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Syphilis

Syphilis, a chronic systemic infection caused by Treponema pallidum subspecies pallidum, is usually sexually transmitted and is characterized by episodes of active disease interrupted by periods of latency. After an incubation period averaging 2 to 6 weeks, a primary lesion appears, often associated with regional lymphadenopathy. A secondary bacteremic stage, associated with generalized mucocutaneous lesions and generalized lymphadenopathy, is followed by a latent period of subclinical infection lasting many years. In about one-third of untreated cases, the tertiary stage is characterized by progressive destructive mucocutaneous, musculoskeletal, or parenchymal lesions; aortitis; or symptomatic central nervous system (CNS) disease.

ETIOLOGY

The Spirochaetales include three genera that are pathogenic for humans and for a variety of other animals: Leptospira, which causes human leptospirosis; Borrelia, which causes relapsing fever and Lyme disease; and Treponema, which causes the diseases known as treponematoses. The genus Treponema includes T. pallidum subspecies pallidum, which causes venereal syphilis; T. pallidum subspecies pertenue, which causes yaws; T. pallidum subspecies endemicum, which causes endemic syphilis or bejel; and T. carateum, which causes pinta. Until recently, the subspecies were distinguished primarily by the clinical syndromes they produce. Researchers have now identified molecular signatures that can differentiate T. pallidum subspecies pallidum from the other pathogenic T. pallidum subspecies by culture-independent, polymerase chain reaction (PCR)–based methods. Other Treponema species found in the human mouth, genital mucosa, and gastrointestinal tract have no proven pathogenic role in human disease. These spirochetes can be confused with T. pallidum on dark-field examination.T. pallidum subspecies pallidum (hereafter referred to in this chapter simply as T. pallidum), a thin delicate organism with 6 to 14 spirals and tapered ends, measures 6 to 15 µm in total length and 0.2 µm in width. The cytoplasm is surrounded by a trilaminar cytoplasmic membrane, which in turn is surrounded by a delicate peptidoglycan layer providing some structural rigidity. This layer is surrounded by a lipid-rich outer membrane that contains relatively few integral membrane proteins. Endoflagella wind around the cell body in the periplasmic space and appear to be responsible for motility.The sequencing of the genome of T. pallidum has yielded information about the organism's metabolic capabilities. T. pallidum lacks the genes required to synthesize enzyme cofactors, fatty acids, and nucleotides de novo. In addition, it lacks genes encoding the enzymes of the Krebs cycle and oxidative phosphorylation. To compensate, the organism contains numerous genes predicted to code for transporters of amino acids, carbohydrates, and cations. In addition, the genome analyses and other studies have revealed the existence of a 12-member gene family (called tpr) that bears similarities to variable outer-membrane antigens of other spirochetes. One member, TprK, has discrete variable (V) regions that are targets of the humoral immune response. Data suggest that sequence variation occurs in TprK during infection and that this variation is a mechanism for immune invasion.The only known natural host for T. pallidum is the human. T. pallidum can infect many mammals, but only humans, higher apes, and a few laboratory animals regularly develop syphilitic lesions. Virulent strains of T. pallidum are grown and maintained in rabbits, as none of the pathogenic treponemes has been successfully cultured.

EPIDEMIOLOGY

Nearly all cases of syphilis are acquired by sexual contact with infectious lesions (i.e., the chancre, mucous patch, skin rash, or condyloma latum). Less common modes of transmission include nonsexual personal contact, infection in utero, and blood transfusion.The total number of cases of syphilis reported annually in the United States declined from 575,593 in 1943 to a low of 31,575 in 2000—a 95% decrease. This downward trend was interrupted by an epidemic peaking in 1990. Surveillance of the number of new cases of infectious syphilis—a better indicator of disease activity—has revealed four cycles of 7 to 10 years, each with a rapid rise and fall in incidence (with peaks in 1965, 1975, 1982, and 1990). From 1990 to 2000, the number of reported cases of infectious syphilis declined by >88%. In 1997, however, the number of cases of early syphilis began to rise in Seattle, Washington, marking the beginning of a trend that, by 2000, included Los Angeles and San Francisco. Infectious syphilis rates have also begun to rise in the southern region of the United States.The populations at highest risk for acquiring syphilis have changed. Between 1977 and 1982, approximately half of all patients with early syphilis in the United States were homosexual or bisexual men. The epidemic of syphilis that peaked in 1990 predominantly involved African-American heterosexual men and women and occurred largely in urban areas, where infectious syphilis has been correlated significantly with the exchange of sex for crack cocaine. Since 1996, syphilis rates have declined steadily among African Americans but remain higher than those for other racial/ethnic groups. Foci of syphilis still exist in a small number of counties in the southern United States, and rates are still increasing there. The current outbreak of syphilis in large cities on the West Coast of the United States is focused in men who have sex with men; a high proportion of the individuals in this group who have syphilis are also infected with HIV.The incidence of congenital syphilis roughly parallels that of infectious syphilis in females. The number of reported cases of congenital syphilis in infants ≤1 year of age was lowest (107 cases) in 1978, when infectious syphilis was most prevalent among homosexual and bisexual men. The dramatic increase in the incidence of primary and secondary syphilis among women from 1986 to 1990 resulted in a proportionate increase in the number of infants born with congenital syphilis—to 4424 infants in 1991. The incidence of early syphilis among women has declined since 1991, as has the number of reported cases of congenital syphilis in infants (with 529 cases in 2000). It is important to note that the case definition for congenital syphilis was broadened in 1989 and now includes all live or stillborn infants delivered to women with untreated or inadequately treated syphilis at delivery.Approximately one of every two individuals named as sexual contacts of persons with infectious syphilis becomes infected. Many sexual contacts will already have developed manifestations of syphilis when they are first seen, and ~30% of apparently uninfected contacts who are examined within 30 days of exposure actually have incubating infection and will later develop infectious syphilis if not treated. Thus, the identification and “epidemiologic” treatment of all recently exposed sexual contacts constitute an important aspect of syphilis control. Also important is the identification of infected persons by serologic testing of pregnant women, persons admitted to hospitals, military inductees, and persons undergoing examination in physicians' offices. Still controversial are laws and regulations requiring routine premarital serologic testing for syphilis, where—though national data are not available—the yield is undoubtedly lower.

