Syphilis in Children: Congenital and Acquired

Syphilis in Children: Congenital and Acquired Charles R. Woods, MD, MS Syphilis rates in women and congenital syphilis rates have declined steadily in the United States in recent years. However, syphilis remains a worldwide public health problem, with more than 12 million cases in adults and more than half a million pregnancies affected yearly. Prenatal screening and treatment programs are limited or nonexistent in many developing countries. The genome of Treponema pallidum, one of the smallest among prokaryotes, has been sequenced, but methods for continuous in vitro cultivation of the microbe remain elusive. There are no promising candidates for future vaccines at this time. Serologic testing, for both specific treponemal and nontreponemal antibodies, continues to be a primary means of diagnosis. Penicillin remains the drug of choice for congenital and acquired syphilis in childhood. The diagnosis of syphilis beyond early infancy raises concerns for possible child sexual abuse, although progression of congenital syphilis may account for some cases. Syphilis is a potentially eradicable disease, but this can be achieved only with sustained international will and cooperation to fund the necessary screening and treatment programs. Semin Pediatr Infect Dis 16:245-257 © 2005 Elsevier Inc. All rights reserved.

S

yphilis has been recognized since antiquity and remains a worldwide public health problem. More than 12 million new cases occur yearly, predominantly in developing nations.1 Syphilis in infants was described as early as 1497, and the causative microbe, Treponema pallidum, was discovered in 1905.2 Much concern is focused on the number of infants born worldwide with human immunodeficiency virus (HIV) infection, and rightly so, but the increasing numbers of infants with congenital syphilis, despite the relative ease of prevention and treatment of the disease, has received relatively little international attention.3 The World Health Organization (WHO) estimates than maternal syphilis leads to 460,000 abortions or stillbirths and 270,000 live-born infants with congenital syphilis yearly.4 The frequency of congenital syphilis in a specific locale is determined ultimately by both the prevalence of syphilis among adults and the effectiveness of prenatal screening and treatment programs. This review will focus primarily on congenital syphilis and acquired syphilis in young children. After a discussion of the general epidemiology and microbiology of syphilis, the clinical, diagnostic, and therapeutic issues, especially those unique to neonates and young children, will be presented. Efforts to understand the microbiology of T. pallidum are

Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC. Address reprint requests to Charles R. Woods, MD, MS, Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC 27157. E-mail: [email protected].

1045-1870/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.spid.2005.06.005

ongoing in efforts to develop a candidate protective vaccine, but this goal remains elusive to date. This bacterium has been termed a “stealth pathogen” because of its ability to evade the immune system.5

Epidemiology Humans are the sole natural host of syphilis. The disease is most common in Sub-Saharan Africa, South and Southeast Asia, and South America, with in excess of 3 million adult cases occurring annually in these regions, compared with approximately 100,000 in North America, in 1999.6 In the United States, an upsurge in the number of syphilis cases that began in the late 1980s has diminished during the past decade.7 Risk factors associated with acquisition of syphilis include poverty, crack cocaine use, trading sex for drugs and money, and infection with HIV.8 Syphilis remains more common among men. The gender gap in primary and secondary syphilis cases that had narrowed in the United States during the 1990s widened in 2002 to 3.8 cases per 100,000 in men compared with 1.1 among women. The increase in male cases has occurred primarily among men who have sex with men. Concurrent gonococcal infection is found in approximately 8 percent of cases.2,7 There has been a long-standing racial disparity in syphilis rates between black and non-Hispanic Caucasians in the United States, but it has narrowed from more than 50-fold in 1991 to 8-fold in 2002. The peak age range of syphilis is 15 to 55 years, which coincides with increased sexual activity. Fe245

C.R. Woods

246

Figure 1 Primary and secondary syphilis in the United States, 2002—Counties with rates greater and less than the Healthy People year 2010 objective of 0.2 cases per 100,000 population. Reprinted with permission from the Centers for Disease Control and Prevention.7

male case rates are higher than male rates in the 15- to 19year-old age range, reflecting sexual activity of women in this age group with older men who have higher infection rates. Syphilis rates vary across the United States and remain higher in the South (Fig. 1).7 Rates of congenital syphilis in the United States increased in the 1980s, in parallel with increased frequency among women of child-bearing age, and similarly have declined since 1991 (Fig. 2). In 2002, the national rate was 11.2 cases per 100,000 live births (451 cases), a 21 percent decrease

Figure 2 Congenital syphilis in the United States between 1970 and 2002 has paralleled the rate of primary and secondary syphilis among women. The case surveillance definition was modified in 1988. Reprinted with permission from the Centers for Disease Control and Prevention.7

from 2000.9 This overall positive trend seen in the United States has not been mirrored worldwide. A major factor leading to vertical transmission is inadequate (or absent) prenatal care, which holds true for cases occurring in the United States as well as all other regions of the world (Fig. 3).9,10 Congenital syphilis increased 26-fold in the Russian Federation from 1991 to 1999, after the collapse of widely available and free prenatal health care services.3,11

Microbiology T. pallidum is a member of the genus Treponema (order Spirochaetales). There are three other Treponema pathogens (Treponema pertenue [yaws], Treponema carateum [pinta], and Treponema endemicum [endemic syphilis, or bejel]) and at least six nonpathogens that can be normal flora in the oral cavity and in the genitourinary and intestinal tracts.12 Treponemes are microaerophilic gram-negative bacteria that are 6to 20-␮m long and 0.1 to 0.5 ␮m in diameter. This size is less than the resolution limits of conventional light microscopy, although the microbe can be visualized by dark-field or phase-contrast microscopy. Individual microbes appear rodshaped, with 8 to 14 flat waves that give a helical appearance. Several flagellum-like organelles axial fibrils extend pole to pole intracellularly within the periplasmic space.3,13 They vary in length and entwine over the cell body, conferring the shape of the microbe as well as its capacity for motility.

Syphilis in young children

247 antibodies generated against one strain to protect against challenge by heterologous strains. Survival of T. pallidum outside an infected host is very limited. Virulent strains have been propagated in rabbits (rabbit infectivity test), and limited in vitro culture on monolayers of several cell types has been achieved.2 A primate model for neurosyphilis has been developed,21 but no methods exist for continuously culturing the microbe.16

Pathogenesis/Pathology

Figure 3 Maternal treatment history among 451 infants with congenital syphilis in the United States in 2002. Reprinted with permission from Centers for Disease Control and Prevention.9 (Color version of figure is available online.)

