin time may be increased.
  
  
  
  • HIV testing: 15% of adolescents and adults with syphilis are co-infected with HIV. All patients that present with syphilis should be offered HIV testing, and all patients who are HIV-positive should be regularly screened for syphilis.
  
  
  
  • Testing for other sexually transmitted diseases (STDs): Anyone diagnosed with either syphilis or HIV should also be tested for Chlamydia species, gonorrhea, hepatitis B, and hepatitis C.
  
  
  

Imaging Studies:

• Chest radiography: Syphilitic pneumonia is common in congenital syphilis and appears as a fluffy diffuse infiltrate termed pneumonia alba.



• Long bone radiography


• • Bone involvement is common in congenital syphilis. Radiologic abnormalities are exceedingly common in early syphilis and are found in 95% of symptomatic infants and as many as 20% of infants with asymptomatic disease.

  • Bone involvement includes multiple sites of osteochondritis at the wrists, elbows, ankles, and knees and periostitis of long bones and, rarely, the skull.

  • Lesions are symmetric and involve multiple bones. The lower extremities almost always are affected.

  • Metaphyseal lesions (ie, osteochondritis) vary from punctate lucencies to more destructive changes.
  
  
  

Procedures:

• Lumbar puncture: In addition to serology (VDRL test), direct examination of CSF by darkfield microscopy may be diagnostic.

TREATMENT

Section 6 of 11

Medical Care: Penicillin remains the DOC to treat all stages of syphilis; no evidence of increasing penicillin resistance exists. Primary, secondary, and early latent disease is treated with a single IM dose of benzathine penicillin G (50,000 U/kg; not to exceed 2.4 million U). Although other regimens can be considered for penicillin-allergic patients, desensitization followed by penicillin is the most preferred method.

Nonpregnant penicillin-allergic patients without neurosyphilis may be treated with either doxycycline (100 mg PO bid for 2 wk) or tetracycline (500 mg PO qid for 2 wk). Shorter-acting forms of penicillin must be used to treat neurosyphilis to produce reliably therapeutic levels in the CSF.

Indications for CSF examination prior to initiating treatment of syphilis include the following:

• Evidence of neurosyphilis

• Evidence of tertiary syphilis (eg, aortitis, gumma, iritis)

• Treatment failure

• HIV-positive patients with late latent syphilis or syphilis of unknown duration

• Rapid plasma reagin (RPR) test result exceeding 1:32 (unless syphilis duration <1 y)

CSF interpretation is difficult in newborns because of a wide range of normal values for CSF cell count and protein concentration. In addition, a negative CSF VDRL test result cannot exclude neurosyphilis. Conversely, the CSF VDRL test result can be positive in an uninfected newborn with a transplacentally acquired high serum VDRL finding. Thus, all infants suspected of having congenital syphilis should be treated for neurosyphilis.

When distribution shortages of aqueous penicillin G occur, substitution of ampicillin or ceftriaxone may be necessary (see the CDC web page "Alternatives to intravenous penicillin G for specific infections" for the most up-to-date recommendations).

• Congenital syphilis in newborns: Treat the congenital infection, either proven or presumed, with 10-14 days of aqueous penicillin G or procaine penicillin G. Aqueous crystalline penicillin G is recommended if congenital syphilis is proved or highly suspected. Base dosage on chronologic, not gestational, age. The recommended dosage is 100,000-150,000 U/kg/d IV q8-12h to complete a 10- to 14-day course. Procaine penicillin G (50,000 U/kg IM) has been recommended as an alternative to treat congenital syphilis, but adequate CSF concentration may not be achieved consistently. Infection is suspected with the following:
  • Physical or radiographic evidence of active disease

  • Serum quantitative nontreponemal titer at least 4 times greater than the maternal titer

  • Reactive CSF VDRL test result or abnormal CSF cell count and/or protein

  • Positive IgM FTA-ABS

  • Positive darkfield microscopy or staining for treponemes in placenta or umbilical cord



• Congenital syphilis in older infants and children: Treat diagnosed infants older than 4 weeks with aqueous crystalline penicillin (200,000-300,000 U/kg/d IV divided q6h for 10-14 d).