NATURAL COURSE AND PATHOGENESIS OF UNTREATED SYPHILIS

T. pallidum rapidly penetrates intact mucous membranes or microscopic abrasions in skin and within a few hours enters the lymphatics and blood to produce systemic infection and metastatic foci long before the appearance of a primary lesion. Blood from a patient with incubating or early syphilis is infectious. The generation time of T. pallidum during early active disease in vivo is estimated to be 30 to 33 h, and the incubation period of syphilis is inversely proportional to the number of organisms inoculated. The concentration of treponemes generally reaches at least 10⁷/g of tissue before the appearance of a clinical lesion. On the basis of intradermal injection of graded doses of T. pallidum into eight volunteers, the 50% infectious dose was calculated to be 57 organisms. The median incubation period in humans (~21 days) suggests an average inoculum of 500 to 1000 infectious organisms for naturally acquired disease. The incubation period (from inoculation until the primary lesion becomes discernible) rarely exceeds 6 weeks. Subcurative therapy during the incubation period may delay the onset of the primary lesion, but it is not certain that such treatment reduces the probability that symptomatic disease will ultimately develop.The primary lesion appears at the site of inoculation, usually persists for 4 to 6 weeks, and then heals spontaneously. Histopathologic examination of primary lesions shows perivascular infiltration, chiefly by lymphocytes (including CD8+ and CD4+ cells), plasma cells, and macrophages, with capillary endothelial proliferation and subsequent obliteration of small blood vessels. The cellular infiltration displays a T_H1-type cytokine profile consistent with the activation of macrophages. At this time T. pallidum is demonstrable in the chancre in spaces between epithelial cells; within invaginations or phagosomes of epithelial cells, fibroblasts, plasma cells, and the endothelial cells of small capillaries; within lymphatic channels; and in the regional lymph nodes. Phagocytosis of organisms by activated macrophages ultimately causes their destruction, which results in spontaneous resolution of the chancre.The generalized parenchymal, constitutional, and mucocutaneous manifestations of secondary syphilis usually appear about 6 to 8 weeks after healing of the chancre, although 15% of patients with secondary syphilis still have persisting or healing chancres. In other patients, secondary lesions may appear several months after the chancre has healed, and some patients may enter the latent stage without ever recognizing secondary lesions. The histopathologic features of secondary maculopapular skin lesions are hyperkeratosis of the epidermis; capillary proliferation with endothelial swelling in the superficial corium; and dermal papillae with transmigration of polymorphonuclear leukocytes and, in the deeper corium, perivascular infiltration by CD8+ lymphocytes, CD4+ lymphocytes and macrophages, and plasma cells. Treponemes are found in many tissues, including the aqueous humor of the eye and the cerebrospinal fluid (CSF). Invasion of the CNS by T. pallidum occurs during the first weeks or months of infection, and CSF abnormalities are detected in as many as 40% of patients during the secondary stage. Clinical hepatitis and immune complex–induced membranous glomerulonephritis are relatively rare but recognized manifestations of secondary syphilis; liver function tests may yield abnormal results in up to a quarter of patients with early syphilis. Generalized nontender lymphadenopathy is noted in 85% of patients with secondary syphilis. The paradoxical appearance of secondary manifestations despite high titers of antibody (including immobilizing antibody) to T. pallidum is unexplained but may result from changes in expression of surface antigens. Secondary lesions subside within 2 to 6 weeks, and the infection enters the latent stage, which is detectable only by serologic testing. In the preantibiotic era, up to 25% of untreated patients experienced at least one generalized or localized mucocutaneous relapse, usually during the first year; therefore, identification and examination of sexual contacts are most important for patients with syphilis of <1 year's duration. Recurrent generalized rash is now rare.In the preantibiotic era, about one-third of patients with untreated latent syphilis developed clinically apparent tertiary disease; today, in industrialized countries, specific treatment and coincidental therapy for early and latent syphilis have all but eliminated tertiary disease except for sporadic cases of neurosyphilis in persons infected with HIV. In the past, the most common type of tertiary disease was the gumma, a usually benign granulomatous lesion. Today, gummas are very uncommon. Cardiovascular syphilis, now also rare, is caused by obliterative small-vessel endarteritis, usually involving the vasa vasorum of the ascending aorta and resulting in aneurysm. Asymptomatic CNS involvement is demonstrable in up to 25% of patients with late latent syphilis. The factors that contribute to the development and progression of tertiary disease are unknown.The course of untreated syphilis was studied retrospectively in a group of nearly 2000 patients with primary or secondary disease diagnosed clinically (the Oslo Study, 1891–1951) and was assessed prospectively in 431 African-American men with seropositive latent syphilis of ≥3 years' duration (the notorious Tuskegee Study, 1932–1972). In the Oslo Study, 24% of patients developed relapsing secondary lesions within 4 years, and 28% eventually developed one or more manifestations of tertiary syphilis. Cardiovascular syphilis, including aortitis, was detected in 10% of patients, none of whom had been infected before age 15; 7% of patients developed symptomatic neurosyphilis, and 16% developed benign tertiary syphilis (gummas of the skin, mucous membranes, and skeleton). Syphilis was the primary cause of death in 15% of men and 8% of women. Cardiovascular syphilis was documented in 35% of men and 22% of women who eventually came to autopsy. In general, serious late complications were nearly twice as common among men as among women.The Tuskegee Study showed that the death rate among untreated African-American men with syphilis (25 to 50 years old) was 17% higher than that among uninfected subjects and that 30% of all deaths were attributable to cardiovascular or CNS syphilis. By far the most important factor in increased mortality was cardiovascular syphilis. Anatomic evidence of aortitis was found in 40 to 60% of autopsied subjects with syphilis (vs. 15% of control subjects), whereas CNS syphilis was found in only 4%. Rates of hypertension were also higher among the infected subjects. The ethical issues eventually raised by this study, begun in the preantibiotic era but continuing into the early 1970s, had a major influence on the development of current guidelines for human medical experimentation, and the history of the study may still contribute to a reluctance of some African Americans to participate as subjects in clinical research.These two studies both showed that about one-third of patients with untreated syphilis develop clinical or pathologic evidence of tertiary syphilis, that about one-fourth die as a direct result of tertiary syphilis, and that there is additional excess mortality not directly attributable to tertiary syphilis.