T. pallidum contains a single circular chromosome of approximately 1140 kb, which is one of the smallest known among prokaryotes, and no extrachromosomal elements.14,15 The full genome was sequenced in 1998 and contains 1041 predicted open reading frames, of which approximately one quarter did not match known sequences in other microbes in 1999.15 Lipoproteins are important integral components of the inner membrane,13,16 and approximately 3 percent of the coding capacity of the genome appears to be for generation of lipoproteins.14 The outer lipid membrane contains only rare transmembrane proteins that remain poorly characterized at the molecular level. The major spirochetal membrane immunogens are hydrophilic lipopeptides that are largely shielded from the antibodies that they induce.13,17 Treponemal lipoproteins and lipopeptides can induce proand anti-inflammatory cytokine responses in monocytes. In some instances, these responses may be initiated via binding with CD-14 receptors on monocytes.18,19 Little is known about functions of specific lipoproteins identified to date, although one (Tp32) appears to be an L-methionine-binding protein and may function as part of a periplasmic uptake transporter system.16 T. pallidum repeat protein K (TprK) is a likely factor in immune evasion. It is encoded by a single genetic locus that contains multiple heterogeneous alleles.20 Each allele has seven discrete variable regions interspersed between conserved regions. This feature provides for considerable antigenic diversity and immune response-evasion capacity of a single infecting strain and accounts for failure of

Sexual contact is the primary means of transmission of syphilis beyond the neonatal period. Risk of infection is approximately 30 percent per sexual contact with an infected partner. T. pallidum is able to invade intact mucous membranes as well as areas of abraded skin. Acquisition via nonsexual contact with infected lesions, including those of congenital syphilis, is a rare event but can occur.2 Syphilis seldom is found in children who have been sexually abused, but in those who develop acquired syphilis in childhood, sexual transmission should be assumed unless another mechanism is identified. Healthcare providers can become infected if appropriate barrier precautions are not used. Four stages of syphilitic disease are defined: primary, secondary, latent, and tertiary (Fig. 4). Infection begins when T. pallidum penetrates the skin or mucous membrane at a site of exposure. An outer membrane protein of the microbe attaches to a receptor(s) on the host cell surface, allowing the organism to persist in extracellular loci. Hyaluronidase production assists epithelial penetration in route to perivascular sites, where capillary cells appear to be the prime target of parasitism.2 The organism subsequently multiplies locally and spreads through the perivascular lymphatic system to the systemic circulation, which disseminates infection widely before the primary lesion(s) becomes evident. During the usual 3-week incubation period (range, 10 to 90 days), an intense local inflammatory response consisting of plasma cells, macrophages, and lymphocytes develops.

Figure 4 The course and stages of untreated syphilis. Reprinted with permission from Sánchez and Gutman.2

C.R. Woods

248 This response produces the red, indurated, ulcerative, spirochete-filled lesion of primary syphylis: the chancre. The host response likely is initiated by chemotactic effects of treponemal lipopeptide antigens,22,23 but it seems to require proliferation to relatively large numbers of treponemes. Associated cellular proliferation in regional lymph nodes produces adenopathy. If the immune response is unable to fully eradicate the infection, over the course of 2 to 10 weeks, replication at the site of early infection leads to dissemination and development of the lesions of secondary syphilis. These lesions occur most commonly in ectodermal tissues: skin, mucous membranes, and the central nervous system (CNS). The immune response is similar to that of primary lesions. The condylomata lata (venereal warts) of secondary syphilis result from epithelial hyperplasia, hyperkeratosis, and plasma cell infiltrate in response to the presence of spirochetes.2 Even if untreated, the clinical manifestations of secondary syphilis resolve, and the disease process enters a period of relative immunologic control: viable organisms remain but in low numbers. Approximately 60 percent of patients will remain in this asymptomatic, or latent, state, with some clearing the infection. Over a period of years, approximately 40 percent will suffer progression to the tertiary stage. Tertiary syphilis can involve any organ system. The typical lesions are gummata, which are focal areas of nonsuppurative inflammatory necrosis surrounded by fibrotic scarring. They appear to represent a granulomatous hypersensitivity reaction. Viable organisms are rare findings or absent. Tertiary lesions also can take the form of a diffuse, chronic, noncaseating infiltrate of plasma cells and other lymphocytes.2 Congenital syphilis occurs when T. pallidum cross the placenta from mother to fetus or during birth by contact with an infectious lesion. Transplacental transmission during maternal spirochetemia can occur as early as 9 to 10 weeks of gestation and at any subsequent times during pregnancy. Vertical transmission during pregnancy occurs more frequently during primary or secondary syphilis than with latent disease. Risk diminishes after 4 years of infection, even when untreated. Transmission in utero causes the wide dissemination of the organism in the fetus (analogous to secondary acquired syphilis), and pathologic changes have been seen as early as 15 weeks gestation. The organs affected most severely include bone, brain, liver, lung, and the skeletal system. Early infection can lead to spontaneous abortion, generally after 18 weeks of gestation. The placenta typically is large and thickened with hypercellular villi with acute and chronic inflammation as well as proliferative fetal vascular changes. Necrotizing funisitis and plasma cell deciduitis are seen in some cases. The umbilical cord often contains abscess-like necrotic foci around the vessels within the Wharton jelly. Spirochetes typically are present in the umbilical vessel walls.2,24 Untreated congenital syphilis can progress through the same stages as postnatally acquired syphilis.

Treponemal-Specific Immune Response IgM and IgG antibodies are detectable by the time the chancre appears, but humoral immunity is insufficient to control

the infection. Cell-mediated immunity is suppressed during the primary and secondary stages of infection.2 Ultimate eradication of infection occurs when T cells infiltrate syphilitic lesions, which leads to activation of CD68-positive macrophages and phagocytosis of antibody-opsonized treponemes. Immune response to TprK appears to be a primary means of killing treponemes. T-cell responses appear directed against conserved epitopes of TprK, whereas opsonic antibodies are directed against variable region epitopes. TprK diversity between strains results in minimal protection by antibodies induced during previous infection against infection by heterologous strains.20,25,26 This factor accounts for the common clinical scenario of syphilitic re-infections. After effective treatment, treponemal-specific IgM antibodies decline over the course of 1 to 2 years, but IgG antibodies usually persist throughout the person’s life.

Clinical Manifestations Healthcare workers providing care to children are most likely to encounter the diagnostic dilemmas of syphilis in the newborn nursery (the possibility of congenital syphilis) or when working with sexually active adolescents. Cases in children are uncommon but can have clinical manifestations similar to those in adolescents and adults.

Acquired Syphilis in Childhood The chancre is the hallmark of acquired primary syphilis at any age, although children often have few dermal findings.27 The chancres arise most often on the genitalia and usually are solitary and nontender. Nontender inguinal (regional) adenopathy is a common finding and may be the only readily apparent sign of primary syphilis, especially in women when the chancre occurs on the cervix or vaginal wall. Healing occurs spontaneously in 3 to 12 weeks.2 Symptoms of secondary syphilis appear 2 to 12 weeks after the chancre and include low-grade fever, sore throat, headache, malaise, and diffuse lymphadenopathy. The most notable manifestation is a rash that may consist of macular, maculopapular, papular, or pustular lesions. Onset typically is on the trunk and is maculopapular. Spread to the extremities, including palms and soles, is a common occurrence. Condylomata lata, which are hypertrophic papular skin lesions found in moist areas such as the anus or vulva, may arise at this stage. All skin and mucous membrane lesions of secondary syphilis harbor abundant treponemes and are highly contagious on direct contact. Neurosyphilis is present in approximately 30 percent of patients with secondary syphilis. CSF pleocytosis and proteinosis are typical findings. Neurosyphilis may be clinically silent or present as meningeal and cranial or spinal nerve involvement. The latter are reversible with proper therapy at this stage. Iritis, anterior uveitis, arthritis, and nephrotic syndrome also can occur during secondary syphilis. These disease manifestations likely are caused by deposition of immune complexes composed of treponemal antigens, fibronectin, antibodies, and complement.2,28

