Treponema pallidum

Essentials of Diagnosis

• Spiral, motile, coil-shaped, elongated (0.10 µm x 5-20 µm) spirochete.
• No reliable method for sustained in vitro cultivation.
• Direct detection using darkfield microscopy or immunofluorescent antibody testing in early syphilis.
• Nontreponemal antibody tests (rapid plasma reagin, Venereal Disease Research Laboratory [VDRL]) for screening and treatment follow-up.
• Treponema-specific antibody tests (fluorescent treponemal antibody test, microhemagglutination-T pallidum test) for confirmation.
• Cerebrospinal fluid (CSF) lymphocytosis, elevated CSF protein, or a reactive CSF VDRL test suggests neurosyphilis.
• PCR, DNA probes, and immunoblotting techniques are promising in congenital syphilis, early syphilis, or neurosyphilis.
• All patients with T pallidum infection should be tested for HIV coinfection, and vice versa.

General Considerations

The term syphilis was first used in 1530 by the Italian physician Girolamo Fracastoro in his epic poem Syphilis Sive Morbus Gallicus. Much has been learned since then about this sexually transmitted disease caused by T pallidum. Public health screening programs and the introduction of antibiotics led to a marked decline in the number of new syphilis cases in the United States after World War II.

However, the emergence of AIDS was associated with an increase in new syphilis cases, which necessitated re-education of health care personnel in the evaluation and management of this disease.

Epidemiology

Genital herpes and syphilis are the most common causes of genital ulcerations in patients presenting to sexually transmitted disease clinics in the United States. Syphilis is usually transmitted through sexual contact with the infectious lesions of primary and secondary syphilis. Syphilis develops in ~ 30-60% of sexual contacts of individuals with infectious syphilis. Syphilis is less commonly transmitted in utero or via blood transfusion, nongenital body contact, or accidental direct inoculation.

The incidence of primary and secondary syphilis (called early syphilis) reached a nadir in 1956 and then increased slowly. Two "epidemics" of early syphilis in the past 20 years have highlighted the role of human behaviour in syphilis epidemiology: one peaked in 1982 and primarily involved bisexual and homosexual men; the second peaked in 1990, when 50,223 new cases of primary and secondary syphilis were reported.

This epidemic was associated with crack cocaine use and its effects on sexual behaviour and disproportionately involved African Americans. The incidence of this outbreak was highest in the southern United States and in the nation's large metropolitan areas. The incidence of congenital syphilis also rose from 4.3 cases/100,000 live births in 1983 to 107 cases/100,000 births in 1991. This change was attributed to the increase in primary and secondary syphilis among women, more active surveillance, and the adoption of a more sensitive case definition for congenital syphilis in 1988-1989.

The incidence of all stages of syphilis, including congenital syphilis, has decreased since 1991. The number of new cases of primary and secondary syphilis in the United States in 1997 was 8,500, an incidence of 3.2 cases/100,000 persons, the lowest rate since 1941. In 1997, the incidence of congenital syphilis was 27 cases/100,000 live births, the lowest rate since the change in the surveillance case definition.

Microbiology

The order Spirochaetales and family Spirochaetaceae include human pathogens within three genera: Treponema, Leptospira, and Borrelia. T pallidum subspecies pallidum is the causative agent of syphilis and is transmitted primarily through sexual contact. Nonvenereally transmitted treponemal infections include those caused by T carateum (pinta), T pallidum subspecies pertenue (yaws), and T pallidum subspecies endemicum (bejel or endemic syphilis). Clinical and epidemiological characteristics are used to distinguish among these treponemal infections because of similarities in serologic host responses, microbial morphology, and antigenic composition. No currently available nucleic acid-based test reliably differentiates between the subspecies of T pallidum.

T pallidum is a microaerophilic spirochete that is tightly wound into a spiral shape, measuring 5-20 µm in length and 0.1-0.2 µm in width. It can bend along its long axis, and it achieves active motility with "corkscrew-like" motions. These organisms are too slender to be seen with light microscopy, but can be readily visualized by darkfield microscopy, direct immunofluorescent staining, or silver staining.