MANIFESTATIONS

Primary SyphilisThe typical primary chancre usually begins as a single painless papule that rapidly becomes eroded and usually becomes indurated, with a characteristic cartilaginous consistency on palpation of the edge and base of the ulcer. In heterosexual men the chancre is usually located on the penis, whereas in homosexual men it is often found in the anal canal or rectum, in the mouth, or on the external genitalia. In women, common primary sites are the cervix and labia. Consequently, primary syphilis goes unrecognized in women and homosexual men more often than in heterosexual men. Multiple primary lesions may be more common among men with concurrent HIV infection.Atypical primary lesions are common. The clinical appearance depends on the number of treponemes inoculated and on the immunologic status of the patient. A large inoculum produces a dark-field-positive ulcerative lesion in nonimmune volunteers but may produce a small dark-field-negative papule, an asymptomatic but seropositive latent infection, or no response at all in individuals with a history of syphilis. A small inoculum may produce only a papular lesion, even in nonimmune individuals. Therefore, syphilis should be considered even in the evaluation of trivial or atypical dark-field-negative genital lesions. The genital lesions that most commonly must be differentiated from those of primary syphilis include those caused by herpes simplex virus infection, chancroid, traumatic injury, and donovanosis. Primary genital herpes may produce inguinal adenopathy, but the nodes are tender and the lesions consist of multiple painful vesicles, which later ulcerate and are often accompanied by systemic symptoms, including fever. Recurrent genital herpes typically begins with a unilateral cluster of painful vesicles, usually without associated adenopathy. Chancroid produces painful, superficial, exudative, nonindurated ulcers, more often multiple than in syphilis; adenopathy is common, can be either unilateral or bilateral, is tender, and may be suppurative. Donovanosis, which is rare in the United States and Europe, is usually seen as a granulomatous ulcer that, although painless, is friable.Regional lymphadenopathy usually accompanies the primary syphilitic lesion, appearing within 1 week of the onset of the lesion. The nodes are firm, nonsuppurative, and painless. Inguinal lymphadenopathy is bilateral and may occur with anal as well as with external genital chancres. The chancre generally heals within 4 to 6 weeks (range, 2 to 12 weeks), but lymphadenopathy may persist for months.Secondary SyphilisThe protean manifestations of the secondary stage usually include localized or diffuse symmetric mucocutaneous lesions and generalized nontender lymphadenopathy. The healing primary chancre is still present in 15% of cases, and the stages may overlap more frequently in persons with concurrent HIV infection than in those without this co-infection. The skin rash consists of macular, papular, papulosquamous, and occasionally pustular syphilides; often more than one form is present simultaneously. The eruption may be very subtle. Approximately 25% of patients with a discernible rash of secondary syphilis may be unaware that they have dermatologic manifestations. Initial lesions are bilaterally symmetric, pale red or pink, nonpruritic, discrete, round macules that measure 5 to 10 mm in diameter and are distributed on the trunk and proximal extremities. After several days or weeks, red papular lesions 3 to 10 mm in diameter also appear. These lesions, which may progress to necrotic lesions (resembling pustules) in association with increasing endarteritis and perivascular mononuclear infiltration, are distributed widely, frequently involve the palms and soles , and may occur on the face and scalp. Tiny papular follicular syphilides involving hair follicles may result in patchy alopecia, with loss of scalp hair, eyebrows, or beard in up to 5% of cases.In warm, moist, intertriginous body areas, including the perianal area, vulva, scrotum, inner thighs, axillae, and skin under pendulous breasts, papules can enlarge and become eroded to produce broad, moist, pink or gray-white, highly infectious lesions called condylomata lata ; these lesions develop in 10% of patients with secondary syphilis. Superficial mucosal erosions, called mucous patches, occur in 10 to 15% of patients and may involve the lips, oral mucosa, tongue, palate, pharynx, vulva and vagina, glans penis, or inner prepuce. The typical mucous patch is a painless silver-gray erosion surrounded by a red periphery. During relapses of secondary syphilis, condylomata lata are particularly common, and skin lesions tend to be asymmetrically distributed and more infiltrated, resembling skin lesions of late syphilis. These characteristics may reflect increasing cellular immunity.Constitutional symptoms that may accompany or precede secondary syphilis include sore throat (15 to 30%), fever (5 to 8%), weight loss (2 to 20%), malaise (25%), anorexia (2 to 10%), headache (10%), and meningismus (5%). Acute meningitis occurs in only 1 to 2% of cases, but numbers of cells and levels of protein in CSF are increased in ≥30% of cases. T. pallidum has been recovered from CSF during primary and secondary syphilis in 30% of cases; this finding is often but not always associated with other CSF abnormalities.Less common complications of secondary syphilis include hepatitis, nephropathy, gastrointestinal involvement (hypertrophic gastritis, patchy proctitis, ulcerative colitis, or a rectosigmoid mass), arthritis, and periostitis. Ocular findings that suggest secondary syphilis include otherwise-unexplained pupillary abnormalities, optic neuritis, and a retinitis pigmentosa syndrome as well as the classic iritis (especially granulomatous iritis) or uveitis. The diagnosis of secondary syphilis is often considered in such patients only after they fail to respond to steroid therapy. Anterior uveitis has been reported in 5 to 10% of patients with secondary syphilis, and T. pallidum has been demonstrated in the aqueous humor from such patients. Hepatic involvement is common in syphilis; although it is usually asymptomatic, at least 25% of patients may have abnormal liver function tests. Frank syphilitic hepatitis is distinguished by an unusually high serum level of alkaline phosphatase and by a nonspecific histologic appearance that is unlike that of viral hepatitis and includes moderate inflammation with polymorphonuclear leukocytes and lymphocytes, some hepatocellular damage, and no cholestasis. Renal involvement produces proteinuria associated with an acute nephrotic syndrome (or rarely with hemorrhagic glomerulonephritis) and is characterized by subepithelial electron-dense deposits and glomerular immune complexes—findings suggesting immune-complex glomerulonephritis. Like those of primary syphilis, the manifestations of the secondary stage resolve spontaneously, usually within 1 to 6 months.Latent SyphilisPositive serologic tests for syphilis, together with a normal CSF examination and the absence of clinical manifestations of syphilis, indicate a diagnosis of latent syphilis. The diagnosis is often suspected on the basis of a history of primary or secondary lesions, a history of exposure to syphilis, or the delivery of an infant with congenital syphilis. A previous negative serologic test or a history of lesions or exposure may help establish the duration of latent infection, which is an important factor in the selection of appropriate therapy. Early latent syphilis encompasses the first year after infection, whereas late latent syphilis (beginning ≥1 year after infection in the untreated patient) is associated with relative immunity to infectious relapse. T. pallidum may still seed the bloodstream intermittently during the latent stage, and pregnant women with latent syphilis may infect the fetus in utero. Moreover, syphilis has been transmitted through the transfusion of blood from patients with latent syphilis of many years' duration. It was previously thought that untreated late latent syphilis had three possible outcomes: (1) it could persist throughout the lifetime of the infected individual; (2) it could end in the development of late syphilis; or (3) it could end with the spontaneous cure of infection, with reversion of serologic tests to negative. It is now apparent, however, that the more sensitive treponemal antibody tests rarely, if ever, become negative without treatment. About 70% of untreated patients with latent syphilis never develop clinically evident late syphilis, but the occurrence of spontaneous cure is in doubt.Involvement of the Central Nervous SystemTraditionally, neurosyphilis has been considered to be a late manifestation of syphilis, but this view is inaccurate. CNS syphilis represents a continuum encompassing early invasion (usually within the first weeks or months of infection), months to years of asymptomatic involvement, and, in some cases, development of early or late neurologic manifestations.