Syphilis in young children Secondary syphilis lesions resolve without treatment in 1 to 2 months. The infection then enters a latent period, without overt evidence of disease. Secondary syphilis signs can recur during the first year (early latency) but not thereafter (late latency). Relative immunity to reinfection exists during latency, and approximately 60 percent of untreated patients will not progress from latency to tertiary syphilis. Approximately 40 percent of untreated patients will progress to tertiary syphilis after latent periods of 3 to 10 years. This time frame renders acquired tertiary syphilis a very rare occurrence during childhood and adolescence. Gummata, the classic lesions of tertiary syphilis, develop in skin, soft tissue, and bone in 15 percent of cases. These lesions have minimal clinical impact, and their presence has been called benign late syphilis. Neurosyphilis untreated during the secondary stage will persist in many untreated patients, including children. It can remain asymptomatic or mimic almost any other neurologic disease. The interval between primary syphilis and late neurosyphilis usually is greater than 5 years. The disease may progress more rapidly in children than in adults. Common presentations include tabes dorsalis, paresis, dementia, meningitis, and amyotrophic lateral sclerosis. Cardiovascular syphilis, which occurs in 10 percent of older patients with late syphilis, generally is not found in children because its onset usually is 10 to 40 years after primary disease is acquired.2

249 Table 1 Frequency of the Common Early Manifestations of Congenital Syphilis Among 139 Symptomatic Infants* Percent Affected Clinical findings Rash Fever Failure to thrive Hepatosplenomegaly Lymphadenopathy Central nervous system involvement Pseudoparalysis Pneumonitis Rhinitis Ascites Laboratory abnormalities Leukocytosis Anemia (Coombs-negative hemolytic anemia) Thrombocytopenia Renal manifestation (eg, proteinuria, hematuria) Radiographic abnormalities Diaphyseal periostitis or metaphyseal osteochondritis

68 42 33 71 14 23 15 17 14 9 72 58 40 16

78

Used with permission from Jensen.29 *These data are combined from 3 case series described in the references.39-41

Congenital Syphilis Congenital syphilis can lead to (1) fetal demise with spontaneous abortion, usually after the first trimester, or late-term stillbirth in 30 to 40 percent of cases or (2) premature or term delivery of live infants who may have obvious signs of infection or be fully asymptomatic (approximately two-thirds of live-born cases).29 Congenital syphilis can be clinically similar to congenital infections caused by cytomegalovirus, toxoplasmosis, herpes simplex virus, and rubella, as well as bacterial sepsis, blood group incompatability, and numerous other neonatal conditions. For live-born infants, manifestations of congenital syphilis are divided into early signs (those appearing in the first 2 years of life) and late signs (those appearing later over the first 2 decades of life). After fetal infection occurs, any organ system can be affected because of widespread spirochetal dissemination. Hepatitis appears to be an early manifestation that can be detected as elevation of transaminase levels in fetal blood. Anemia and thrombocytopenia appear to occur later. Hydrops fetalis, or diffuse edema, results from anemia-related congestive heart failure. A negative Coombs test in the setting of hydrops highly suggests the etiology of congenital syphilis.30 Hepatomegaly and ascites are attributed largely to heart failure but may be caused in part by hepatic infection. Maternal treatment can interrupt this progression but is less likely to be successful once fetal hepatomegaly and ascites have developed.31 Intrauterine growth retardation may be present.32 The ultimate clinical outcome is related to the timing of fetal infection and timing of subsequent maternal treatment

(when available). In the United States, between 1992 and 1998, the case fatality ratio for congenital syphilis was 6.4 percent.33 Risk of death was associated inversely with the number of prenatal care visits. Almost 90 percent of the fatal cases were associated with lack of or inadequate maternal treatment. Early Congenital Syphilis The frequencies of common early manifestations in symptomatic infants are listed in Table 1. The timing of infection in utero impacts whether early signs are present at birth. Hepatomegaly is seen in the most symptomatic infants. Liver function may be normal, but jaundice caused by syphilitic hepatitis usually is associated with elevated serum transaminase and alkaline phosphatase concentrations. Direct hyperbilirubinemia from cholestasis can occur, and the prothrombin time may be prolonged. Liver disease may resolve slowly and even transiently worsen after treatment. Splenogemaly is present in half of cases, and generalized nonsuppurative adenopathy, including epitrochlear sites, is present in some cases.32,34-40 Mucocutaneous involvement is present in as many as 70 percent of infants and may be apparent at birth or develop during the first few weeks of life. The typical skin eruption consists of small copper-red maculopapular lesions (reminiscent of secondary acquired syphilitic lesions). The hands and feet often are most severely affected (Fig. 5). Desquamation and crusting occur over the course of 1 to 3 weeks. Involvement of nasal mucous membrane takes the form of snuffles (syphilitic rhinitis), which appear after the first week of life.

250

Figure 5 Typical skin lesions in an infant with symptomatic congenital syphilis. Desquamating and exudative lesions around the toes are shown. These lesions are highly contagious by contact. Reprinted with permission from the Committee on Infectious Diseases, American Academy of Pediatrics.48 (Color version of figure is available online.)

The discharge often is blood-tinged; purulence may indicate bacterial superinfection. All mucocutaenous lesions and discharges contain abundant spirochetes and are contagious via contact. Condylomata can arise on mucous membranes or other areas of skin affected by moisture or friction. Mucous patches may been seen in the mouth and genitalia. Fissures may occur around the lips, nares, or anus.32,34 Petechiae may be seen if severe thrombocytopenia is present. Bone involvement occurs in 60 to 80 percent of untreated early congenital cases. It usually is multiple and symmetric. Periostitis and cortical demineralization occur in the metaphyseal and diaphyseal portions of long bones, whereas osteochondritis affects the joints, primarily knees, ankles, wrists, and elbows (Fig. 6). The bony involvement can be very painful, causing the infant to refuse to move the involved extremity. This clinical finding is termed pseudoparalysis of Parrot. When demineralization or destruction of the upper medial tibial metaphysis is evident radiographically, this is called Wimberger sign. Bony involvement usually resolves spontaneously during the first 6 months of life.32,41,42 Neurosyphilis often is asymptomatic and may arise from ongoing dissemination after the neonatal period if the infection goes untreated. Cerebrospinal fluid (CSF) findings are considered suggestive of neurosyphilis in infants with more than 25 WBC/mm3 (up to 200 mononuclear cells per mm3) and protein greater than 150 mg/dL (⬎170 mg/dL in premature infants). A reactive CSF Venereal Disease Research Laboratory (VDRL) test generally indicates the presence of neurosyphilis, although false-positive results may occur. CNS infection can be present with normal CSF indices. CSF findings consistent with neurosyphilis are very common findings among infants with other clinical signs of congenital syphilis and are present in approximately 8 percent of asymptomatic infants born to mothers with untreated early syphilis.32,43,44

C.R. Woods There are two primary clinical presentations of neurosyphilis, although overlap may be considerable. Acute syphilitic leptomeningitis usually becomes apparent during the first several months of life, with signs suggestive of acute bacterial meningitis (eg, vomiting, bulging fontanelle, splitting of sutures, enlarging head circumference). The CSF findings suggest an aseptic process. This form generally responds well to antibiotic therapy.32,45 Chronic meningovascular neurosyphilis generally presents toward the end of the first year of life, with signs of progressive hydrocephalus, cranial nerve palsies, and neurodevelopmental regression. Seizures also are common occurrences, and cerebral infarction from syphilitic endarteritis may occur in the second year of life. Ocular involvement presents most commonly as chorioretinitis, but congenital glaucoma and uveitis also occur.32 Anemia, thrombocytopenia, leukopenia, and leukocytosis are common findings in congenital syphilis. Nonimmune hemolytic anemia can occur and persist for weeks after effective treatment. Pneumonia alba, a fibrosing pneumonitis, occurs in a minority of cases. Radiographically it appears as a slowly resolving, diffuse pulmonic infiltrate. Other findings include failure to thrive, pancreatitis, nephritis, nephrotic syndrome, myocarditis, ileitis, malabsoprtive gastrointestinal fibrosis, testicular masses, alopecia, nail exfolioation, and pituitary gumma.32

Figure 6 Typical radiographic findings in congenital syphilis. Radiograph of the wrist showing deep soft tissue swelling, periosteal reactions of the radius and ulna, and metaphyseal demineralization (metaphysitis) in both long bones with sparing of the distal ends. Courtesy of Richard I. Markowitz, MD.