• Syphilis in pregnancy


• • Treat all pregnant patients with syphilis with penicillin, regardless of the stage of pregnancy.

  • Administer 3 doses of benzathine penicillin (2.4 million U IM at 1-wk intervals).

  • No proven alternative therapy is available for penicillin-allergic patients.

  • Erythromycin treatment for the penicillin-allergic pregnant patient is not a reliable treatment for the fetus.
  
  
  
• Early-acquired syphilis (ie, primary, secondary, latent syphilis of <1 y duration): A single dose of IM benzathine penicillin G in a total dose of 50,000 U/kg (not to exceed 2.4 million U) is the recommended treatment. Exclude neurosyphilis by CSF examination in all pediatric patients.

• Syphilis (>1 y duration): The recommended treatment is benzathine penicillin G, 50,000 U/kg IM (not to exceed 2.4 million U) weekly for 3 successive weeks.



• Neurosyphilis: The recommended treatment is aqueous crystalline penicillin G, 200,000-300,000 U/kg/d IM (50,000 U/kg q4-6h) for 10-14 days (adult dose: 12-24 million U/d; 2-4 million U q4h), followed by a single dose of benzathine penicillin 50,000 U/kg/dose (not to exceed 2.4 million U) in 3 weekly doses.

Consultations:

• Consultation with an infectious disease specialist is useful in most cases.



• Consultation with a neurologist is prudent if neurosyphilis is present or suspected.



• Ophthalmology: Keratitis and optic atrophy are common; slit lamp examination and follow-up are important.



• Orthopedics: Skeletal gummas most often involve the legs. Bony involvement in congenital syphilis frequently resolves in the first 6 months, but lesions may be painful until healed.

MEDICATION

Section 7 of 11

T pallidum is extremely sensitive to penicillin. Primary, secondary, and early latent syphilis are treated with a single IM dose of penicillin G benzathine (50,000 U/kg; not to exceed 2.4 million U). Nonpregnant penicillin-allergic patients with no evidence of neurosyphilis can be treated with either doxycycline or tetracycline. Incubating syphilis also can be managed with penicillin. Spectinomycin is ineffective for incubating syphilis. Current recommendations for management of congenital syphilis include administration of IV penicillin G aqueous and IM penicillin G procaine for 10-14 days. Either penicillin regimen is considered adequate to manage congenital syphilis.

The Jarisch-Herxheimer reaction is the major complication of therapy and occurs in 50% of patients with primary syphilis, in 90% of those with secondary syphilis, and in 25% of those with early latent syphilis. First described in patients with syphilis by Jarisch in 1895 and then Herxheimer in 1902, the reaction occurs during the first 24 hours of treatment and consists of the abrupt onset of fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension.

Onset begins within 2 hours of treatment initiation; the temperature peaks at about 7 hours, and defervescence takes place within 12-24 hours. The reaction, which is self-limited, is associated with an increase in circulating levels of tumor necrosis factor, interleukin 6 (IL-6), and IL-8.

Drug Category: Antibiotics -- Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the clinical setting. Antibiotic selection should be guided by blood-culture sensitivity whenever feasible.

Drug Name	Penicillin G benzathine (Bicillin L-A, Permapen) -- An injection (300,000 & 600,000 U/mL) that provides sustained levels for 2-4 wk; interferes with synthesis of cell wall mucopeptides during active multiplication, which results in bactericidal activity.
Adult Dose	Primary, secondary, and early latent syphilis (disease duration <1 y): 2.4 million U IM once divided in 2 injection sites Late latent syphilis (disease duration > 1 y): 2.4 million U divided in 2 injection sites qwk for 3 doses
Pediatric Dose	Disease duration <1 year: 50,000 U/kg IM once; not to exceed 2.4 million U/dose Disease duration > 1 year: 50,000 U/kg IM q wk for 3 doses; not to exceed 2.4 million U/dose
Contraindications	Documented hypersensitivity
Interactions	Probenecid can increase effectiveness by decreasing clearance; coadministration with tetracyclines can decrease effectiveness
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	IM administration only, do not administer IV; cardiac arrest and death may occur with large doses; not recommended for congenital syphilis; caution in impaired renal function