ASYMPTOMATIC NEUROSYPHILIS

The diagnosis of asymptomatic neurosyphilis is made in patients who lack neurologic symptoms and signs but who have CSF abnormalities including mononuclear pleocytosis, increased protein concentrations, or a reactive Venereal Disease Research Laboratory (VDRL) slide test. Such abnormalities are found in up to one-quarter of patients with untreated latent syphilis, and these are the patients who are known to be at risk for neurologic complications. In primary and secondary syphilis, such abnormalities may be found in up to 40% of untreated patients, and T. pallidum can be isolated from CSF of 30% of patients even in the absence of other CSF abnormalities. Although the therapeutic implications of these findings in early syphilis are uncertain, it seems appropriate to conclude that even patients with early syphilis who have such findings do indeed have asymptomatic neurosyphilis and should be treated for neurosyphilis. In patients with untreated asymptomatic neurosyphilis, the overall cumulative probability of progression to clinical neurosyphilis is about 20% in the first 10 years but increases with time; the likelihood is highest among patients with the greatest degree of pleocytosis or protein elevation. Patients with untreated latent syphilis and normal CSF probably run no risk of subsequent neurosyphilis. In one study, neurosyphilis was associated with a rapid plasma reagin (RPR) titer of ≥1:32, regardless of clinical stage or HIV infection status.

SYMPTOMATIC NEUROSYPHILIS

Although mixed features are common, the major clinical categories of symptomatic neurosyphilis include meningeal, meningovascular, and parenchymatous syphilis. The last category includes general paresis and tabes dorsalis. The onset of symptoms usually comes <1 year after infection for meningeal syphilis, at 5 to 10 years for meningovascular syphilis, at 20 years for general paresis, and at 25 to 30 years for tabes dorsalis. However, symptomatic neurosyphilis, particularly in the antibiotic era, often presents not as a classic picture but rather as mixed and subtle or incomplete syndromes.Meningeal syphilis may involve either the brain or the spinal cord, and patients may present with headache, nausea, vomiting, neck stiffness, cranial nerve involvement, seizures, and changes in mental status. This condition may be concurrent with or may follow the secondary stage. Patients presenting with uveitis or iritis frequently have meningeal syphilis. Meningovascular syphilis reflects diffuse inflammation of the pia and arachnoid together with evidence of focal or widespread arterial involvement of small, medium, or large vessels. The most common presentation is a stroke syndrome involving the middle cerebral artery of a relatively young adult; however, unlike the usual thrombotic or embolic stroke syndrome of sudden onset, meningovascular syphilis often becomes manifest after a subacute encephalitic prodrome (with headaches, vertigo, insomnia, and psychological abnormalities), which is followed by a gradually progressive vascular syndrome.The manifestations of general paresis reflect widespread late parenchymal damage and include abnormalities corresponding to the mnemonic paresis: personality, affect, reflexes (hyperactive), eye (e.g., Argyll Robertson pupils), sensorium (illusions, delusions, hallucinations), intellect (a decrease in recent memory and in the capacity for orientation, calculations, judgment, and insight), and speech. Tabes dorsalis is also a late manifestation of syphilis that presents as symptoms and signs of demyelination of the posterior columns, dorsal roots, and dorsal root ganglia. Symptoms include ataxic wide-based gait and footslap; paresthesia; bladder disturbances; impotence; areflexia; and loss of position, deep pain, and temperature sensations. Trophic joint degeneration (Charcot's joints) and perforating ulceration of the feet can result from loss of pain sensation. The small, irregular Argyll Robertson pupil, a feature of both tabes dorsalis and paresis, reacts to accommodation but not to light. Optic atrophy also occurs frequently in association with tabes.Other Manifestations of Late SyphilisThe slowly progressive inflammatory disease leading to tertiary manifestations begins early during the pathogenesis of syphilis, although these manifestations may not become clinically apparent for years. Early syphilitic aortitis becomes evident soon after secondary lesions subside, and treponemes that trigger the development of gummas may have seeded the tissue years earlier.

CARDIOVASCULAR SYPHILIS

Cardiovascular manifestations are attributable to endarteritis obliterans of the vasa vasorum, which provide the blood supply to large vessels. This condition results in uncomplicated aortitis, aortic regurgitation, saccular aneurysm, or coronary ostial stenosis, with symptoms usually appearing 10 to 40 years after infection. In the preantibiotic era, symptomatic cardiovascular complications developed in ~10% of persons with late untreated syphilis, although syphilitic aortitis was demonstrated at autopsy in about one-half of African-American men with untreated syphilis.Linear calcification of the ascending aorta on chest x-ray films suggests asymptomatic syphilitic aortitis, as arteriosclerosis seldom produces this sign. Syphilitic aneurysms—usually saccular, occasionally fusiform—do not lead to dissection. Only 1 in 10 aortic aneurysms of syphilitic origin involves the abdominal aorta.