Syphilis in young children

251

Table 2 Clinical and Surveillance Case Definitions for Congenital Syphilis The diagnosis of congenital syphilis is considered confirmed or definite when Treponema pallidum is identified by darkfield microscopy, direct fluorescent antibody, or other specific stains in specimens from any of the following: 1. infant lesions 2. placenta 3. umbilical cord 4. amniotic fluid 5. autopsy material The diagnosis of congenital syphilis is considered presumptive or probable when 1. An infant is born to a mother who (a) had untreated syphilis, (b) has no documentation of treatment; (c) received treatment with a nonpenicillin therapy, or (d) received penicillin treatment <30 days before delivery; or 2. An infant or child has a reactive treponemal test for syphilis and any one of the following: a. Any evidence of congenital syphilis on clinical exam b. Any evidence of congenital syphilis on long bone radiograph c. Reactive cerebrospinal fluid (CSF) VDRL d. Elevated CSF white blood cell count or protein concentration (without other cause) e. Quantitative nontreponemal serologic titer >4-fold higher than a maternal titer drawn near the time of birth f. Reactive treponemal antibody test beyond age 15 months The diagnosis of congenital syphilis is considered possible in asymptomatic infants when 1. Treponemal or nontreponemal tests are reactive in the absence of evidence of clinical disease. 2. Maternal treatment for syphilis during pregnancy but without the expected post-treatment fall in nontreponemal titers. 3. Maternal treatment for syphilis before pregnancy but with insufficient serologic follow-up to assess treatment response or potential reinfection. Infants whose mothers (a) were treated >1 month before delivery AND (b) have a documented fourfold or greater decline in nontreponemal antibody titers for early syphilis or remained stable for late syphilis AND (c) have no evidence of reinfection or relapse are unlikely to have infection but are considered to have possible congenital syphilis by some experts.

Syphilitic stillbirth is defined as death of a fetus weighing >500 g or having gestational age >20 weeks in which the mother had untreated or inadequately treated syphilis (presumptive case criterion 1 above) or there is direct evidence of T. pallidum in autopsy specimens (as in the confirmed case definition above). Note: The terms confirmed and presumptive typically are used when making assessments for epidemiologic surveillance purposes. The terms definite, probable, and possible are used here in the context of clinical decisionmaking for the purposes of diagnostic evaluation and treatment. Adapted from Sánchez and Gutman2; Ingall and Sánchez32; Committee on Infectious Disease, American Academy of Pediatrics.48

Late Congenital Syphilis Treatment of neonates with congenital syphilis has nearly eliminated these consequences in developed countries, but late manifestations occur in approximately 40 percent of untreated survivors. Many of these manifestations are the destructive residua of early lesions, and, therefore, are not reversible with antibiotic treatment. Nasal cartilage destruction resulting from snuffles can lead to a saddle-nose deformity. Prolonged periostitis can lead to frontal bossing (olympian brow), thickening of the sternoclavicular portion of the clavicle (Higouménakis sign), anterior bowing of the mid-tibia (saber shins), and scaphoid scapula. Clutton joints are symmetric, painless, sterile, synovial effusions, usually localized to the knees. Perforation of the hard palate can be seen.2,32 Syphilitic vasculitis around the time of birth can damage the developing tooth bugs and lead to dental anomalies called Hutchinson teeth (peg-shaped, notched central incisors) and mulberry molars (multicuspid first molars). Deciduous teeth are largely unaffected except for a possible predisposition to dental caries.46 Eye involvement can lead to interstitial keratitis (usually between 5 and 20 years of age), secondary glaucoma, or corneal scarring. Keratitis may respond to cortico-

steroids but not antibiotic therapy.32 Eighth nerve deafness develops in approximately 3 percent of untreated cases and often starts with high frequency hearing loss when the child is between 8 and 10 years of age. Together, Hutchinson teeth, interstitial keratitis, and eighth nerve deafness comprise the Hutchinson triad. Rhagades are spoke-like scars that can develop from earlier fissures around the mouth, anus, and genitalia. Early retinal involvement or hydrocephalous can lead to optic atrophy. Other findings during early congenital syphilis also can persist and progress.2

Diagnosis Diagnostic Testing The diagnosis of syphilis, whether congenital or acquired, is suspected based on clinical findings and confirmed by direct identification of treponemes in clinical specimens or by positive serologic findings (Table 2). Currently available methods for direct identification of T. pallidum in clinical specimens obtained from a primary chancre or active secondary lesions are 1) dark-field microscopy, 2) direct fluorescent

C.R. Woods

252 antibody (DFA) testing, and 3) the rabbit infectivity test, which remains a reference standard but is not available outside research settings.32 Specific tests for antibody to T. pallidum include the fluorescent treponemal antibody absorption (FTA-ABS) test and the treponemal-specific microhemagglutination test (MHATP). The MHA-TP has largely been replaced by the T. pallidum particle agglutination test (TP-PA), which is now used more widely than is the FTA-ABS, which is more difficult to perform. These tests are positive in 75 percent (TP-PA) to 85 percent (FTA-ABS) of patients with primary syphilis and in 100 percent of patients with secondary syphilis. False-positive results of specific treponemal tests rarely occur but may do so in patients with other spirochetal diseases, including Lyme disease, leptospirosis, and diseases caused by other pathogenic Treponema spp. Specific treponemal tests usually remain positive for life. Titers do not correlate with disease activity.2 Nontreponemal tests for syphilis detect antibodies to cardiolipin, a component of membranes and mammalian tissue. The two nontreponemal currently available tests, the rapid plasma reagin test and the VDRL test, use purified cardiolipin in lecithin-cholesterol liposomes. The rapid plasma regain test is positive in approximately 85 percent of cases of primary syphilis and in 98 percent of cases of secondary syphilis. VDRL is positive in approximately 80 percent of primary cases and in 95 percent of secondary cases and is the only serology approved for testing reactivity of spinal fluid.2 Nontreponemal antibody titers reflect disease activity: fourfold decreases suggest adequate therapy, whereas fourfold increases indicate active disease (treatment failure or reinfection). Patients usually revert to seronegative within a year after receiving adequate treatment of primary syphilis and within two years with secondary syphilis. A small minority of patients will remain serofast, with persisting low positive titers despite receiving adequate therapy. Nontreponemal tests are inexpensive but are less sensitive than are the specific treponemal tests. They are used primarily for screening and monitoring of therapy, whereas the treponemal tests are used to establish presumptive diagnosis.2 False-positive reactions with nontreponemal tests occur in approximately 1 percent of normal adults. The reaginic antibody cross reacts with more than 200 non-T. pallidum antigens (although not with the agents of Lyme disease). Falsepositive reactions can occur during some viral infections (eg, infectious mononucleosis, varicella, measles, and perhaps HIV infection), systemic lupus erythematosus, lymphoma, malaria, tuberculosis, hepatitis, and endocarditis, and among injection drug users. False-negative results can occur when a high concentration of antibody inhibits agglutination (the prozone phenomenon), which can be avoided with serial dilutions of the serum. Over the course of time, even some untreated patients may revert to seronegative nontreponemal status. Specific treponemal IgM tests have been developed and assessed in small studies, but at this time none is recommended for use. Polymerase chain reaction (PCR)-based tests and immunoglobulin M immunoblotting tests have been de-

veloped but are not available commercially.32,47,48 PCR-based tests eventually may replace the rabbit infectivity test as the reference standard for syphilis diagnostic tests.43 A number of rapid, low-cost specific antibody detection tests based on immunochromatography or latex particle agglutination have been developed, but they have not been fully validated in field use.49