This agent has resisted characterization because it cannot be sustained using in vitro culture methods. Instead, it requires rabbit or guinea pig inoculation for laboratory propagation. The organism is surrounded by an outer membrane consisting primarily of phospholipids and a low concentration of membrane proteins. This characteristic, when coupled with the organism's slow multiplication time, may explain its ability to persist in the infected host. Examination of the full 1.14-Mbp genome sequence of T pallidum reveals a large family of duplicated genes that are predicted to encode outer membrane porins and adhesins. These genes may reflect a mechanism for antigenic variation, as well as targets for vaccine-induced immunity.

Axial filaments, or endoflagella, are attached to each end of the organism in the periplasmic space and mediate host cell adherence and motility. Recent investigations suggest that a sensory transducing chemotaxis protein may modulate this flagella-associated motility. The organism also contains a peptidoglycan layer and is susceptible to ß-lactam agents such as penicillin. Replication occurs by transverse fission.

Pathogenesis

T pallidum gains access to subepithelial tissues through microperforations in the skin or through intact mucous membranes. A visible localized reaction occurs at the site of inoculation after 10-90 days, which reflects the slow division time of this organism. This reaction presents as a papule and then ulcerates to form the classic lesion of primary syphilis, the chancre.

Histopathologic examination reveals perivascular inflammation consisting of lymphocytes and plasma cells. Spirochetes also disseminate to regional lymph nodes and enter the bloodstream during this stage. The chancre usually heals spontaneously within 1-8 weeks, likely because macrophages phagocytose treponemes. The secondary stage of infection begins ~ 6-10 weeks after the disappearance of the chancre. Spirochetemia is at its highest level during this stage, despite a vigorous humoral immune response, and patients often present with constitutional symptoms of malaise, fever, weight loss, and generalized lymphadenopathy.

Most patients develop skin and mucous membrane lesions. The lesions of both primary and secondary syphilis are highly infectious. The resolution of the signs and symptoms of untreated secondary syphilis marks the beginning of the latent stage of infection. This stage is clinically asymptomatic and is indicated only by positive treponemal serology. This phase is divided into an early latent stage (the first year after infection) and the late latent stage. Approximately one-third of untreated patients with latent infection will develop manifestations of late (or tertiary) disease after an indeterminate period of time.

Destructive tissue lesions of the tertiary stage of infection involve the skin and bone (leading to a gumma), the aorta, and the central nervous system (CNS). Histopathologic examination of these lesions reveals the characteristic obliterative endarteritis seen in other stages of syphilis. The lesions of late syphilis contain few visible spirochetes, which suggests a role for a delayed-type hypersensitivity reaction to T pallidum.

Much of the information regarding the natural course of untreated syphilis was obtained from two reports: the Oslo Study of untreated Norwegian patients diagnosed with early syphilis (1890-1951), and the Tuskegee Study, initiated by the United States Public Health Service (U.S. PHS) in 1932. This prospective study of ~ 400 Black men with untreated latent syphilis in Macon County, Alabama, was terminated in 1972.

Latent Syphilis

Clinical Findings

The manifestations of primary and secondary syphilis resolve without therapy. The ensuing clinically silent phase of infection, known as the latent stage, is characterized by positive serologies and normal CSF (see Table 1). Patients can relapse with manifestations of secondary syphilis during this stage, usually during the early latent period. Asymptomatic infection lasting longer than one year (late latent syphilis) persists for the remainder of life in approximately two-thirds of untreated patients. The remaining one-third of patients develop symptomatic disease, ie, late syphilis.

Congenital Syphilis

Clinical Findings

Signs and Symptoms

Most infants acquire congenital syphilis from the transplacental dissemination of maternal T pallidum after the 16th week of gestation, and less commonly from contact with an infectious lesion at the time of delivery (Table 2). The likelihood of fetal infection is inversely related to the duration of maternal infection; the risk of fetal transmission declines from 70-100% during early syphilis to 10-30% during latent disease. Congenital infections can be prevented through appropriate identification and treatment of infected pregnant women. In 1988, the Centers for Disease Control increased the sensitivity of the congenital syphilis case definition by including all infants, symptomatic and asymptomatic, born to mothers with untreated or inadequately treated syphilis.

