Mary Allen Staat
Syphilis is a sexually transmitted disease caused by Treponema pallidum. The organism is a thin, delicate spirochete 6 to 20 μm long that has the appearance of a helical coil on dark-field microscopy or immunofluorescence.
Human beings are the only host. Nearly all transmission is through sexual contact, although very close physical contact between mucous membranes might also permit transmission.1 Congenital syphilis may occur transplacentally or by passage through an infected birth canal. Long, clinically latent periods are common; the infection may persist through the patient’s lifetime with a variety of clinical manifestations. Syphilis causes significant complications if untreated and facilitates the transmission of HIV. Pediatricians may have to treat children or adolescents with acquired syphilis or infants with congenital syphilis, but the most common presenting problem is the management of a well-appearing infant born to a serologically positive mother.
Whereas syphilis rates in the United States declined between 1990 and 2000, the rates in all categories, primary and secondary, early-latent, late-latent, and congenital syphilis and all age, sex, racial, and ethnic groups increased between 2005 and 2006.2 The increase in rates was largely attributed to increased rates in men having sex with men, HIV coinfection and high-risk sexual behavior.
Congenital syphilis rates in the United States declined from 1996 to 2005.2 However, the rate of congenital syphilis increased 4% between 2005 and 2006 (from 8.2 to 8.5 cases per 100,000 live births) with 349 reported cases. In 2006, 26 states, the District of Columbia, and one outlying area had rates of congenital syphilis that exceeded the Healthy People target of one case per 100,000 live births (eFigs. 288.1 and 288.2 ).3
Children and adolescents who acquire syphilis follow a clinical course similar to adults. In infected children, sexual abuse must be presumed and laws require that a report be made and an investigation takes place.
The incubation period is approximately 3 weeks (10–90 days)4 followed by the appearance of the primary stage, which is characterized by a painless, indurated chancre that appears at the site of contact—the glans penis, the labia, or within the vagina.5,6 Primary lesions may also appear on the lips or tongue, within the anus, or on the cervix (Fig. 288-1A). Regional lymph nodes are usually very enlarged, hard, and painless. The serologic tests for syphilis (STS) may not yet be positive during the primary stage. The chancre usually disappears in 3 to 5 weeks without treatment, to be followed by the secondary stage. Secondary syphilis usually appears 6 to 10 weeks after the infection.5 It is characterized by malaise, fever, adenopathy, and a generalized cutaneous rash that may be macular, papular, papulosquamous, or bullous (Fig. 288-1B). Mucous patches are also common. Alopecia and condylomas may occur later. The patient is very infectious at this stage: The lesions are often positive for treponemes by either dark-field microscopy or immunofluorescence. The STSs are always positive at this stage. As the secondary stage subsides, the patient enters the latent phase. The patient continues to be seropositive without clinical manifestations. Late manifestations of syphilis (tertiary stage) are gummatous lesions, which are probably the result of hyper-sensitivity, as well as cardiovascular disease and neurosyphilis, both the result of longstanding vascular capillary disease and endarteritis.5
There are two general categories of serologic tests for syphilis, nontreponemal antigen tests and treponemal antigen tests.4-7 Nontreponemal antigen tests use a component of normal tissue (eg, beef-heart cardiolipin) as an antigen to measure reagin, a nonspecific antibody formed by syphilitic patients. The most common nontreponemal tests are the Venereal Disease Research Laboratory (VDRL) and the rapid plasma reagin (RPR) flocculation tests. The VDRL test usually becomes positive 4 to 6 weeks after the infection (several weeks after the primary lesion appears) and is almost always positive at a high titer (greater than 1:32) during the secondary stage. The titer often falls during the latent phase, as it does following therapy. False-positive reactions are encountered in nonvenereal treponemal infections, and, more important, in a wide variety of disease states, including infectious mononucleosis, collagen vascular diseases, malaria, drug addiction, many febrile diseases, and, occasionally, in pregnancy. The RPR test is a simpler test than the traditional VDRL, capable of automation, and in all other respects comparable to VDRL.