Definitive and Probable Diagnoses A definitive laboratory diagnosis of syphilis can be made when the presence of T. pallidum is confirmed by direct tests of clinical specimens. A probable diagnosis of syphilis can be made when (1) specific or nonspecific serologic tests are reactive in the presence of clinical findings compatible with syphilis, (2) CSF is reactive by VDRL testing, and 3) a specific treponemal antibody test is reactive in a young child older than 15 months of age (Table 2).32 In the absence of definitive laboratory confirmation, specific treponemal tests should be used to confirm diagnoses suspected on the basis of clinical findings or positive nontreponemal tests. In children with postnatally acquired syphilis, further laboratory evaluation can be based on clinical findings and concerns for potential coinfections.

Congenital Syphilis The maternal serologic status for syphilis should be determined before hospital discharge of newborn infants. In many cases, the first clues are the results of routine maternal screening tests for syphilis.29 Tests of infant serum can be nonreactive if maternal titers are low or the mother was infected late in pregnancy. Cord blood should not be tested because it frequently yields false-positive and false-negative results. When the only evidence of possible syphilis is a newly positive maternal nontreponemal test, the maternal diagnosis should be confirmed with a treponemal test before an otherwise asymptomatic infant undergoes evaluation and treatment for congenital syphilis (unless the wait for results would unduly delay providing appropriate care for the infant).48 Assessment of maternal treatment for syphilis, in terms of the regimen used, timing or therapy relative to delivery (⬍4 weeks versus ⱖ4 weeks), and maternal follow-up and results of serial nontreponemal antibody titers, plays a key role in determining the extent of evaluation and treatment needed for an infant at risk for congenital syphilis. The only maternal treatment considered effective for fetal treatment is Benzathine penicillin G, 2.4 million units intramuscularly, with a single dose deemed sufficient when the mother has primary, secondary, or early latent syphilis (Fig, 4). Three doses administered at 1-week intervals are required for late latent or tertiary syphilis.50 Clinical and surveillance case definitions for congenital syphilis are provided in Table 2. One should note that infant nontreponemal titers fourfold higher than maternal titers are uncommon even in symptomatic cases, and that infant: mother ratios less than fourfold do not exclude congenital infection. It is not necessary to send infant serum for treponemal tests because positive tests do not distinguish between

Syphilis in young children infant or maternal origin of the antibody, and negative tests do not rule out infection. High nontreponemal titers at the time of maternal treatment during pregnancy and at delivery and gestational age less than 37 weeks at delivery are risk factors for the acquisition of congenital syphilis in the neonate even when maternal treatment was adequate (penicillin regimen administered more than 30 days before delivery).51 Recommendations for the evaluation of infants with suspected or confirmed congenital syphilis are listed in Table 3. Long bone radiographs are one of the most sensitive clinical studies for detection of physical evidence of congenital syphilis in otherwise asymptomatic infants.52 Infants who have (a) normal physical findings AND (b) a serum quantitative nontreponemal antibody titer that is fourfold or less than the maternal titer do not require further laboratory or imaging studies IF (a) maternal treatment adequate for the stage of syphilis was administered more than 4 weeks before delivery (including before pregnancy) AND either (b1) if the mother had early syphilis at the time of treatment, her nontreponemal titers decreased at least fourfold and have remained low and stable through the time of delivery, or (b2) if the mother had late syphilis at the time of treatment, her nontreponemal titers have remained low and stable, and there is no evidence of relapse or reinfection.32,53

Treatment Parenteral penicillin G remains the preferred drug for all stages of syphilis. Penicillin G is the only agent documented to be effective for patients with neurosyphilis, congenital syphilis, or syphilis during pregnancy. Penicillin resistance has yet to develop in T. pallidum. Three basic regimens are used in children: 10 to 14 days of procaine penicillin intramuscularly (IM); 10 to 14 days of aqueous penicillin administered intravenously (IV); and a single dose of benzathine penicillin, IM. The choice among these is dictated by the clinical manifestations and the likelihood of follow-up for monitoring of treatment response.48 In scenarios of serious allergic reaction to penicillin, children generally should be desensitized and then treated with penicillin. If this is not possible, expert consultation should be obtained. Treatment recommendations may change in the next few years should more information supporting the use third-generation cephalosporins (not currently recommended) become available. The Jarisch–Herxheimer reaction, which presents as fever, headache, myalgia, and malaise, occurs in some patients 2 to 12 hours after receiving therapy for active syphilis (especially early stages). The reaction is thought to be produced by the release of treponemal endotoxin-like compounds during penicillin-mediated lysis. The reaction is a rare event in newborns but can occur in later infancy and beyond.32

Acquired Syphilis Early acquired syphilis (primary, secondary, or early latent stages) should be treated with 50,000 U/kg of benzathine penicillin G, IM, in a single dose (up to the maximum adult dose of 2.4 million units). Children with neurosyphilis

253 Table 3 Evaluation of Neonates With Suspected or Confirmed Congenital Syphilis Evaluation of infants for suspected†† or confirmed congenital syphilis should include: 1. Detailed physical examination for signs of congenital syphilis 2. Quantitative nontreponemal serologic test of infant serum 3. Specimens for testing for the presence of spirochetes (eg, swab samples) from mucocutaneous lesions, if these are present 4. Complete blood count to assess for anemia, thrombocytopenia 5. CSF analysis for cell count, protein concentration, and VDRL testing*‡ a. Perform in all infants who have (1) abnormal physical findings compatible with congenital syphilis, (2) quantitative nontreponemal titer >4fold higher than the current maternal titer, or (3) direct evidence of T. pallidum in clinical specimens b. White blood cell counts >25/mm3 and protein concentrations >150 mg/dL are considered compatible with congenital neurosyphilis† 6. Long bone radiographs (unless the diagnosis has been confirmed otherwise) 7. Other tests as clinically indicated: a. Chest radiograph if any signs of lower respiratory tract disease (pneumonia alba) b. Liver function test if hepatomegaly or jaundice are present c. Urinalysis d. Ophthalmologic examination e. Imaging studies of the CNS f. Hearing evaluation (otoacoustic emissions or auditory brainstem-evoked response) 8. Pathologic examination of the placenta or umbilical cord if the specimens are available Adapted from Committee on Infectious Diseases, American Academy of Pediatrics48 and Jensen.29 ††Infants who have (a) normal physical findings AND (b) a serum quantitative nontreponemal antibody titer that is the <4-fold the maternal titer do not require further laboratory or imaging studies if the maternal treatment was adequate and maternal nontreponemal titers have showed the expected fall and/or remained low through the time of delivery. [L156] *Some experts also recommend performing the FTA-ABS test on CSF since it may be more sensitive for neurosyphilis, though less specific, than the VDRL. ‡Negative results of CSF serologic tests do not exclude the diagnosis of congenital neurosyphilis. †Some experts recommend that white blood cell counts >5/mm3 and protein concentrations >40 mg/dL be considered the upper limits of normal for purposes of treating neurosyphilis.