Drug Name	Penicillin G procaine (Crysticillin A.S., Wycillin) -- An injection (300,000 U/mL, 500,000 U/mL, and 600,000 U/mL) that contains 120 mg procaine per 300,000 U; seldom recommended for congenital syphilis because adequate levels in the CSF may not be achieved.
Pediatric Dose	Congenital syphilis: Neonates: 50,000 U/kg/d IM qd for 10-14 d
Contraindications	Documented hypersensitivity
Interactions	Increases risk of bleeding when administered concurrently with warfarin; ethacrynic acid, aspirin, indomethacin, and furosemide may compete with penicillin G for renal tubular secretion increasing penicillin serum concentrations; probenecid increases serum levels
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	IM administration only, do not administer IV; cardiac arrest and death may occur with high doses

Drug Name	Penicillin G (Pfizerpen) -- Aqueous penicillin injection (K): 1, 5, 10, 20 million U (contains 1.7 mEq K and 0.3 mEq Na/1 million U penicillin G) Injection (Na): 5 million U (contains 2 mEq Na/1 million U penicillin G) Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.
Adult Dose	Neurosyphilis: 2.4 million U IV q4h for 10-14 d
Pediatric Dose	Congenital syphilis: Neonates: 50,000 U/kg IV q12h for first 7 d, then 50,000 U/kg IV q8h for a total of 10-14 d Infants and children 4 wk and older: 200,000-300,000 U/kg/d IV divided q6h for 10-14 d
Contraindications	Documented hypersensitivity
Interactions	Probenecid can increase effects of penicillin; coadministration of tetracyclines can decrease effects of penicillin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in impaired renal function

Drug Name	Tetracycline (Sumycin) -- May be an alternative to penicillin in nonpregnant patients who are allergic to penicillin; inhibits bacterial protein synthesis by binding with 30S and, possibly, 50S ribosomal subunits.
Adult Dose	500 mg PO qid for 2 wk
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (final half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Doxycycline (Vibramycin) -- Another alternative to penicillin for nonpregnant penicillin-allergic patients; inhibits protein synthesis and, thus, bacterial growth by binding to 30S and, possibly, 50S ribosomal subunits.
Adult Dose	100 mg PO bid for 2 wk
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (final half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Erythromycin (E.E.S., E-Mycin, Ery-Tab) -- An alternative to penicillin for penicillin-allergic patients; inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes causing RNA-dependent protein synthesis to arrest.
Adult Dose	500 mg PO qid for 2 wk
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; hepatic impairment
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin, increases risk of rhabdomyolysis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Does not treat fetal infection effectively; caution in liver disease; GI adverse effects are common (administer give doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Standard precautions are recommended for all patients with primary and secondary syphilis because these lesions are moist and potentially infectious.

Further Outpatient Care:

• Follow up congenital syphilis with evaluation at ages 1, 2, 4, 6, and 12 months. Obtain nontreponemal titers at ages 3, 6, and 12 months after conclusion of treatment. Nontreponemal antibody titers should decline by age 3 months and should be nonreactive by age 6 months. Consider retreatment for patients with persistently stable titers, including low titers.



• Infants who are treated for congenital neurosyphilis should undergo repeat clinical evaluation and CSF examination at 6-month intervals until their CSF examination result is normal. A positive CSF VDRL result at age 6 months is an indication for retreatment.



• Follow up early-acquired syphilis with a quantitative nontreponemal test at 3-, 6-, and 12-month intervals after conclusion of treatment. Patients with syphilis for more than 1 year also should undergo serologic testing 24 months after treatment. Pregnant patients who have received treatment should have quantitative serologic testing monthly for the remainder of their pregnancy.

Transfer:

• Transfer to another facility is appropriate if the required specialists and/or treatments are unavailable locally.

Deterrence/Prevention:

• Although rates of early syphilis are declining, maintaining a high index of suspicion about at-risk patients is important. Indications for syphilis screening include the following:


• • Exposure to a known case of infectious syphilis

  • All women at first prenatal visit and high-risk women again at 28 weeks' gestation (Forty-six of the 50 states [90%] and the District of Columbia have laws regarding antenatal syphilis screening during pregnancy and at delivery.)

