Pediatrics

Syphilis

OVERVIEW: What every practitioner needs to know

Syphilis in children may occur as an acquired or congenital infection. Treponema pallidum subspecies pallidumis the causative microbe.

Syphilis beyond early infancy is a sexually transmitted infection (STI). The most common clinical manifestation of acquired infection from childhood to adults is the chancre, a painless papule or ulcer with indurated borders.

Persistent disseminated infection can cause myriad clinical manifestations that are divided into secondary and tertiary stages of disease. Asymptomatic, or latent, periods of infection also occur.

Congenital presentations range from asymptomatic to severe, multi-organ disease. Congenital syphilis is covered as a separate topic.

Are you sure your patient has syphilis? What are the typical findings for this disease?

Primary syphilis occurs primarily in sexually active adolescents and occasionally in sexually abused children. It is characterized by the chancre, which begins as a papule that progresses to central ulceration with raised, firm borders. Chancres are painless unless secondarily infected by other microbes. This is more common with anal and oral lesions. Most infected patients have only a single chancre, but multiple lesions can be present. In females, primary lesions on the cervix or vaginal walls are common and often thus go unrecognized. The only other sign of primary infection is nontender, regional adenopathy, which may be the only sign when primary lesions are not readily visible. Systemic signs are absent. Spontaneous healing of primary lesions occurs in 3 to 12 weeks.

Secondary syphilis is described as "the great imitator" due to its protean potential manifestations. Any organ system can be involved. The symptoms and signs of secondary syphilis appear 2 to 10 weeks after primary lesions develop. Primary lesions may still be present at this time. Secondary syphilis represents symptomatic systemic dissemination of the microbes and is the period of highest microbial burden.

Skin lesions occur in about 90% of patients with secondary syphilis. Generalized lymphadenopathy and mucous membrane lesions are common. Low grade fever, myalgias, arthralgias, malaise, and headache are other frequent systemic manifestations. The rash appears as nonpruritic macular, papular, and/or pustular lesions. Lesions often begin centrally and spread to ultimately involve the palms and soles. Individual lesions are pink to red and range from 3 to 10 mm in size. Macular lesions may evolve to papules and then pustules. Infection of hair follicles may cause patches of alopecia. Vesicles are not seen except in congenital syphilis. Young children with acquired syphilis sometimes have minimal dermal findings during secondary syphilis.

Papules that arise in moist intertriginous areas (e.g., vulva, scrotum, medial thighs, finger webs, other skin folds) may coalesce into broad, erythematous plaques called condyloma lata. Similar lesions that develop on mucous membranes are called mucous patches. These are silvery gray with superficial erosion and erythematous borders. All skin lesions of secondary syphilis are teeming with spirochetes and are highly contagious.

Neurosyphilis develops in about 30% of patients during the early stages of primary and secondary syphilis. It may be asymptomatic or cause symptoms and signs of meningitis and cranial or spinal nerve involvement. Cerebrospinal fluid (CSF) typically shows pleocytosis and elevated protein concentration.

Early neurosyphilis resolves in about half of cases but can progress to late neurosyphilis over 5 years or more. Late neurosyphilis therefore is almost never seen during childhood or adolescence after acquired infection. Classic manifestations of late neurosyphilis are dementia, tabes dorsalis, optic atrophy, and seizures. Gummatous lesions in the cord, meningovascular involvement, and/or other sequelae of neurosyphilis can cause signs that mimic almost any other neurologic disease.

The adenopathy of secondary syphilis is generalized and painless. Epitrochlear node enlargement is common and should raise suspicion for secondary syphilis. Secondary syphilis can involve any organ. Other possible manifestations include uveitis, hepatitis, synovitis, osteitis and renal involvement.

Manifestations of secondary syphilis abate without treatment in 3 to 12 weeks, and the infection then enters a latent period. About 60% of patients will have complete resolution of infection without treatment.

Latent syphilis is divided into two phases. Early latent syphilis is defined as a time period of absence of overt evidence of disease during the first 12 months after initial infection. This first year after initial infection is the time period of greatest communicability. Late latent syphilis thus is absence of signs or symptoms in untreated patients >12 months after initial infection.

Reactivation of secondary stage manifestations can occur during the first four years of latency and is much more common in the first year of latency. Transient intermittent treponemal bacteremia can occur throughout latency and result in transplacental transmission during pregnancy.