FIGURE 288-1. Primary and secondary syphilis. A 24-year-old male with painful lesion on the tongue and disseminated rash. A. Extragenital primary on tongue. A large ulceration on the tip of the tongue. B. A disseminated papulosquamous eruption, i.e., secondary syphilis, was present at the time of the examination. (From Wolff K, Johnson RA. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York: McGraw-Hill, 2009.)
Of the treponemal antigen tests, the most widely used are the Treponema pallidum particle agglutination (TPPA) and fluorescent treponemal antibody absorption test (FTA-ABS) assays.4-7 These tests are both sensitive and specific for treponemal antibody and are used extensively to determine whether positive nontreponemal antigen tests are true positives or false positives. These tests usually remain permanently positive despite successful treatment. False-positive tests occur rarely in mixed connective tissue and autoimmune diseases and other spirochetal diseases including Lyme disease. Each of these assays measure IgG and, therefore, do not distinguish disease in an infant from passively transferred maternal antibody. Antitreponemal IgM antibody testing using a method recognized by the Centers for Disease Control and Prevention as a standard may be used to determine whether an infant has congenital syphilis but these tests are not yet widely available.4,7
Examination of dried smears of fluid or smears taken from syphilitic lesions can be performed by either dark-field microscopy or immunofluorescence to provide an early and specific diagnosis.4-7 In selected patients, the spinal fluid should be examined for neurosyphilis. Positive findings for neurosyphilis include an elevated white blood cell count, an increase in the total protein and gamma globulin, and a positive reagin (VDRL) test. The VDRL is the preferred test to examine the spinal fluid; the FTA-ABS is highly sensitive but less specific (more false positives).
Early syphilis (primary, secondary, or latent of less than 1 year’s duration) should be treated with a single injection of 2.4 million units of benzathine penicillin given intramuscularly for adults or teenagers. Syphilis of more than 1 year’s duration should be treated with benzathine penicillin 2.4 million units intramuscularly once a week for 3 consecutive weeks.4,7 Penicillin is the best therapeutic agent and the only one shown to protect the fetus. In penicillin-allergic individuals, tetracycline or erythromycin given orally for 2 weeks provides an alternative. Special guidelines for treatment of pregnant women and neurosyphilis can be found in the CDC STD Treatment Guidelines that are routinely updated.7
Penicillin treatment may be complicated by a Jarisch-Herxheimer reaction manifested by fever and an aggravated clinical picture ascribed to sudden massive destruction of spirochetes and release of their toxic products.8 Treatment with antipyretics is useful for management.4,7
In addition to treating the patient, sexual partners should be treated.7 Syphilis is a reportable disease in the United State and when diagnosed, the patient should be examined for other sexually transmitted diseases, including HIV.4,7
Congenital syphilis results from the transplacental infection of the developing fetus. An infected pregnant woman has a high probability of transmitting the infection to the fetus. Treponemal organisms can cross the placenta at any stage of pregnancy, but appear to elicit little tissue response before the 15th week of gestation.9 The rate of vertical transmission is 70% to 100% for primary syphilis, 40% for early-latent syphilis and 10% for latent disease.10Adequate treatment of the mother with penicillin protects the fetus, but the mother may become re-infected. Fetal mortality is high—17% to 25% of infected infants die in utero; another 23% die perinatally.10-12 The signs and symptoms are varied and may appear at any time between birth and 3 months of life.13
Early Congenital (Prenatal) Syphilis
Untreated syphilis in the pregnant woman can result in stillbirth, spontaneous abortion, non-immune hydrops, premature delivery, perinatal death, and early or late congenital syphilis.11 Women with primary or secondary syphilis are more likely to have infants with adverse outcomes compared to women with early- or late-latent syphilis. Most live-born syphilitic infants have no visible lesions at birth.14,15 When lesions are present, they are most commonly on the skin and in the bones. In the first week of life, syphilis may produce bullous lesions of the skin on the palms and soles (Fig. 288-2).4,6,10,12 The more usual pattern of skin involvement is a diffuse, symmetric, copper-colored maculopapular rash that when gently scraped with a scalpel yields serum teeming with treponemes. Thus, either dark-field microscopy or direct fluorescent antibody examination may result in a rapid and definitive diagnosis. If left untreated, most syphilitic infants will eventually have some kind of skin lesion. Many varieties of papular skin rashes may occur and recur over the next months, with a high predilection for oral or anal muco-cutaneous sites. Perioral lesions may result in scarring, with fissures that persist. The recurrences become progressively less symmetric with time. The perianal condylomatous lesion (condyloma latum), seen in adults, is also seen in infancy.