Congenital syphilis is divided into an early stage and a late stage. The early stage, seen primarily in infants 2-25 weeks of age, may be asymptomatic or may be associated with long-bone skeletal abnormalities, including osteochondritis and periostitis; hepatosplenomegaly and abnormal liver function studies; low birth weight; serous nasal discharge (snuffles); maculopapular rash; anemia; nephrotic syndrome; and CNS abnormalities. If untreated, these lesions may result in late congenital syphilis, which classically appears after 2 years and manifests as frontal bossing, saddle nose, interstitial keratitis, notched and peg-shaped upper Hutchinson's incisors, poorly developed mulberry molars, anterior bowing of the lower extremities, perioral and perinasal fissures, bilateral effusions of the knee (Clutton's joints), and deafness.

Laboratory Findings

See Diagnosis below.

Differential Diagnosis

The differential diagnosis of congenital syphilis includes other congenitally acquired infections such as toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and hepatitis B.

Complications

Infants with untreated early syphilis may develop manifestations of late congenital syphilis, as described above.

Diagnosis

Direct Microscopic Examination

Darkfield microscopy reveals T pallidum in the transudative fluid of a chancre, in which the density of organisms approaches 10,000-100,000/mL. These spirochetes exhibit "corkscrew" motility and central flexion. Highly suspicious lesions should be examined on three successive days before syphilis is excluded. Alternative diagnostic methods such as fluorescent antibody staining should be considered when evaluating oral lesions, because saprophytic spirochetes in the oral cavity morphologically mimic T pallidum. Silver stains or specific immunofluorescent antibody stains may be useful for detecting pathogenic spirochetes in tissue biopsy specimens.

Serologic Tests

The majority of syphilis cases are diagnosed by serologic testing. These tests are categorized according to the type of antibody produced by the host: nonspecific and specific. Nonspecific, or nontreponemal, antibody tests use reaginic lipoidal antigens to demonstrate the presence of cross-reacting antibodies (immunoglobulin G [IgG] and IgM) elicited by T pallidum infection. Specific, or treponemal, antibody tests use T pallidum antigens to detect antibodies.

Nontreponemal antibody tests include the rapid plasma reagin and the VDRL flocculation assays. These screening tests may be reactive in the setting of other infectious and noninfectious conditions such as intravenous drug use, tuberculosis, vaccinations, pregnancy, infectious mononucleosis, HIV infection, rickettsial diseases, other spirochetal diseases, connective tissue diseases, and bacterial endocarditis.

False-negative nontreponemal tests can occur early in the course of disease when antibody levels are low, and later in the disease when antibody levels are overwhelming (for example, during secondary syphilis). This pattern necessitates dilution of the serum sample to overcome this "prozone" effect. Approximately 75%, 100%, and 75% of patients with untreated primary, secondary, and late syphilis, respectively, have reactive nontreponemal tests. Positive test results are usually quantitated to monitor therapy.

Nontreponemal tests are not interchangeable (rapid plasma reagin titres are usually higher at any given time), and the optimal approach to patient management should include use of the same laboratory and test. Conversion to nonreactivity (seroreversion) or a sustained decline in titre of at least fourfold is expected in patients with early syphilis 2 years after effective therapy.

The more sensitive and specific treponemal antibody tests are used primarily to confirm results from nontreponemal antibody testing. The T pallidum hemagglutination and microhemagglutination-T pallidum tests depend on the agglutination of antitreponemal antibodies from the patient's serum with red blood cells that have surface-associated T pallidum. In the fluorescent treponemal antibody test, a killed strain of T pallidum serves as the antigen for the patient's absorbed serum. Labeled antihuman immunoglobulin is then visualized using fluorescent microscopy. The fluorescent treponemal antibody test is more sensitive for detecting early syphilis than the other specific tests.

Seropositivity with specific treponemal tests usually persists for the individual's lifetime, which means these tests cannot be used to monitor response to therapy. However, seroreversion can occur in promptly treated primary syphilis and in advanced HIV infection. In addition, treponeme-specific antibody tests are reactive in diseases caused by other pathogenic treponemes, including yaws, pinta, and bejel, as well as Lyme disease, relapsing fever, and leptospirosis. False positives have also been reported in individuals with malaria and leprosy.

Molecular techniques, including polymerase chain reaction, are not routinely available, but may be useful for resolving selected diagnostic conundrums involving early primary syphilis, congenital syphilis, and neurosyphilis.