LATE BENIGN SYPHILIS (GUMMA)

Gummas may be multiple or diffuse but are usually solitary lesions that range from microscopic in size to several centimeters in diameter. Histologic examination shows a granulomatous inflammation with a central area of necrosis. Although rarely demonstrated microscopically, T. pallidum has reportedly been recovered from these lesions. The most commonly involved sites include the skin and skeletal system, the mouth and upper respiratory tract, the larynx, the liver, and the stomach; however, any organ may be involved. Gummas of the skin produce painless and indurated nodular, papulosquamous, or ulcerative lesions that are usually indolent. These lesions may resemble those of many other chronic granulomatous conditions, including tuberculosis and sarcoidosis, leprosy, and deep fungal infections. Skeletal gummas most frequently involve the long bones of the legs, although any bone may be affected. Radiographic abnormalities with advanced gummas of bone include periostitis or destructive or sclerosing osteitis. Upper respiratory gummas can lead to perforation of the nasal septum or palate.Because the histologic changes may be suggestive but are nonspecific, the diagnosis of late benign syphilis is confirmed by serologic testing and by therapeutic trial. Treatment with penicillin results in rapid healing of active gummatous lesions.Congenital SyphilisTransmission of T. pallidum from a syphilitic woman to her fetus across the placenta may occur at any stage of pregnancy, but the lesions of congenital syphilis generally have their onset after the fourth month of gestation, when fetal immunologic competence begins to develop. This timing suggests that the pathogenesis of congenital syphilis depends on the immune response of the host rather than on a direct toxic effect of T. pallidum. The risk of infection of the fetus during untreated early maternal syphilis is estimated to be 75 to 95%, decreasing to about 35% for maternal syphilis of >2 years' duration. Adequate treatment of the mother before the 16th week of pregnancy should prevent fetal damage. Untreated maternal infection may result in a rate of fetal loss of up to 40% (with stillbirth more common than abortion because of the late onset of fetal pathology), prematurity, neonatal death, or nonfatal congenital syphilis. Among infants born alive, only fulminant congenital syphilis is clinically apparent at birth, and these babies have a very poor prognosis. The most common clinical problem is the healthy-appearing baby born to a mother with a positive serologic test. Routine serologic testing in early pregnancy is considered cost-effective in virtually all populations, even in areas with a low prenatal prevalence of syphilis. Where the prevalence of syphilis is high or when the patient is at high risk, serologic testing should be repeated in the third trimester and at delivery.The manifestations of congenital syphilis can be divided into three types according to their timing: (1) early manifestations, which appear within the first 2 years of life (often between 2 and 10 weeks of age), are infectious and resemble the manifestations of severe secondary syphilis in the adult; (2) late manifestations, which appear after 2 years and are noninfectious; and (3) residual stigmata. The earliest sign of congenital syphilis is usually rhinitis, or “snuffles” (23%), which is soon followed by other mucocutaneous lesions (35 to 41%). These may include bullae (syphilitic pemphigus), vesicles, superficial desquamation, petechiae, and (later) papulosquamous lesions, mucous patches, and condylomata lata. The most common early manifestations are bone changes (61%), including osteochondritis, osteitis, and periostitis. Hepatosplenomegaly (50%), lymphadenopathy (32%), anemia (34%), jaundice (30%), thrombocytopenia, and leukocytosis are common. T. pallidum can be isolated, by rabbit inoculation, from the CSF of 22% of infected neonates without prior antibiotic exposure.Neonatal congenital syphilis must be differentiated from other generalized congenital infections, including rubella, cytomegalovirus or herpes simplex virus infection, and toxoplasmosis, as well as from erythroblastosis fetalis. Neonatal death is usually due to pulmonary hemorrhage, secondary bacterial infection, or severe hepatitis.Late congenital syphilis is that which remains untreated after 2 years of age. In 60% of cases, the infection remains subclinical; the clinical spectrum in the remainder of cases differs in certain respects from that of acquired late syphilis in the adult. For example, cardiovascular syphilis rarely develops in late congenital syphilis, whereas interstitial keratitis is much more common and occurs between the ages of 5 and 25. Other manifestations include eighth-nerve deafness and recurrent arthropathy. Bilateral knee effusions are known as Clutton's joints. Asymptomatic neurosyphilis is present in about one-third of untreated patients, and clinical neurosyphilis occurs in one-quarter of untreated individuals >6 years old. Gummatous periostitis occurs between the ages of 5 and 20 and, as in nonvenereal endemic syphilis, tends to cause destructive lesions of the palate and nasal septum.Characteristic stigmata include Hutchinson's teeth—centrally notched, widely spaced, peg-shaped upper central incisors—and “mulberry” molars—sixth-year molars with multiple, poorly developed cusps. The abnormal facies of patients with congenital syphilis include frontal bossing, saddle nose, and poorly developed maxillae. Saber shins, characterized by anterior tibial bowing, are rare. Rhagades are linear scars at the angles of the mouth and nose that are caused by secondary bacterial infection of the early facial eruption.