FIGURE 288-2. Bullous eruptions on the soles of a newborn with early prenatal syphilis. Bullae have ruptured and now present as erosions (“syphilitic pemphigus”). (From Wolff K, Goldsmith LA, Katz SI, et al (eds). Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: McGraw-Hill, 2008.)
A characteristic mucous membrane lesion of infants that has no counterpart in the adult is snuffles, a rhinitis producing a serous discharge that frequently becomes secondarily infected. Postinflammatory scarring beneath the nose is called rhagades.16-18 The lesion may extend to the nasal cartilage and cause sufficient damage to result in saddle-nose deformity.
Congenital syphilis produces widespread lesions in the skeleton, resulting in osteochondritis at metaphyseal plates, a generalized symmetric periosteal elevation, and symmetrically occurring osteomyelitic lesions on radiographs.17-19 The humerus is the most commonly involved bone, with the tibia next, which often has a highly characteristic pattern with a bilateral moth-eaten appearance. More than 90% of infants with congenital syphilis manifest skeletal lesions that begin between 1 and 3 months of age; the process is usually self-limited, with healing occurring spontaneously over the next few months, regardless of treatment. Radiographic findings usually disappear by age 5 months. The bone lesions are often asymptomatic. Occasionally, there is pain, often manifested by a pseudoparalysis that may be unilateral, involving either an arm or a leg (Parrot paralysis). Later in infancy, there may be recurring isolated bone lesions; dactylitis, frequently asymmetric, is a typical example.
Central nervous system involvement with abnormal cerebrospinal fluid findings are present in 40% to 60% of infants with syphilis.12,18 Jaundice as a manifestation of syphilitic hepatitis sometimes appears early in congenital syphilis and is resolved with treatment. Syphilitic pneumonitis or pneumonia alba is uncommon. Splenomegaly and generalized lymphadenopathy are frequent manifestations of the early systemic illness. The epitrochlear nodes commonly enlarge. Involvement of the kidney, when present, takes the form of a glomerulonephritis that presents as nephrotic syndrome.
Late Congenital Syphilis
Late congenital syphilis may be suspected from the stigmata, from the presence of continued active disease, or from persistently positive tests in an otherwise asymptomatic child.17,20,21 Hutchinson triad, described in the 19th century includes: Hutchinson teeth, interstitial keratitis, and eighth nerve deafness. The most common stigmata are Hutchinson teeth, a screwdriver or peg-shaped deformity of the upper central incisors of the second dentition. Molars may have extra cusps and are referred to as “Mulberry” molars. They are poorly formed and crumble under normal use. All syphilitic teeth demonstrate deficient enamel and decay more readily than normal teeth. Hutchinson incisors are visible by radiography in its pre-eruptive site from about age 1 year.
Interstitial keratitis begins between ages 5 and 16 year.21 The keratitis is an intense inflammatory vascular infiltration of the cornea that may be accompanied by an iritis, which may be followed by a dense cicatricial scar that produces blindness. Although usually bilateral, it may appear in one eye before it appears in the other eye. The lesion is not prevented by treatment given after the first year of disease. Early stages are characterized by marked photophobia, lacrimation, and a hazy appearance of the cornea. Later, scarring occurs.
Other active forms of late disease are gummas and osteitis, which are among the late benign syphilitic lesions.17 The palate and nasal septum are predilectional sites for destructive gummas, with saddle nose and perforated palatal deformities possible end results. Persistent periostitis gives rise to thickened clavicles and to a usually asymmetric saber shin. Clutton joints are symmetric synovial effusions, usually of the knees, that are sometimes painless, but which are more often warm and painful.