  • All women that deliver a stillborn infant

  • All newborns older than 22 weeks' gestation whose mothers were not screened

  • Anyone diagnosed with a sexually transmitted infection or anyone presenting for STD evaluation

  • Any person who tests positive for HIV

  • Anyone engaging in high-risk behaviors (eg, drug use, prostitution, unprotected sex)
  
  
  
• Drainage and secretion precautions are necessary for all patients who have suspected or proven syphilis until therapy has been administered for at least 24 hours.



• Trace and contact all sexual partners of infected patients



• All persons (including health care providers) who have had close, unprotected contact with early congenital syphilis before identification of the disease or during the first 24 hours of therapy should be examined clinically for the presence of lesions 2-3 weeks after contact. Serologic testing should be performed and repeated 3 months after contact or earlier if symptoms occur. Consider immediate treatment if the degree of exposure may have been significant.



• Many people who are sexually assaulted do not comply with recommended follow-up, so consider empiric therapy for these patients.

Complications:

• Virtually any organ in the body can be involved.

Prognosis:

• With adequate and timely treatment, prognosis is excellent.

Patient Education:

• Until a practical and effective vaccine is developed, syphilis prevention depends on abstinence, use of condoms, and detection and identification of infectious cases. Education about STDs, treatment of sexual contacts, and reporting of each case to local public health authorities are essential.



• 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 11

Medical/Legal Pitfalls:

• Routine prenatal screening for syphilis remains the most important factor in identifying infants at risk of developing congenital syphilis; screening is required legally at the beginning of prenatal care in all states.



• No newborn should leave the hospital without determination of maternal serologic status at least once during pregnancy.



• Testing of mother's serum is preferred to testing cord blood or the infant's serum because the titers frequently are lower in the infant and may be nonreactive if the mother was infected late in pregnancy.



• Test for syphilis any woman who delivers a stillborn infant after 20 weeks' gestation.



• Screen women at high risk for syphilis more frequently because they may have repeat infections during pregnancy or become reinfected late in pregnancy.



• Laboratory evaluation of sexually abused children should include serologic testing for syphilis if the assailant has a history of syphilis or other STD. A suspicion of child sexual abuse mandates filing a report with child protective services or law enforcement agencies.



• Syphilitic stillbirth is considered fetal death after 20 weeks' gestation or when a fetus weighs more than 500 grams and the mother had untreated or inadequately treated syphilis at delivery. Report these cases as congenital syphilis.



• Diseases that cause genital ulcers, including syphilis, may provide vascular portals of entry for HIV. Evaluate any patient with known or suspected syphilis for the possibility of neurosyphilis, which is known to have an increased incidence in the HIV-infected population.



• Consider STD prophylaxis for rape victims.

Special Concerns:

• Syphilis in pregnancy


• • Treponemes appear able to cross the placenta at any time during pregnancy, thereby infecting the fetus. Syphilis can cause preterm delivery, stillbirth, congenital infection or neonatal death, depending on the stage of maternal infection and duration of fetal infection prior to delivery. The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics in their joint publication, Guidelines for Perinatal Care, recommend screening for syphilis at the first prenatal visit for all women and at 32-36 weeks of gestation for women who are at risk. In the Red Book 2000, the American Academy of Pediatrics recommends screening early in pregnancy and preferably again at delivery.

  • All pregnant women should have a nontreponemal serologic test for syphilis at the first prenatal visit. Perform a second test during the third trimester, especially in those at increased risk of contracting disease. Seropositivity with a nontreponemal test requires complete evaluation, including quantitative nontreponemal serology and confirmatory treponemal serology.

  • CDC policy states that no newborn should leave a hospital without documentation of the mother's serologic status at least once during the pregnancy. Serologic testing also should be performed at delivery in communities and populations at risk of acquiring congenital syphilis.

  • Penicillin is the only recommended therapy for syphilis in pregnancy. If the patient has a penicillin allergy that is confirmed by the demonstration of an immediate wheal-and-flare response to skin testing with penicilloyl-polylysine or penicillin G minor determinant mixture, desensitization and penicillin treatment should be performed in a hospital, following the 1993 STD guidelines issued by CDC.