LABORATORY EXAMINATIONS

Demonstration of the OrganismT. pallidum cannot be detected by culture; therefore, other tests are necessary. Dark-field microscopic examination of lesion exudate is useful in evaluating moist cutaneous lesions, such as the chancre of primary syphilis or the condylomata lata of secondary syphilis. The identification of a single characteristic motile organism by a trained observer is sufficient for diagnosis. Examination of oral lesions and anal ulcers by this method is not recommended, as it is difficult to differentiate T. pallidum from other spirochetes that may be present.Most syphilis is diagnosed in settings where dark-field microscopy is not available. The direct fluorescent antibody T. pallidum (DFA-TP) test, an alternative available at central laboratories, uses fluorescein-conjugated polyclonal antitreponemal antibody for the detection of T. pallidum in fixed smears prepared from suspect lesions. More sensitive PCR tests have been developed but are available only in research laboratories.T. pallidum can be found in tissue with appropriate silver stains, although these results should be interpreted with caution because artifacts resembling T. pallidum are often seen. Treponemes can be demonstrated more reliably in tissue by immunofluorescence or immunohistochemical methods using specific monoclonal or polyclonal antibodies to T. pallidum.Serologic Tests for SyphilisThere are two types of serologic test for syphilis: nontreponemal and treponemal. Both types of test are reactive in persons with any treponemal infection, including yaws, pinta, and endemic syphilis.The nontreponemal tests measure IgG and IgM directed against a cardiolipin-lecithin-cholesterol antigen complex. The most widely used nontreponemal antibody tests for syphilis are the RPR test, which can be automated (ART), and the VDRL slide test. The RPR test is easier to perform and uses unheated serum; it is the test of choice for rapid serologic diagnosis in a clinic or office setting. The VDRL test, however, remains the standard for use with CSF.The RPR and VDRL tests are equally sensitive and may be used for initial screening or for quantitation of serum antibody. The titer reflects the activity of the disease. Titers rise during the evolution of early syphilis; VDRL titers usually reach 1:32 or higher in secondary syphilis. A persistent fall by two dilutions (fourfold) or more after treatment of early syphilis provides essential evidence of an adequate response to therapy. VDRL titers do not correspond directly to RPR titers, and sequential quantitative testing (as for response to therapy) must employ a single test.Two standard treponemal tests are used for confirmation of reactive nontreponemal results: the fluorescent treponemal antibody–absorbed (FTA-ABS) test and the agglutination assays for antibodies to T. pallidum. The microhemagglutination assay for T. pallidum (MHA-TP) has been replaced by the Serodia TP-PA test (Fujirebio, Tokyo), which is more sensitive for primary syphilis. The T. pallidum hemagglutination test (TPHA) is widely used in Europe but is not available in the United States. Both the agglutination assays and the FTA-ABS test are very specific and, when used for confirmation of positive nontreponemal tests, have a very high positive predictive value for the diagnosis of syphilis. However, even these tests give false-positive results at rates as high as 1 to 2% when used for the screening of normal populations. New enzyme-linked immunosorbent assays have also been approved as confirmatory tests.The relative sensitivities of the VDRL and RPR tests, the FTA-ABS test, and the TP-PA test in the various stages of untreated syphilis are shown in Table 1. The nontreponemal tests may be nonreactive in very early primary syphilis, and the detection of antibody can be maximized by the performance of a treponemal test. All treponemal and nontreponemal tests are reactive during secondary syphilis, and a nonreactive result virtually excludes syphilis in a patient with otherwise-compatible mucocutaneous lesions. (Fewer than 1% of patients with secondary syphilis have a VDRL test that is nonreactive or weakly reactive with undiluted serum but is positive at higher serum dilutions—the prozone phenomenon.) Although the nontreponemal tests will become nonreactive or will be reactive at lower titers after therapy for early syphilis, the treponemal tests often remain reactive after therapy and therefore are not helpful in determining the infection status of persons with past syphilis. Treatment of early primary syphilis may result in seroreversion in treponemal tests.

For practical purposes, most clinicians need to be familiar with the three uses of serologic tests for syphilis: (1) testing of large numbers of sera for screening or diagnostic purposes (e.g., the RPR or VDRL test), (2) quantitative measurement of antibody titer to assess the clinical activity of syphilis or to monitor the response to therapy (e.g., the RPR or VDRL test), and (3) confirmation of the diagnosis of syphilis in a patient with a positive nontreponemal antibody test or with a suspected clinical diagnosis of syphilis (e.g., the FTA-ABS test or the Serodia TP-PA test).For measurement of IgM in neonates in whom congenital syphilis is suspected, the syphilis Captia-M test (Trinity Biotech, Jamestown, NY) and the 19S IgM FTA-ABS test are available.False-Positive Serologic Tests for SyphilisBecause the antigen used in nontreponemal tests is found in other tissues, the tests may be reactive in persons without treponemal infection, although rarely do titers exceed 1:8 in such patients. In a population selected for screening because of clinical suspicion, history of exposure, or increased risk for sexually transmitted infections, fewer than 1% of reactive tests are falsely positive. The modern VDRL and RPR tests are 97 to 99% specific, and false-positive reactions are now limited largely to those conditions listed in Table 2. False positivity is common among persons with autoimmune disorders. The prevalence of false-positive nontreponemal tests increases with advancing age; 10% of people >70 years of age have false-positive reactions. In the patient with a false-positive nontreponemal test, syphilis is excluded by a nonreactive treponemal test.