should receive aqueous crystalline penicillin G, IV, 200,000 to 300,000 U/kg/d divided every 4 to 6 hours, for 10 to 14 days. Limited data suggest that ceftriaxone may be effective for early syphilis in adults, but this agent is not yet recommended for treatment of syphilis in young children. A single dose is not effective in adults. A single oral dose of azithromycin, 2 g, may be effective in HIV-negative adults, but treat-

C.R. Woods

254 ment failures have been noted.54 Azithromycin has not been evaluated for syphilis in children. In nonpregnant patients 8 years of age or older who are allergic to penicillin, 14-day courses of doxycline or tetracycline may be given. These agents may be considered in younger children if the benefits of therapy are considered to be greater than the risks of dental staining. When any nonpenicillin regimen is used at any age, close follow-up is essential. In penicillin-allergic children younger than 8 years of age, especially in those for whom close follow-up is not assured, consideration should be given to hospitalization and desensitization followed by treatment with penicillin G. Incubating syphilis may be eliminated with penicillin, ampicillin, amoxicillin, ceftriaxone, or azithromycin (but not spectinomycin) treatments given for gonorrhea or chlamydia infection.55

Congenital Syphilis Infants with definite or probable congenital syphilis (Table 1) should be treated with either (1) IV aqueous crystalline penicillin G for a total of 10 to 14 days at 50,000 U/kg per dose every 12 hours (100,000 U/kg/d) during the first 7 days of life and every 8 hours during days of life 8 to 30 (150,000 U/kg/d) or (2) IM procaine penicillin G, 50,000 U/kg/d as a single dose for 10 to 14 days. Higher CSF concentrations of penicillin G are attained with IV aqueous penicillin than with IM procaine penicillin, but both are considered adequate therapy for congenital syphilis. A full 10-day course of penicillin is preferred even if the infant received ampicillin initially for possible sepsis. Also, if more than one day of therapy is missed, the entire course should be restarted.32,48 Infants initially identified as having probable syphilis (Table 2) but who are asymptomatic and have normal evaluation, including CBC, CSF studies, and long bone radiographs, and for whom medical follow-up is certain may be treated with a single IM dose of benzathine penicillin G, 50,000 U/kg. This regimen is based on observations that the likelihood of spirochetal invasion of the CNS is very low in infants who have no clinical or laboratory evidence of congenital syphilis.43,56,57 Some experts prefer the 10-day course for all infants in this category. If any part of the evaluation is abnormal or uninterpretable (eg, CSF contaminated by blood), a full 10- to 14-day regimen is recommended.48 For asymptomatic infants with possible congenital syphilis (Table 1) and for those born to mothers who received adequate treatment before or during pregnancy (unlikely but possible congenital syphilis), the single-dose benzathine penicillin above generally is recommended. Some experts would not treat these infants but follow them closely with clinical and serologic monitoring, if adherence to follow-up appears certain.32,48,50 When congenital syphilis of any stage and site is identified beyond the neonatal period, the treatment regimen for acquired neurosyphilis generally should be used: IV aqueous crystalline penicillin G for 10 days, 200,000 to 300,000 U/kg per day divided every 6 hours. Some experts would follow this regimen with IM doses of benzathine penicillin G,

50,000 U/kg weekly for 3 weeks, and others use this regimen as treatment if disease manifestations are minimal and CSF findings, including VDRL results, are negative.48 When IV or IM penicillin preparations are unavailable58 or cannot be tolerated, IV ampicillin or parenteral ceftriaxone can be considered as alternative therapy. Careful clinical and serologic follow-up is essential when these regimens are used because data for efficacy are insufficient.32,59

Follow-Up Infants should be re-evaluated after treatment for congenital syphilis at 1, 2, 3, 6, and 12 months of age. Nontreponemal tests should be repeated every 2 to 3 months until they have become nonreactive or diminished four-fold. When nontreponemal antibodies are of maternal origin, titers usually become negative within 3 months and should be negative by 6 months of age if the infant was not infected. If titers of nontreponemal antibodies remain stable or increase after ages 6 to 12 months, the child should be re-evaluated (including CSF analysis) and treated with a 10-day parenteral course of penicillin G.48 Treponemal-specific antibodies of maternal origin may persist for as long as 12 to 15 months in 15 percent of uninfected infants born to seropositive women,60 rendering these tests of little help during infancy. Reactivity at 18 months or beyond is indicative of congenital infection. Infants with congenital neurosyphilis (abnormal or uninterpretable CSF WBC count or protein concentration or positive CSF VDRL) should have repeat clinical and CSF evaluations every 6 months until their CSF indices are normal. A reactive CSF VDRL test at any 6-month evaluation represents indication for retreatment. If CSF WBC counts do not steadily decline at each examination or remain abnormal at 2 years, retreatment also is indicated. For children who acquired syphilis less than a year before treatment (early), quantitative nontreponemal tests should be repeated at 3, 6, and 12 months after treatment. Those children with syphilis for longer than a year (late) should have repeat testing at 12 and 24 months. If nontreponemal titers rise or do not fall fourfold within 6 months for early disease or 12 to 24 months with late disease, the child should be re-evaluated for neurosyphilis and HIV infection and should be retreated using the late-disease regimen above.48

Prenatal Testing, Prevention, and International Adoptees All pregnant women should undergo serologic screening early in pregnancy and again at delivery. Women at high risk for having syphilis should undergo testing again at 28 weeks’ gestation.48 Forty-six of the 50 U.S. states and the District of Columbia have laws pertaining to prenatal syphilis screening. Of these, 34 mandate at least one prenatal serology, and 12 include a third-trimester test for either all or high-risk women.61 The presence of state laws

Syphilis in young children tends to correlate with the burden of congenital syphilis among the states. Prenatal screening program costs in developing countries are modest in cost and generally less than $1.00 in countries with syphylis prevalences less than 15 percent. In high-prevalence countries, the cost of preventing a single case of congenital syphilis may be as low as $12 to $70,3 whereas in low-prevalence areas (eg, 1%) the cost is in the range of $50 to $177.62 On-site testing may reduce these costs further.

Contact Isolation Moist open lesions and blood from infants with congenital syphilis and children with acquired primary or secondary syphilis should be considered contagious until they have completed 24 hours of treatment. Gloves should be worn by staff for all patient contact during this time period.48 Confirmed cases of congenital and childhood-acquired syphilis should be reported to local public health authorities.