Tertiary syphilis occurs in about 40% of untreated infected persons and refers to the development of nonprogressive localized nodules (gummata) in the skin and supporting structures of the body. Gummata are granulomatous and fibrotic with central necrosis and represent an immune response of the host. Treponemas are sparse or absent in the lesions. Gummata appear 15 to 30 years after initial infection or 3 to 10 years after the last evidence of secondary syphilis. Thus, tertiary syphilis is almost never seen in childhood or adolescence.

Persons with HIV infection and syphilis

Children or adolescents with HIV infection and syphilis are at risk for faster progression of syphilis. Such cases mostly will be limited to sexually active teens. Among adults with co-infection, chancres may be numerous and larger. Ocular infection and neurosyphilis are more common. Gummata formation may be accelerated.

What other disease/condition shares some of these symptoms?

The presentations of primary acquired syphilis can have overlap with other ulcerative STIs such as genital herpes, chancroid, and donovanosis (granuloma inguinale). Primary genital herpes often has clusters of painful vesicles, systemic symptoms, and regional adenopathy.

Recurrent genital herpes usually has mild to moderately painful vesicles that ulcerate before healing. Syphilitic chancres may become painful if secondarily infected (more common for oral and anal lesions).

Persons with multiple, secondarily infected chancres most closely mimic genital herpes. Chancroid typically presents as a painful genital ulcer with associated tender, suppurative inguinal adenitis.

Donovanosis is extremely rare in the United States and presents as slowly progressive, painless genital ulceration without associated adenopathy.

Lymphogranuloma venereum (Chlamydia trachomatis) and early stages of venereal warts (human papillomavirus) sometimes resemble syphilis.

Skin manifestations of anthrax, tularemia, rat bite fever, tuberculosis, atypical mycobacterial infections, sporotrichosis, or other infections that appear in the perineal regions can appear similar to primary syphilis.

Local traumatic lesions of the genitalia and perineal regions, especially when secondarily infected, are a common mimicker of chancres. Other non-STI conditions that can have similar manifestations include perineal yeast infection, apthae (e.g., Behçet's disease, HIV infection), psoriasis, fixed drug eruptions, and carcinomas.

Co-infection with genital herpes and syphilis, as well as other STIs, can occur. Persons of any age with suspected or confirmed syphilis should be tested for co-infection with HIV.

Secondary syphilis, "the great imitator," can mimic many systemic diseases, including infectious mononucleosis, subacute or chronic bacterial infections, rheumatologic conditions, and malignancies. Secondary syphilis is in the differential diagnosis of many disease presentations, including those with components of meningitis, hepatitis, nephritis, and arthritis. Condyloma lata of secondary syphilis can be confused with venereal warts.

Tertiary syphilis is exceedingly rare in children or adolescents. In adults it most often causes neurologic symptoms (including ocular), which can range widely, and cardiovascular disease, which most frequently involves the aorta and aortic root, including the ostia of coronary arteries.

What caused this disease to develop at this time?

How is syphilis transmitted?

Acquired syphilis is transmitted predominantly by sexual activity of any type (e.g., penile-vaginal, penile-anal, and penile-oral) that leads to direct skin or mucous membrane contact with an infectious skin lesion (chancre, condyloma lata, mucous patch, rash) of a person with syphilis. Similarly, transmission can occur by mouth to mouth or mouth to other body sites (e.g., genitalia, breasts, digits) from persons with oral syphilitic lesions.

Ultimately, any direct physical contact of any skin or mucous membrane surface to an infected lesion on another person can result in transmission of infection at the site of contact. Transmission from contact is not universal but occurs in about one third of episodes.

The incubation period for syphilis ranges from 3 to 90 days, with a median of 3 weeks. Once an immunocompetent person has been infected for more than four years, he or she is extremely unlikely to spread infection by sexual contact even if never treated. By this time the organism burden has greatly decreased due to accumulating immunity that controls the infection in most immunocompetent hosts.

Transfusion of fresh human blood from persons with active infection can transmit infection, but T. pallidum does not survive beyond 24 to 48 hours under modern blood banking storage conditions. In the United States, blood is screened for syphilis with nontreponemal serologic tests. Accidental inoculation from needles used in infected persons or during handling of infected clinical specimens also can lead to infection.

Children identified with evidence of primary syphilis, especially if anogenital or oral, should undergo evaluation for child sexual abuse. Humans are the only natural reservoir of T. pallidum. Young children with evidence of secondary syphilis potentially could represent missed cases of congenital syphilis, especially if asymptomatic. However, postnatal acquisition also could be possible in childhood secondary syphilis, and careful clinical and forensic investigation is required.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Definitive diagnosis of syphilis is made by dark field microscopy or tests that detect T. pallidum in lesion exudates or tissue specimens. PCR-based tests are available in some locations but are not commercially available. Presumptive diagnosis of syphilis is made by two types of serologic tests: 1) nontreponemal tests and 2) specific treponemal tests. Presumptive diagnosis is the most commonly used approach clinically.