Evaluation for NeurosyphilisInvolvement of the CNS is detected by examination of CSF for pleocytosis (>5 white blood cells/mm³), increased protein concentration (>45 mg/dL), or VDRL reactivity. CSF abnormalities can be demonstrated in up to 40% of cases of primary or secondary syphilis and in 25% of cases of latent syphilis. In older asymptomatic seropositive individuals, the yield of lumbar puncture is relatively low. T. pallidum has been recovered by CSF inoculation into rabbits from up to 30% of patients with primary or secondary syphilis but rarely from those with latent syphilis. The demonstration of T. pallidum in CSF is often associated with other CSF abnormalities; however, organisms can be recovered from patients with otherwise-normal CSF. Before the advent of penicillin, the risk of developing clinical neurosyphilis was roughly proportional to the intensity of CSF changes. CSF examination is recommended by the Centers for Disease Control and Prevention (CDC) in the evaluation of any seropositive patient with neurologic signs and symptoms, patients with other late syphilis, cases of suspected treatment failure, and HIV-infected patients with untreated syphilis of unknown duration or of >1 year's duration. The possibility of asymptomatic neurosyphilis in some patients with early disease is not addressed by these recommendations. Because standard therapy with penicillin G benzathine (benzathine benzylpenicillin) for early syphilis fails to result in treponemicidal drug levels in the CSF, some experts also advise lumbar puncture in early syphilis, particularly in patients with HIV infection or with nontreponemal test titers of ≥1:32.The CSF VDRL test is highly specific but is insensitive and may be nonreactive even in cases of progressive symptomatic neurosyphilis. The degree of sensitivity is highest in meningovascular syphilis and paresis and is lower in asymptomatic neurosyphilis and tabes dorsalis. The unabsorbed FTA test on CSF is reactive far more often than the CSF VDRL test in all stages of syphilis, but FTA reactivity may reflect passive transfer of serum antibody into the CSF. A nonreactive CSF FTA test, however, may be used to rule out neurosyphilis.Evaluation for Syphilis in Patients Infected with HIVBecause persons at highest risk for syphilis (inner-city populations, homosexually active men, and people in many developing countries) are also at increased risk for HIV infection, these two infections frequently coexist. There is evidence that syphilis and other genital-ulcer diseases may be important risk factors for the acquisition and transmission of HIV infection.The manifestations of syphilis may be altered in patients with concurrent HIV infection, and multiple cases of neurologic relapse after standard therapy have been reported in HIV-infected patients. T. pallidum has been isolated from the CSF of several patients after therapy for early syphilis with penicillin G benzathine. A multicenter U.S. study of early syphilis found similar clinical responses to therapy in persons with and without concurrent HIV infection, although the study lacked sufficient statistical power to exclude an effect of HIV and 41% of subjects were lost to follow-up. Serologically defined treatment failure was more common among HIV-infected patients than among those without this co-infection. This investigation confirmed the high rate of CNS invasion in early syphilis and the persistence of T. pallidum after standard therapy: 11 of 43 HIV-infected patients and 21 of 88 HIV-uninfected patients had T. pallidum detectable in CSF before therapy; 7 of the 35 patients who underwent lumbar puncture after therapy (some HIV-infected and others uninfected) still had T. pallidum detectable in CSF.There is no clear evidence that the sensitivity of serologic tests for syphilis differs in HIV-infected versus HIV-uninfected patients. Rates of decline of serologic titers appear to be slower in HIV-infected individuals. The clinical significance of this observation is unclear.Persons with newly diagnosed HIV infection should be tested for syphilis; conversely, all patients with newly diagnosed syphilis should be tested for HIV infection. Some authorities, persuaded by reports of the persistence of T. pallidum in the CSF of HIV-infected persons after standard penicillin benzathine therapy for early syphilis, recommend examination of CSF for evidence of neurosyphilis for all co-infected patients, regardless of the clinical stage of syphilis, with treatment for neurosyphilis if CSF abnormalities are found or if CSF examination is not performed. Others do not recommend routine CSF examination for HIV-co-infected patients with early syphilis and believe that standard therapy is sufficient. Serologic testing after treatment is important for all patients with syphilis, particularly those also infected with HIV.

TREATMENT

Treatment of Acquired SyphilisThe CDC's 2002 guidelines for the treatment of syphilis are summarized in Table 3 and are discussed below. Penicillin G is the drug of choice for all stages of syphilis. T. pallidum is killed by very low concentrations of penicillin G, although a long period of exposure to penicillin is required because of the unusually slow rate of multiplication of the organism. The efficacy of penicillin against syphilis remains undiminished after 50 years of use. Other antibiotics effective in syphilis include the tetracyclines, erythromycin, and the cephalosporins. Aminoglycosides and spectinomycin inhibit T. pallidum only in very large doses, and the sulfonamides and the quinolones are inactive. Azithromycin shows significant promise as an effective oral agent against T. pallidum.

Serum levels of penicillin G of ≥0.03 µg/mL for at least 7 days are considered necessary for the cure of early syphilis. Recurrence rates for a given regimen increase as infection progresses from incubating to seronegative primary to seropositive primary to secondary to late syphilis. Therefore, it is probable, but unproven, that a longer duration of therapy is required to effect cure as the infection progresses.

PATIENTS WITH EARLY SYPHILIS AND THEIR CONTACTS

Preventive (abortive, “epidemiologic”) treatment is recommended for seronegative individuals without signs of syphilis who have been exposed to infectious syphilis within the previous 3 months. Before treatment is given, every effort should be made to establish a diagnosis by examination and serologic testing. The regimens recommended for prevention are the same as those recommended for early syphilis.Penicillin G benzathine is the most widely used agent for the treatment of early syphilis, although it is more painful on injection than penicillin G procaine. A single dose of 2.4 million units cures more than 95% of cases of primary syphilis. Because the drug's efficacy in secondary syphilis may be slightly lower, some physicians administer a second dose of 2.4 million units 1 week after the initial dose at this stage of disease. Clinical relapse can follow treatment with penicillin G benzathine in patients with both HIV infection and early syphilis. Because the risk of neurorelapse may be higher in HIV-infected patients, examination of CSF from HIV-seropositive individuals with syphilis of any stage is recommended by some experts; therapy appropriate for neurosyphilis should be given if there is any evidence of CNS syphilis.For penicillin-allergic patients with early syphilis, a 2-week course of therapy with doxycycline or tetracycline is recommended. These regimens appear to be effective, although no well-controlled studies have been performed and poor compliance may be problematic. Limited studies suggest that ceftriaxone (1 g/d, given intramuscularly or intravenously, for 8 to 10 days) and azithromycin (a single oral dose of 2 g) may be effective against early syphilis. These nonpenicillin regimens have not been evaluated in HIV-infected individuals and should be used with caution.

LATE LATENT AND LATE SYPHILIS

If CSF abnormalities are found, the patient should be treated for neurosyphilis. The recommended treatment for late latent syphilis with normal CSF, for cardiovascular syphilis, and for late benign syphilis (gumma) is penicillin G benzathine, 2.4 million units intramuscularly once a week for 3 successive weeks (7.2 million units total). Doxycycline or tetracycline (given for 4 weeks) offers an untested alternative for penicillin-allergic patients with latent or late syphilis and normal CSF. Penicillin-allergic HIV-infected persons with late latent or late syphilis should be desensitized and treated with penicillin if compliance and follow-up cannot be ensured. The clinical response to treatment for benign tertiary syphilis is usually impressive; however, responses to therapy for cardiovascular syphilis are not dramatic because aortic aneurysm and aortic regurgitation cannot be reversed by antibiotic treatment.NEUROSYPHILISPenicillin G benzathine, given in total doses of up to 7.2 million units to adults, or 50,000 units/kg to infants, does not produce detectable concentrations of penicillin G in CSF, and asymptomatic neurosyphilis may relapse in patients treated with 2.4 million units; the risk may be higher in HIV-infected patients. Therefore, the use of penicillin G benzathine alone for the treatment of neurosyphilis is not recommended. On the other hand, administration of intravenous penicillin G in recommended doses is thought to ensure treponemicidal concentrations of penicillin G in CSF. The clinical response to penicillin therapy for meningeal syphilis is dramatic, but the response to treatment for parenchymal neurosyphilis is variable. In general, treatment of neurosyphilis with existing damage may produce no clinical change but may arrest disease progression.Several recent publications have reported neurologic relapse after high-dose intravenous penicillin therapy for neurosyphilis in HIV-infected patients. No alternative therapies have been explored, but careful follow-up is essential, and re-treatment is warranted in such patients.No data support the use of antibiotics other than penicillin G for the treatment of neurosyphilis; however, some of the third-generation cephalosporins and azithromycin may deserve further evaluation. In patients with penicillin allergy demonstrated by skin testing, desensitization and treatment with penicillin is the recommended course.