Syphilis and HIV Coinfection Pregnant women who are known to be infected with HIV are considered at high risk for having active syphilis.63 Serologic tests for syphilis in patients with HIV generally can be interpreted as for HIV-negative persons, but false-negative results have been reported. At this point, infants born to mothers who are coinfected with HIV and syphilis should be evaluated for both diseases according to guidelines for each individual infection. If such an infant is infected with both syphilis and HIV infection, at this time the antibiotic treatment and follow-up recommendations remain the same as for HIVnegative infants with congenital syphilis.64

International Adoptees Syphilis has been identified in international adoptees but is an uncommon finding overall. Congenital syphilis sometimes is undiagnosed and often inadequately treated in developing countries.65 Syphilis testing, therefore, is recommended as part of the evaluation of internationally adopted children, regardless of history or report of evaluation and treatment abroad.

Implications of Syphilis in Young Children Identification of syphilis in young children raises the question of possible sexual abuse. It is an uncommon finding among sexually-abused children, found in 1 percent or less in series in the United States.66,67 The frequency of syphilis transmission to sexually-abused children may be higher in regions with higher adult prevalences of the disease. The clinical manifestations (eg, primary chancre, secondary syphilitic rash, presence of Huthinson teeth) may provide insight into the timing of acquisition of infection. This information may not always help to resolve the potential dilemma of whether the clinical findings are those of previously unrecognized congenital syphilis versus postnatally-acquired syphilis, which suggests a high likelihood of sexual abuse.

255 Also, researchers have postulated that antibiotics commonly prescribed for common childhood illnesses may partially treat congenital syphilis and alter the nature of late clinical manifestations.66 Evaluation of children by specialists in the area of child sexual abuse is recommended. Children diagnosed with syphilis also should be evaluated for HIV infection and other sexually transmitted diseases as clinically indicated. Mothers of infants with congenital syphilis should be evaluated for gonorrhea as well Chlamydia trachomatis, HIV, hepatitis B, and potentially hepatitis C infections. All cases should be reported to local public health authorities, who can undertake evaluation of recent sexual contacts for possible syphilis and other sexually transmitted diseases.48

Future Directions Development of a vaccine to prevent syphilis would represent a major advance and provide a foundation for ultimate worldwide elimination of the disease because there is no nonhuman reservoir. The fully sequenced genome ultimately may provide clues that permit an effective vaccine to be produced, but this advance does not appear to be imminent at this time. Development of an in vitro culture method also could be a useful step that genomic evaluation may facilitate.14,18 Meanwhile, development of even less expensive diagnostic tests and procurement of funds for prenatal screening programs, contact investigations, and antibiotic treatment of all persons identified with syphilis could go a long way toward achieving this goal, even in the absence of a vaccine. This, like many other public health issues, will require international goodwill and cooperation across all levels of government worldwide.

References 1. Hook EW III, Peeling RW: Syphilis control—a continuing challenge. N Enl J Med 351:122-124, 2004 2. Sánchez PJ, Gutman LT: Syphilis, in Feigin RD, Cherry JD, Demmler GJ, et al (eds): Textbook of Pediatric Infectious Diseases (5th ed.) Philadelphia, W.B. Saunders, Co., 2004, pp 1724-1743 3. Walker DG, Walker GJA: Forgotten but not gone: The continuing scourge of congenital syphilis. Lancet Infect Dis 2:432-436, 2002 4. Finelli L, Berman SM, Koumans EH, et al: Congenital syphilis. Bull World Health Org 76:126-128, 1998 (suppl 2) 5. Radolf JD: Role of outer membrane architecture in immune evasion by Treponema pallidum and Borrelia burgdorferi. Trends Microbiol 2:307311, 1994 6. World Health Organization Global prevalence and incidence of selected curable sexually transmitted diseases. World Health Organization, 2001. Available at http://www.who.int/docstore/hiv/GRSTI/ 005.htm; Internet; accessed June 29, 2005 7. Centers for Disease Control and Prevention: Sexually transmitted disease surveillance 2002 supplement, Syphilis surveillance report. Atlanta, GA, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2004 8. Sison CG, Ostrea EM, Reyes MP, et al: The resurgence of congenital syphilis: A cocaine-related problem. J Pediatr 130:289, 1997 9. Centers for Disease Control and Prevention: Congenital syphilis— United States, 2002. MMWR 53:716-719, 2004 10. Saloojee H, Velaphi S, Goga Y, et al: The prevention and management of congenital syphilis: and overview and recommendations. Bull World Health Org 82:424-430, 2004

C.R. Woods

256 11. Salakhov E, Tikhonova L, Southwick K, et al: Congenital syphilis in Russia. The value of counting epidemiologic cases and clinical cases. Sex Transm Dis 31:127-132, 2004 12. Bruckner DA: Nomenclature for aerobic and anaerobic bacteria, in Feigin, RD, Cherry, JD, Demmler GJ (eds): Textbook of Pediatric Infectious Diseases (5th ed). Philadelphia, W.B. Saunders, Co., 2004, pp. 1082-1099 13. Salazar JC, Hazlett KRO, Radolf JD: The immune response to infection with Treponema pallidum, the stealth pathogen. Microbe Infect 4:1133-1140, 2002 14. Fraser CM, Norris SJ, Weinstock GM, et al: Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science 281:375-388, 1998 15. Norris SJ, Weinstock GM: The genome sequence of Treponema pallidum, the syphilis spirochete: Will clinicians benefit? Curr Opinion Infect Dis 13:29-36, 2000 16. Deka RK, Neil L, Hagman KE, et al: Structural evidence that the 32kilodalton lipoprotein (Tp32) of Treponema pallidum is an L-methionine-binding protein. J Biol Chem 279:55644-55650, 2004 17. Treponema Pallidum Polypeptide Research Group: Polypeptides of Treponema pallidum: Progress toward understanding their structural, functional, and immunologic roles. Microbiol Rev 57:750-779, 1993 18. Porcella SF, Schwan TG: Borrelia burgdorferi and Treponema pallidum: A comparison of functional genomics, environmental adaptations, and pathogenic mechanisms. J Clin Invest 107:651-656, 2001 19. Sellati TJ, Bouis DA, Caimano MJ, et al: Activation of human monocytic cells by Borrelia burgdorferi and Treponema pallidum is facilitated by CD14 and correlates with surface exposure of spirochetal lipoproteins. J Immunol 163:2049-2056, 1999 20. Morgan CA, Lukehart SA, Van Voorhis WC: Protection against syphilis correlates with specificity of antibodies to the variable regions of Treponema pallidum repeat protein K. Infect Immun 71:5605-5612, 2003 21. Marra CM, Castro CD, Kuller L, et al: Mechanisms of clearance of Treponema pallidum from the CSF in a nonhuman primate model. Neurol 51:957-961, 1998 22. Sellati TJ, Waldrop SL, Salazar JC, et al: The cutaneous response in humans to Treponema pallidum lipoprotein analogues involves cellular elements of both innate and adaptive immunity. J Immunol 166:41314140, 2001 23. Musher DM, Hague-Park M, Gyrokey F: The interaction between Treponema pallidum and human polymorphonuclear leukocytes. J Infect Dis 147:77-86, 1983 24. Sheffield JS, Sanchez PJ, Wendel GD, et al: Placental histopathology of congenital syphilis. Obstet Gynecol 100:126-133, 2002 25. Guarner J, Greer PW, Bartlett J, et al: Congenital syphilis in a newborn: an immunopathologic study. Mod Pathol 12:82-87, 1999 26. Morgan CA, Molini BJ, Lukehart SA, et al: Segragation of B and T cell epitopes or Treponema pallidum repeat protein K to variable and conserved regions during experimental syphilis infection. J Immunol 169: 952-957, 2002 27. Ackerman AB, Goldfaden G, Cosmides JC: Acquired syphilis in early childhood. Arch Dermatol 106:92, 1972 28. Gutman, LT Congenital syphilis, in Mandell GL (ed): Atlas of Infectious Disease (Vol. 5). Sexually Transmitted Diseases. Philadelphia, Current Medicine, 1996 29. Jensen HB: Congenital syphilis. Semin Pediatr Infect Dis 10:183-194, 1999 30. Bulova SI, Schwartz E, Harrer WV: Hydrops fetalis and congenital syphilis. Pediatrics 49:285-287, 1972 31. Hollier LM, Harstad TW, Sanchez PJ, et al: Fetal syphilis: clinical and laboratory characteristics. Obstet Gynecol 97:947-953, 2001 32. Ingall D, Sánchez PJ. Syphilis, in Remington JS, Klein JO (eds): Infectious Diseases of the Fetus and Newborn Infant (5th ed). Philadelphia, W.B. Saunders, Co. 2001, pp 643-681 33. Gust, DA, Levine, WC, St Louis, ME, et al: Mortality associated with congenital syphilis in the United States, 1992-1998. Pediatrics 2002. Availabe at: http://www.pediatrics.org/cgi/content/full/109/5/e79; Internet; accessed June 29, 2005 34. Saxoni F, Lapaanis P, Pantelakis SN: Congenital syphilis: A description