Neurosyphilis

The diagnosis of neurosyphilis is based on both clinical and laboratory findings. Although some experts evaluate the CSF of all patients with late latent syphilis, the U.S. PHS recommends a lumbar puncture when any of the following are present: clinical manifestations of neurologic involvement, evidence of nonneurologic late active syphilis, treatment failure, or late latent disease (including syphilis of unknown duration) in the HIV-coinfected host. VDRL reactivity in the CSF is specific for the diagnosis of neurosyphilis, although caution is warranted when interpreting a positive result from a traumatic lumbar puncture. In addition, the modest sensitivity of this test (~ 50%) does not rule out neurosyphilis when the result is negative. Patients with systemic serologic evidence of syphilis and a CSF lymphocytic pleocytosis or an elevated CSF protein level should be treated for presumptive neurosyphilis.

Congenital Syphilis

U.S. PHS recommendations for the evaluation of an infant with suspected congenital syphilis include radiographs of the long bones, routine CSF examination including VDRL reactivity, nontreponemal serologies of the infant's blood, and immunofluorescent antibody staining of the placenta or amniotic fluid/cord. If this initial evaluation is negative, specific antitreponemal IgM antibody testing is indicated. A definitive diagnosis of congenital syphilis requires identification of T pallidum in neonatal tissue.

Treatment

The drug of choice for all stages of syphilis is penicillin. Specific treatment recommendations are dictated by the stage of disease. Because of the organism's slow replication, prolonged treponemicidal antimicrobial therapeutic levels are required. Although alternatives to penicillin are available, non-penicillin-based therapy is not recommended for patients who are pregnant or who have congenital syphilis, neurosyphilis, or HIV coinfection.

Patients with spirochetal diseases may develop an acute systemic reaction consisting of fever, chills, headache, and myalgias within the first day after effective therapy. This Jarisch-Herxheimer reaction is usually seen during treatment of earlier stages of syphilis, especially secondary syphilis, and resolves spontaneously after 12-24 h. This reaction is probably caused by lysis of spirochetes with subsequent release of antigen and toxic by-products. Symptomatic relief with anti-inflammatory agents may be helpful.

The recommendations in Boxes 3, 4, and 5 for therapy and follow-up are based primarily on U.S. PHS recommendations.

Incubating Syphilis

Treatment of presumed incubating syphilis with the same regimen prescribed for early syphilis is recommended for all sexual contacts of patients with primary, secondary, or early latent syphilis within the prior 90 days. Although multiple-dose azithromycin and ceftriaxone appear promising in the treatment of early syphilis, single-dose therapy with either agent for incubating syphilis requires further evaluation.

Primary and Secondary Syphilis

The recommended therapy for adults with acquired primary and secondary syphilis is shown in Table 3. Erythromycin therapy is less effective than penicillin, doxycycline, or tetracycline. Single-dose ceftriaxone or azithromycin should not be used as alternative therapy. Follow-up in non-HIV-infected patients should include nontreponemal titres at 3, 6, and 12 months after treatment.

Clinical manifestations of infection that recur or do not resolve, or fourfold increases in nontreponemal titres, suggest treatment failure or reinfection. These findings should prompt further evaluation for neurosyphilis and HIV infection. Effective therapy usually results in a fourfold decrease in titre by 3-6 months after treatment, and a sustained fourfold or greater decline is considered an appropriate therapeutic response. Seroreversion does not occur by 24 months after appropriate treatment in ~ 25% of patients with primary and secondary infection. Patients who are considered treatment failures and who have no evidence of neurosyphilis should be treated with the benzathine penicillin G regimen recommended for late latent syphilis.

Early Latent Syphilis

Adults and children with early latent infection are treated in the same manner as those with primary and secondary syphilis.

Late Latent Syphilis or Syphilis of Unknown Duration

Nontreponemal serologic follow-up is recommended at 6, 12, and 24 months. Assessment for neurosyphilis and possible retreatment should be considered for patients in whom titres increase fourfold, for those in whom a fourfold decline is not seen in 1-2 years, or for those in whom clinical manifestations develop.

Late Syphilis

Patients with late benign syphilis or cardiovascular syphilis and no evidence of neurosyphilis are treated in the same manner as those with late latent disease. In addition to antitreponemal agents, therapy for cardiovascular syphilis includes appropriate medical and surgical management of heart failure and aneurysm. Reversal of the complications of aortitis is unlikely, although progression of disease may be halted with antibiotics. The lesions of late benign syphilis are responsive to penicillin therapy.