An important form of active late congenital syphilis involves the central nervous system, most commonly meningovascular.17 Paresis, a potentially more dangerous form of central nervous system syphilis, occurs in juveniles, and may be detected in a preparetic state by examination of cerebrospinal fluid (CSF). The examination shows complement-fixing antibody, pleocytosis, and elevation of protein concentration.
Both treponemal and nontreponemal antibodies are transmitted from the mother to the infant.4-7 If the infant is not infected, the maternal antibodies disappear by age 4 months. In an infected infant, a rising VDRL or RPR titer can be anticipated.
An accurate diagnosis is difficult, particularly in the first few days or weeks of life, unless treponemes are visible in lesions. If treponemes are not found, one must consider the status of the maternal infection, whether the mother has been treated, the serologic tests in the infant, the clinical findings in the infant, and the results of bone radiographs and examination of CSF. Usually one can conclude that infection in the infant is possible, probable, or unlikely. Serologic tests are described earlier in this chapter. The CDC and American Academy of Pediatrics (AAP) provide detailed guidelines for evaluation, treatment, and follow-up.4,7
Because the probability of neurosyphilis cannot be definitively ruled out in most neonates, benzathine penicillin should not be used because it does not provide a treponemicidal level in CSF. The regimens of choice in proven or highly probable congenital syphilis in infants 4 weeks or younger are4
• Aqueous crystalline penicillin G, 100,000 to 150,000 U/kg/day (administered as 50,000 U/kg IV every 12 hours during the first 7 days of life and every 8 hours thereafter) for a total of 10 days; or
• Procaine penicillin G, 50,000 U/kg intramuscularly daily in a single dose for 10 days. Adequate CSF concentrations may not be achieved with this regimen.
The treatment regimen for children > 4 weeks of age is 200,000 to 300,000 U/kg/day administered as 50,000 U/kg IV every 4 to 6 hours for 10 days.4 If one or more days of therapy are missed, the entire course needs to be restarted. These infants should be seen frequently with a careful developmental evaluation, including vision and hearing testing. Nontreponemal tests should be repeated 3, 6, and 12 months after therapy.4,7 Titers are expected to decline and become nonreactive or stabilize at very low levels. In infants with congenital neurosyphilis, or in those children not evaluated for neurosyphilis, the CSF should also be examined toward the end of therapy. Repeat treatment should be considered if the titer increases or fails to decrease fourfold within 1 year.
Penicillin G is the treatment of choice for congenital syphilis and neurosyphilis, and every effort should be made to treat these infections with penicillin G. Because of recent shortages of penicillin G, the CDC has developed guidelines for use of alternative treatments when intravenous penicillin is not available and can be found online at www.cdc.gov/nchstp/dstd/penicillinG.htm.4,7 If intravenous penicillin is not available or is limited, procaine penicillin G at 50,000 U/kg/dose given intramuscularly in a single dose each day for 10 days can be given as a substitute for all or some of the doses. If neither aqueous nor procaine penicillin G is available, ceftriaxone may be given at a dose of 75 mg/kg/day intramuscularly or intravenously for 10 to 14 days in infants less than 30 days old; for older infants, a single dose of 100 mg/kg/day should be given. The use of ceftriaxone has not been well studied; thus, if this regimen is used, careful follow-up should be done including a repeat CSF exam at age 6 months if the initial exam was abnormal.
Serologic tests for syphilis should be performed in all pregnant women prior to delivery and are required by law in many states.7,22 No infant should leave the hospital without the serologic status of the infant’s mother having been documented at least once during pregnancy. Serologic testing also should be performed at delivery in communities and populations at risk for congenital syphilis. Serologic tests can be nonreactive among infants infected late during their mother’s pregnancy. Penicillin is the only drug that, when given during pregnancy, reliably protects the fetus. If other drugs such as erythromycin are used, the infant should be treated again after birth. The infected pregnant woman’s sexual partners must also be treated because the mother could become reinfected and could also re-infect her infant after penicillin therapy.7 Because most open lesions and possibly blood are contagious, standard precautions are recommended for all patients with suspected or proven syphilis until therapy has been administered for at least 24 hours.4