Nontreponemal tests traditionally have been used and are still recommended by the CDC as the initial serologic test for diagnosis of syphilis, followed by treponemal tests when the nontreponemal test is positive. Positive results of both tests at the same time support the presumptive diagnosis of active syphilis infection.

Nontreponemal tests. Nontreponemal test titers usually correlate with disease activity. These tests detect antibodies that react with cardiolipin embedded in lecithin-cholesterol liposomes. The titers of these antibodies rise as the spirochetal infection progresses and then fall with eradication of infection by treatment or gradual immunologic control when untreated.

The two available nontreponemal assays are the Venereal Disease Research Laboratory (VDRL) and Rapid Plasma Reagin (RPR) tests. Most patients become nonreactive by these tests after successful treatment or spontaneous resolution of the infection. A minority of infected persons have persisting low titers (e.g., 1:4, 1:2) for months to years after resolution of infection (serofast reaction). Reinfection or relapse leads to a rise in titer. Four-fold changes in titer are considered indicative of response to treatment when decreasing (e.g., 1:32 to 1:8) or active infection when increasing (e.g., 1:4 to 1:16).

Serial testing should be done using the same assay, preferably in the same laboratory. RPR titers often are slightly higher than VDRL titers in the same specimen; therefore, results of the two tests generally should not be directly compared.

False positive nontreponemal test results occur in about 1% of adults. False positive results can occur in association with Epstein-Barr virus infection, hepatitis, varicella, measles, tuberculosis, malaria, HIV, and endocarditis. Lymphoma, rheumatologic conditions (especially systemic lupus erythematosus), pregnancy, injection drug abuse, and immunizations (e.g., MMR, influenza, smallpox) also can cause false-positive results, as can Wharton jelly contamination of cord blood specimens. Of note, Lyme disease does not cause positive nontreponemal tests.

False negative nontreponemal tests can occur in early primary syphilis. Since late latent syphilis and late congenital syphilis represent periods of minimal microbial replication, VDRL and RPR tests are typically negative during these periods.

False-negative nontreponemal test results can occur in patients with very high levels of reactive antibodies, which may prevent the flocculation of test antigen required to produce a positive result. This situation, called the prozone phenomenon, is most common during early secondary syphilis. Dilution of the serum specimen prior to testing can overcome this inhibition and permits the appropriate positive reaction. Clinicians should request testing of diluted specimens when the clinical presentation suggests syphilis infection and the nontreponemal test result is unexpectedly negative. The prozone phenomenon does not occur with specific treponemal tests.

Treponemal tests. Several specific treponemal tests are available: 1) fluorescent treponemal antibody absorbed (FTA-ABS) tests; 2) T. pallidum passive particle agglutination (TP-PA); 3) various enzyme immunofluorescence assays (EIAs), and 4) chemiluminscence assays (CIAs). A positive specific test indicates current or past infection. Most patients ever infected with syphilis remain seropositive for life, but 15% to 25% revert to seronegative status after 2 to 3 years. Treponemal test antibody titers do not correlate with disease activity and cannot be used to assess treatment response or re-infection status.

False positive treponemal tests can occur in patients with other treponemal infections, including yaws, pinta, leptospirosis, rat-bite fever (Spirillum minus), relapsing fever, and Lyme disease.

Interpretation of results. Patients with a positive nontrepomenal test followed by a positive trepomenal test result have presumptive syphilis. Those with a positive nontreponemal test and negative treponemal test likely have a false positive nontreponemal result. Clinical findings dictate whether observation or further investigation for specific conditions known to be associated with such false positive results is needed. In such patients with clinical findings that suggest syphilis, repeat testing with a different specific treponemal test should be considered.

Reverse sequence screening. Many clinical laboratories and blood banks have switched the order of serologic testing, using automatable treponemal EIAs or CIAs as the first screening step, as a cost saving measure. Positive EIA or CIA tests are then reflexed to nontreponemal testing. If the nontreponemal test is positive as well, the patient has presumptive syphilis and should be treated.

The CDC still recommends the use of traditional nontreponemal tests (RPR-based) as a screening method with reflex to treponemal tests if they are positive. When reverse sequence approach is used, studies have shown that in low prevalence settings this algorithm is less cost efficient. In other populations the reverse sequence has facilitated the identification of untreated latent syphilis and earlier serological detection of syphilis.