35. 36. 37.

38. 39. 40. 41. 42. 43.

44. 45. 46. 47.

48.

49.

50. 51.

52.

53.

54.

55.

56.

57.

58. 59. 60.

of 18 cases and re-examination of an old but ever-present disease. Clin Pediatr 6:687-691, 1967 Dorfman DH, Glaser JH: Congenital syphilis presenting in infants after the newborn period. N Engl J Med 323:1299-1302, 1990 Shah MC, Barton LL: Congenital syphilis hepatitis. Pediatr Infect Dis J 8:891-892, 1989 Long WA, Ulshen MA, Lawson EE: Clinical manifestations of congenital syphilitic hepatitis: Implications for pathogenesis. J Pediatr Gastroenterol Nutr 3:551-555, 1984 Chawla V, Pandit PB, Nkrumah FK: Congenital syphilis in the newborn. Arch Dis Child 63:1393-1394, 1988 Mascola L, Pelosi R, Blount JH, et al: Congenital syphilis revisited. Am J Dis Child 139:575-580, 1985 Berry MC, Dajani AS: Resurgence of congenital syphilis. Infect Dis Clin North Am 6:19-29, 1992 Wilkinson RH, Heller RM: Congenital syphilis: Resurgence of an old problem. Pediatrics 47:27-30, 1971 Teberg A, Hodgman JE: Congenital syphilis in newborn. Calif Med 118:5-10, 1973 Sánchez PJ, Wendel GD, Grimprel K, et al: Evaluation of molecular methodologies and rabbit infectivity testing for the diagnosis of congenital syphilis and neonatal central nervous system invasion by Treponema pallidum. J Infect Dis 167:148-157, 1993 Michelow IC, Wendel GD, Norgard MV, et al: Central nervous system infection in congenital syphilis. N Engl J Med 346:1792-1798, 2002 Wolf B, Kalangu K: Congenital neurosyphilis revisited. Eur J Pediatr 152:493, 1993 Nabarro D: Congenital syphilis. London, E Arnold, 1954 Rawstron SA, Mehta S, Bromberg K: Evaluation of a Treponema pallidum-specific IgM enzyme immunoassay and Treponema pallidum western blot antibody detection in the diagnosis of maternal and congenital syphilis. Sex Transm Dis 31:123-126, 2004 Committee on Infectious Diseases, American Academy of Pediatrics. Syphilis, in 2003 Red Book. Elk Grove Village, IL, American Academy of Pediatrics, 2003, pp 595-607 World Health Organization: Laboratory-based evaluation of rapid syphilis diagnostics. The Sexually Transmitted Diseases Diagnostic Initiative. UNDP/World Bank/WHO Special Programme for Research & Training in Tropical Diseases. Geneva, Switzerland. Available at: www.who.int/std_diagnostics; Internet; accessed June 29, 2005 Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR 51(RR-6):18-29, 2002 Sheffield JS, Sánchez PJ, Morris G, et al: Congenital syphilis after maternal treatment for syphilis during pregnancy. Am J Obstet Gynecol 186:569-573, 2002 Moyer VA, Schneider V, Yetman R, et al: Contribution of long-bone radiographs to the management of congenital syphilis in the newborn infant. Arch Pediatr Adolesc Med 152:353, 1998 Stoll BJ, Lee FK, Larsen S, et al: Clinical and serologic evaluation of neonates for congenital syphilis: a continuing diagnostic dilemma. J Infect Dis 167:1093-1099, 1993 Centers for Disease Control and Prevention: Brief report: Azithromycin treatment failures in syphilis infections—San Francisco, California, 2002—2003. MMWR 53:197-198, 2004 Hook EW 3rd, Stephens J, Ennis DM: Azithromycin compared with penicillin G benzathine for treatment of incubating syphilis. Ann Intern Med 131:434-437, 1999 Paryani SG, Vaughn AJ, Crosby M, et al: Treatment of asymptomatic congenital syphilis: Benzathine versus procaine penicillin G therapy. J Pediatr 125:471-475, 1994 Radcliffe M, Meyer M, Roditi D, et al: Single-dose benzathine penicillin in infant’s at risk of congenital syphilis: Results of a randomized study. S Afr Med J 87:62-65, 1997 Centers for Disease Control and Prevention: Notice to readers: Shortage of intravenous penicillin G—United States. MMWR 48:974, 1999 Centers for Disease Control and Prevention. Alternatives to intravenous penicillin G for specific infections. MMWR 48:974, 1999 Marcellino L, Rawstron SA, Mehta S, et al: Congenital syphilis and

Syphilis in young children

61. 62. 63.

64.

fluorescent treponemal antibody test reactivity after the age of 1 year. Sex Transm Dis 28:412-416, 2001 Hollier LM, Hill J, Sheffield JS, et al: State laws regarding prenatal syphilis screening in the United States. Am J Obstet Gynecol 189:1178-1183, 2003 Schmid G: Economic and programmatic aspects of congenital syphilis prevention. Bull World Health Org 82:402-409, 2004 Schulte JM, Burkham S, Hamaker D, et al: Syphilis among HIV-infected mothers and their infants in Texas from 1988 to 1994. Sex Transm Dis 28:315-320, 2001 Mofenson LM, Oleske J, Serchuck L, et al: Treating opportunistic infections among HIV-exposed and infected children: Recommendations

257 from the Centers for Disease Control and Prevention, the National Institutes of Health, and the Infectious Diseases Society of America. Clin Infect Dis 40:S1-S60, 2005 65. Staat MA: Infectious disease issues in internationally adopted children. Pediatr Infect Dis J 21:257-258, 2002 66. Christian, CW, Lavelle, J, Bell, LM Preschoolers with syphilis. Pediatrics 103:e4, 1999. Available at: http://www.pediatrics.org/cgi/content/ full/103/1/e4; Internet; accessed June 29, 2005 67. Ingram DL, Everett VD, Lyna PR, et al: Epidemiology of adult sexually transmitted disease agents in children being evaluated for sexual abuse. Pediatr Infect Dis J 11:945-950, 1992