  • Warn patients about the risk of a Jarisch-Herxheimer reaction; this reaction may be associated with mild premature contractions but rarely results in premature delivery.
  
  
  
• Syphilis in persons with HIV


• • Concomitant HIV and syphilis is common.

  • Serologic tests for syphilis may be modified by the presence of HIV, usually resulting in extremely high titers and failure to decrease in response to adequate treatment.

  • A serologic response may fail to develop.

  • Cure of co-infected individuals may require high-dose or prolonged therapy.

  • Some authorities, persuaded by reports of the persistence of T pallidum in the cerebrospinal fluid (CSF) of persons infected by HIV after standard penicillin benzathine therapy for early syphilis, now recommend CSF examination of all co-infected patients for neurosyphilis, regardless of the clinical stage of syphilis. These authorities treat for neurosyphilis when no CSF examination is performed or when examination reveals CSF abnormalities.

  • Serologic testing after treatment is important for all patients with syphilis, particularly those co-infected with HIV.
  
  
  
• Persistent infection


• • The question of persistent infection despite adequate therapy has been controversial. Sequestration of spirochetes has been reported in such sites as the anterior chamber of the eye, the CNS, and the labyrinth of the inner ear. CSF parameters are expected to normalize within 2 years. Failure to normalize may warrant retreatment.
  
  
  
  • Anyone with neurologic, optic, or otic abnormalities who has or has a history of syphilis (current or untreated) should be considered for CSF examination and should be treated for neurosyphilis.
  
  
  

TEST QUESTIONS

Section 10 of 11

CME Question 1: 1. Which of the following is associated with secondary syphilis?

A: Painless hard chancre
B: Infectious skin lesions
C: Condyloma acuminata
D: False-negative Venereal Disease Research Laboratory (VDRL) test result
E: CNS involvement

The correct answer is B: Darkfield microscopy of scrapings from primary, congenital, or secondary lesions can reveal Treponema pallidum, often before serology test results become positive. Manifestations of secondary syphilis are related to spirochetemia and include a nonpruritic maculopapular rash. Condyloma lata (ie, gray-white to erythematous wart-like plaques) can occur in moist areas around the anus and vagina. Condyloma acuminata and syphilis are unrelated. The VDRL test almost always is reactive in secondary syphilis. A painless chancre is found in primary syphilis.

CME Question 2: Which of the following tests is considered confirmatory for syphilis?

A: Rapid plasma reagin (RPR) test
B: Venereal Disease Research Laboratory (VDRL) test
C: Automated reagin test (ART)
D: Fluorescent treponemal antibody absorption (FTA-ABS) test
E: Immunoglobulin M fluorescent treponemal antibody absorption (IgM FTA-ABS) test

The correct answer is D: Nontreponemal tests, such as the VDRL, RPR, and ART, detect antibodies against a cardiolipin-cholesterol-lecithin complex not specific for syphilis. The quantitative results of these nontreponemal tests tend to correlate with disease activity and are very helpful in screening. Treponemal tests, which measure antibodies specific for Treponema pallidum, include the T pallidum immobilization (TPI), the FTA-ABS, and the microhemagglutination assay for antibodies to T pallidum (MHA-TP). Treponemal tests are used to confirm positive results from nontreponemal antibody tests.

Pearl Question 1 (T/F): Penicillin resistance is common in syphilis treatment.

The correct answer is False: Treponema pallidum is extremely sensitive to penicillin, and no evidence exists of increasing penicillin resistance.

Pearl Question 2 (T/F): The microhemagglutination assay for antibodies to Treponema pallidum (MHA-TP) usually becomes negative 2 weeks after adequate therapy.

The correct answer is False: Treponemal antibody titers become positive soon after the initial infection and usually remain positive for life, even with adequate therapy. An MHA-TP positive result remains positive.

Pearl Question 3 (T/F): The lesions of primary syphilis are painless but highly contagious.