If the nontreponemal test is negative after a positive EIA/CIA treponemal test, the TP-PA test should be performed as a confirmatory treponemal test. If the TP-PA is positive and there is history of prior treatment for syphilis, the patient may be observed unless the person's sexual history suggests potential re-exposure. Those with no history of treatment should be offered treatment.

If the TP-PA test is negative, it has been postulated that no further evaluation or treatment is needed. A recent study in adults has suggested that this scenario of positive CIA plus negative nontreponemal test plus negative TP-PA test may in fact represent evidence of syphilis infection in some cases. Follow-up of such patients may be warranted.

Neurosyphilis. Diagnosis of neurosyphilis requires cerebrospinal fluid (CSF) analysis. The diagnosis ultimately is based on a combination of results of serum and CSF tests and clinical symptoms and signs (e.g., cranial nerve dysfunction, auditory or ophthalmic abnormalities, meningitis, stroke, altered mental status, and loss of vibration sense). CSF protein is usually elevated above age-related norms and pleocytosis is usually present. The CSF white blood cell count may be less informative in persons with HIV infection, who may have lower cell counts with neurosyphilis than HIV-negative persons.

The VDRL test is the nontreponemal test used for spinal fluid. It has high specificity but is relatively insensitive. The VDRL can be falsely positive in neonates born to mothers with syphilis due to transplacental and trans blood:CSF barrier passage of maternal antibodies. Some experts prefer the FTA-ABS test for CSF. The FTA-ABS test on CSF is highly sensitive but less specific. A negative CSF FTA-ABS makes neurosyphilis highly unlikely.

Additional Considerations in HIV infection. Serologic tests generally can be interpreted at face value for most HIV-infected patients. However, if titers are unusually high or unusually low in settings of suspected active syphilis or serial results are fluctuating, biopsy or dark field microscopy may be necessary. These concerns apply primarily to sexually active adolescents with HIV infection.

Pregnancy. Pregnant adolescents should undergo syphilis screening similar to pregnant women beyond adolescence. Testing ideally should be conducted with nontreponemal tests early in pregnancy and again at delivery. Currently reverse sequence screening is widely used. For women treated for infection during pregnancy, serial titers should be followed to assess response to therapy.

Congenital syphilis can cause fetal demise. When any pregnancy results in stillbirth after 20 weeks gestation, the mother should be tested for syphilis. Mothers of infants with congenital syphilis should be evaluated for other STIs, including Chlamydia trachomatis, gonococcal, HIV, hepatitis B and possibly hepatitis C infections.

Management of syphilis should include ultrasound evaluation of the fetus for congenital syphilis. Presence of hydrops, hepatomegaly, ascites, or thickened placenta among others signs suggest higher risk of fetal treatment failure. Evidence to recommend specific therapy in these cases is insufficient.

Other Laboratory Tests

Children with suspected or confirmed syphilis should have a CBC (with differential and platelet count). Other tests (e.g., serum chemistries, long bone radiographs, ophthalmologic examinations) are considered as clinically indicated. Children suspected of having previously undiagnosed or inadequately treated congenital syphilis generally should have CSF evaluation as per the approach to congenital syphilis below. Hearing should also be evaluated by age-appropriate testing in such children.

When should child sexual abuse be considered in a child with evidence of syphilis?

Syphilis is found in <1% of sexually abused children in the United States. However, identification of syphilis in a child raises the question of possible child sexual abuse.

Postnatally acquired syphilis is highly suggestive of sexual abuse and should be evaluated as such. The clinical findings may help determine whether an individual case represents late, previously undiagnosed congenital infection versus acquired infection. It is postulated that antibiotics commonly prescribed for routine childhood infections may partially treat congenital syphilis and alter the nature of late clinical manifestations. Forensic evaluation by providers with expertise in child sexual abuse evaluation should be sought.

Transmission via fomite should not be considered a plausible means of transmission for syphilis.

If you are able to confirm that the patient has syphilis, what treatment should be initiated?

Penicillin G, parenterally administered, is the preferred agent for treating all stages and types of syphilis. The stage of disease and clinical manifestations determine the preparation, dosage, and length of treatment.

For children and adolescents, early acquired syphilis (defined as primary, secondary without clinical evidence of neurosyphilis, and early latent syphilis) should be treated with a single dose of benzathine penicillin G, intramuscularly (IM), at a dosage of 50,000 units/kg, up to the adult maximum of 2.4 million units in a single dose. Thus, an child with weight of 48 kg or above should receive the adult dose.

Pregnant women or adolescents receiving therapy for latent syphilis should not miss any doses. If they do, they must repeat the full course of therapy.