MANAGEMENT OF SYPHILIS IN PREGNANCY

Every pregnant woman should undergo a nontreponemal test at her first prenatal visit, and women at high risk of exposure should have a repeat test in the third trimester and at delivery. In the untreated pregnant patient with presumed syphilis, expeditious evaluation and initiation of treatment appropriate to the stage of the disease are essential. Patients should be warned of the risk of a Jarisch-Herxheimer reaction, which may be associated with mild premature contractions but rarely results in premature delivery.Penicillin is the only recommended therapy for syphilis in pregnancy. If the patient has a well-documented penicillin allergy, desensitization and penicillin therapy should be undertaken according to the CDC's 2002 treatment guidelines. After treatment, a quantitative nontreponemal test should be repeated monthly throughout pregnancy. Treated women whose titers rise by fourfold or who do not show a fourfold decrease in titer over a 3-month period should be re-treated.Evaluation and Management of Congenital SyphilisNewborn infants of mothers with reactive serologic tests may themselves have reactive tests, whether or not they have become infected, because of transplacental transfer of maternal IgG antibody. Rising or persistent titers indicate infection, and the infant should be treated. Neonatal IgM antibody can be detected in cord or neonatal serum with the syphilis Captia-M or 19S IgM FTA-ABS test; its detection indicates active infection. For asymptomatic infants born to women treated adequately with penicillin during pregnancy, monthly quantitative nontreponemal tests may be performed to monitor for appropriate declines in titer.An infant should be treated at birth if the seropositive mother has received penicillin therapy in the third trimester, inadequate penicillin treatment, or therapy with a drug other than penicillin; if her treatment status is unknown; or if the infant may be difficult to follow. It is unwise to require proof of diagnosis before treatment in such cases. The CSF should be examined to obtain baseline values before treatment. Penicillin is the only recommended drug for syphilis in infants. The penicillin dosage used for the treatment of the patient with late congenital syphilis is calculated in the same way as for the infant, until dosage based on weight reaches that used for adult neurosyphilis. Specific recommendations for the treatment of infants are included in the CDC's 2002 guidelines.Jarisch-Herxheimer ReactionA dramatic though usually mild reaction consisting of fever (average temperature elevation, 1.5°C), chills, myalgias, headache, tachycardia, increased respiratory rate, increased circulating neutrophil count, and vasodilation with mild hypotension may follow the initiation of treatment for syphilis. This reaction occurs in ~50% of patients with primary syphilis, 90% of those with secondary syphilis, and 25% of those with early latent syphilis, and defervescence takes place within 12 to 24 h. The reaction is more delayed in neurosyphilis, with fever peaking after 12 to 14 h. In patients with secondary syphilis, erythema and edema of the mucocutaneous lesions may increase. Patients should be warned to expect such symptoms, which can be managed with symptom-based treatment. Steroid and other anti-inflammatory therapy is not required for this mild transient reaction.Follow-Up Evaluation of Responses to TherapyThe response of syphilis to treatment should be determined by monitoring of the quantitative VDRL or RPR titer (Table 4). More frequent serologic examination is recommended for patients concurrently infected with HIV. Because the FTA-ABS and agglutination tests remain positive in most patients treated for seropositive syphilis, these tests are not useful in following the response to therapy. After successful treatment of seropositive first-episode primary or secondary syphilis, the VDRL titer progressively declines, becoming negative by 12 months in 40 to 75% of seropositive primary cases and in 20 to 40% of secondary cases. Patients with a history of syphilis have less rapid declines in titer and are less likely to become VDRL- or RPR-negative. Re-treatment should be considered if serologic responses are not adequate or if clinical signs persist or recur. Every effort should be made to differentiate treatment failure from reinfection, and the CSF should be examined. Patients in whom treatment failure is suspected, especially those with abnormal CSF, should be treated for neurosyphilis. If the patient remains seropositive but asymptomatic after such re-treatment, no further therapy is necessary. Patients treated for late latent syphilis frequently have low initial VDRL or RPR titers and may not have a fourfold drop after therapy with penicillin; about half of these patients remain seropositive (with low titers) for years after therapy. Re-treatment P.985
is not warranted unless the titer rises or signs and symptoms of syphilis appear.

The activity of neurosyphilis correlates best with CSF pleocytosis, and this measure provides the most sensitive index of response to treatment. An elevated CSF cell count falls to normal in 3 to 12 months in adequately treated HIV-uninfected patients. The persistence of mild pleocytosis in HIV-infected patients may be due to the presence of HIV in CSF; this scenario may be difficult to distinguish from treatment failure. Elevated levels of CSF protein fall more slowly, and the CSF VDRL titer declines gradually over a period of several years.

IMMUNITY TO AND PREVENTION OF SYPHILIS

The rate of development of acquired resistance to T. pallidum after natural or experimental infection is related to the size of the antigenic stimulus, which depends on both the size of the infecting inoculum and the duration of infection before treatment. The role of serum antibody in conferring immunity to syphilis remains undefined, although antibodies have been implicated in strain-specific immunity. Cellular immunity is considered to be of major importance in immunity and in the healing of early lesions. The cellular infiltration, predominantly T lymphocytes and macrophages, produces a T_H1 cytokine milieu consistent with the clearance of organisms by activated macrophages. Specific antibody enhances phagocytosis and is required for macrophage-mediated killing of T. pallidum. Recent unpublished studies indicate that sequence variation of TprK occurs during T. pallidum infection. This observation suggests a role for antigenic variation in the persistence of infection and in susceptibility to reinfection with another strain.

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