The correct answer is True: Primary syphilis is characterized by syphilitic chancre and regional lymphadenitis. A painless papule appears at the site of inoculation 2-6 weeks after Treponema pallidum has been introduced. The papule soon develops into a clean, painless ulcer with raised borders called a chancre. The chancre, usually on the genitals, contains viable T pallidum and is highly contagious. Extragenital chancres can occur, depending on the site of primary inoculation.

Pearl Question 4 (T/F): Maternal treatment of syphilis with erythromycin is considered inadequate.

The correct answer is True: Nonpenicillin regimens are considered inadequate treatment of syphilis.

BIBLIOGRAPHY

Section 11 of 11

• American Academy of Pediatrics: Syphilis. 2003 Red Book: Report of the Committee on Infectious Diseases 2003; 26th Edition, 595-607.
• Behrman RE, Kliegman RM, Jenson HB: Syphilis. Textbook of Pediatrics 2004; 978-982.
• Brion LP, Manuli M, Rai B: Long-bone radiographic abnormalities as a sign of active congenital syphilis in asymptomatic newborns. Pediatrics 1991 Nov; 88(5): 1037-40[Medline].
• Brown DL, Frank JE: Diagnosis and management of syphilis. Am Fam Physician 2003 Jul 15; 68(2): 283-90[Medline].
• Feigin RD, Cherry JD: Syphilis. Textbook of Pediatric Infectious Diseases 1998; 1543-56.
• Fiumara NJ: The diagnosis and treatment of infectious syphilis. Compr Ther 1995 Nov; 21(11): 639-44[Medline].
• Gomella TL, Cunningham MD, Eyal FG: Syphilis. Neonatology 1999; 430-2.
• Gorbach SL, Bartlett JG, Blacklow NR: Syphilis. Infectious Diseases 1998; 980-6.
• Hirshfeld AB, Getachew A, Sessions J: Drug doses. The Harriet Lane Handbook: A Manual for Pediatric House Officers 2000; 599-892.
• Hollier LM, Cox SM: Syphilis. Semin Perinatol 1998 Aug; 22(4): 323-31[Medline].
• Hollier LM, Harstad TW, Sanchez PJ, et al: Fetal syphilis: clinical and laboratory characteristics. Obstet Gynecol 2001 Jun; 97(6): 947-53[Medline].
• Hollier LM, Hill J, Sheffield JS, Wendel GD Jr: State laws regarding prenatal syphilis screening in the United States. Am J Obstet Gynecol 2003 Oct; 189(4): 1178-83[Medline].
• Long SS, Pickering LK, Prober CG: Treponema pallidum (syphilis). Principles and Practice of Pediatric Infectious Diseases 1997; 1049-56.
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• Lynn WA, Lightman S: Syphilis and HIV: a dangerous combination. Lancet Infect Dis 2004 Jul; 4(7): 456-66[Medline].
• Mandell GL, Bennett JE, Dolin R: Treponema pallidum (syphilis). Principles and Practice of Infectious Diseases 2000; 2474-90.
• Noordhoek GT, Cockayne A, Schouls LM: A new attempt to distinguish serologically the subspecies of Treponema pallidum causing syphilis and yaws [published erratum appears in J Clin Microbiol 1990 Dec;28(12):2853]. J Clin Microbiol 1990 Jul; 28(7): 1600-7[Medline].
• Pandhi D, Kumar S, Reddy BS: Sexually transmitted diseases in children. J Dermatol 2003 Apr; 30(4): 314-20[Medline].
• Rome ES: Sexually transmitted diseases: testing and treating. Adolesc Med 1999 Jun; 10(2): 231-41, vi[Medline].
• Sanchez PJ, Wendel GD: Syphilis in pregnancy. Clin Perinatol 1997 Mar; 24(1): 71-90[Medline].
• Stamos JK, Rowley AH: Timely diagnosis of congenital infections. Pediatr Clin North Am 1994 Oct; 41(5): 1017-33[Medline].
• Steele RW: Prevention and management of sexually transmitted diseases in adolescents. Adolesc Med 2000 Jun; 11(2): 315-26[Medline].
• Tintinalli JE, Kelen KD, Stapczynski JS: Sexually transmitted diseases. Emergency Medicine 2004; 909-13.

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