Neurosyphilis

All patients with ocular and auditory involvement secondary to syphilis should be treated for presumptive neurosyphilis. Follow-up examination of the CSF should be performed every 6 months. Effective therapy should result in a decrease in the CSF cell count by 6 months. CSF protein and VDRL titres do not respond as quickly as the cell count, but repeat therapy may be warranted if these two parameters are still abnormal 2 years after treatment. Treatment of late-stage neurosyphilis is most effective at limiting further CNS damage, but it is unlikely to result in symptom resolution.

Congenital Syphilis

Appropriate therapy and follow-up of early congenital syphilis should prevent the development of late congenital syphilis (see Table 5). Benzathine penicillin G, 50,000 U/kg administered once intramuscularly, is recommended for neonates without clinical or laboratory evidence of syphilis when the mother's syphilis serologies indicate treatment failure. Neonates whose mothers received prenatal erythromycin therapy for syphilis, or who received therapy for syphilis in the month before parturition, should also be treated with this regimen.

Treponemicidal CSF concentrations of penicillin may not be attained with the procaine penicillin regimen recommended for early congenital syphilis. Nontreponemal antibody test results should be negative by 6 months after therapy. Rising or persistent titres should prompt appropriate re-evaluation and management, including CSF examination and retreatment. Infants with abnormal CSF examinations should have follow-up lumbar punctures performed every 6 months, with an expected serial decline in the cell count to normal levels by 2 years after therapy and a negative CSF-VDRL by 6 months. Retreatment is indicated if these parameters are not met.

Syphilis and Pregnancy

Therapy for all pregnant women known to be infected for < 1 year should include benzathine penicillin G, 2.4 million U given intramuscularly 1 week apart for a total of two doses. Other stages of disease are treated in the same manner outlined for nonpregnant adults, except there is no alternative to penicillin-based therapy. Nontreponemal antibody titres should be performed monthly, and principles of retreatment are guided by the disease stage. Treatment of all sexual partners is imperative.

Syphilis and HIV

HIV antibody testing is recommended for all patients with T pallidum infection because of the increased incidence of HIV coinfection in these patients. HIV transmission may be facilitated by genital ulcer disease. A weakened cellular immune system may explain why HIV-infected individuals develop atypical laboratory and clinical features of syphilis. Persistent chancres and initial presentations with secondary syphilis are reported more frequently in HIV-infected individuals. False-positive and false-negative serologies are more common in this patient population. Diminished serologic responses to therapy have also been observed in patients with early syphilis and HIV coinfection. The earlier appearance of neurosyphilis and other later stages of disease in HIV-infected patients has been ascribed to a decrease in the efficacy of standard therapy for early syphilis, although at least one recent randomized, double-blind study does not confirm this observation.

The evaluation and management of neurosyphilis in these patients are complicated by elevated CSF protein and cell counts that can occur in HIV infection alone. Despite these observations, standard serologic tests for syphilis are still recommended for diagnosis. However, some experts recommend more aggressive treatment of syphilis and a more thorough evaluation for CNS infection in the HIV-infected host, regardless of the stage of T pallidum infection. Penicillin-based therapies are recommended, and close follow-up of response to therapy is essential.

Prevention and Control

No vaccine is currently available for the prevention of syphilis (Table 6). Primary prevention measures include behaviour modification among patients engaged in high-risk practices such as sexual promiscuity, as well as health programs designed to educate the public about sexually transmitted diseases, including the benefits of condom use. Secondary prevention measures include effective, affordable, prompt, and more accessible diagnostic and therapeutic interventions with appropriate follow-up for infected patients. Screening of all HIV-infected individuals and pregnant women is part of any effective public health prevention program. Reliable and thorough case reporting with partner notification and epidemiologic treatment is also essential.

Early, < 1 year after infection; late, ≥ 1 year after infection.

1) All patients who are pregnant or have HIV infection, congenital syphilis, or neurosyphilis should be treated with penicillin-based regimens.

2) Except neurosyphilis.

1) All patients who are pregnant or have HIV infection, congenital syphilis, or neurosyphilis should be treated with penicillin-based regimens.

2) Except neurosyphilis.

1) All patients who are pregnant or have HIV infection, congenital syphilis, or neurosyphilis should be treated with penicillin-based regimens.