Late latent syphilis and tertiary syphilis in HIV-negative children and non-pregnant adolescent females should be treated with three doses of IM benzathine penicillin G, 50,000 units/kg per dose (up to the adult maximum of 2.4 million units in a single dose), at 1-week intervals.

Neurosyphilis. Symptomatic neurosyphilis is rare in childhood and adolescence. If a child or teen with evidence of syphilis should have any clinical evidence of central nervous system (CNS) or ocular involvement, CSF and ophthalmologic examinations should be obtained. Syphilitic eye disease (e.g., uveitis, neuroretinitis, or optic neuritis) without other CNS findings on physical examination still warrants CSF evaluation. Eye disease should be managed in conjunction with an ophthalmologist.

The primary recommended regimen for neurosyphilis in HIV-negative children and adolescents is aqueous penicillin G intravenously (IV). Children with suspected or confirmed neurosyphilis residual to undiagnosed or inadequately treated congenital infection should be given 200,000 to 300,000 units/kg day divided every 4 to 6 hours for 10-14 days, not to exceed the adult dose. The adult dose is 3 to 4 million units IV every 4 hours (18 to 24 million units per day). Continuous IV infusion is an option for adolescents and adults.

For adolescents managed as adults, if adherence can be ensured, an alternative is procaine penicillin, 2.4 million units IM once daily plus probenecid 500 mg orally 4 times daily, both for 10 to 14 days. If the patient also is considered to have late syphilis, the 3 week course of therapy can be completed with 1 or 2 weekly doses of benzathine penicillin as above.

Management of Patients with Penicillin Allergy

Desensitization and treatment with benzathine penicillin is always an option to consider. Among nonpregnant adolescents with syphilis, the limited data for adults regarding alternatives to penicillin may be considered applicable.

Pregnant females and young children with penicillin allergy should be desensitized and treated with the penicillin regimen recommended for their syphilis stage and clinical manifestations. Data are insufficient to recommend nonpenicillin regimens for older children. If such regimens are used, close serologic and CSF follow-up are indicated.

Alternatives for early syphilis in adolescents are limited to doxycycline (100 mg orally twice daily for 14 days), tetracycline (500 mg orally four times a day for 14 days), ceftriaxone (1-2 g parenterally daily for 10-14 days), and azithromycin (2 g orally as a single dose). Adherence is an issue with the multi-day regimens. Gastrointestinal side effects can occur with the oral regimens. Azithromycin-resistant strains of T. pallidum have been seen in the United States. Azithromycin should not be used in males who have sex with males or in pregnant females.

The only alternatives to penicillin for treatment of latent syphilis are doxycycline and tetracyline, both for 28 days. Ceftriaxone may be effective, but the optimal regimen is unknown and can be considered in consultation with a specialist.

Management during Periods of Penicillin Shortage

Penicillin shortages have been a problem in recent years and could be again in the future. Procaine penicillin G, if available, IM once a day can be substituted for some or all daily doses of aqueous penicillin G IV. Ceftriaxone may be considered as a substitute in consultation with a specialist.

What are the adverse effects associated with each treatment option?

Allergic reactions (e.g., rashes, hives, anaphylaxis) are the primary side effects that can occur with administration of antibiotics to treat syphilis.

The Jarisch-Herxheimer reaction is an acute febrile event that usually occurs within 2 to 12 hours after initiation of any therapy for syphilis. It is characterized by headache, fever, myalgia, and diaphoresis. It occurs predominately in early stages of syphilis (primary or secondary) when organism burdens are highest. It is likely due to release of treponemal endotoxin-like compounds as the microbes lyse. It has been described in infancy and beyond.

What are the possible outcomes of syphilis?

What follow-up testing is needed, and what are the possible outcomes of syphilis?

Clinical and serological evaluations should be performed at 6 and 12 months after treatment. Most patients who respond to therapy will be clinically asymptomatic and demonstrate four-fold or greater declines in nontreponemal titers during this time period. Persisting or recurrent signs or symptoms or a four-fold rise in titer indicates treatment failure or re-infection. Re-evaluation and retreatment is warranted. CSF evaluation is warranted in such cases as treatment failure may be the result of previously occult and unresolved central nervous system infection.

Failure of nontreponemal titers to decline four-fold within 6 to 12 months after treatment could indicate a serofast state, HIV co-infection, treatment failure, or re-infection. Continued follow-up without retreatment is an option for asymptomatic patients. If follow-up is not certain, retreatment is recommended. If treatment failure is a concern, CSF evaluation for neurosyphilis should be considered.

Retreatment, when required, consists of weekly injections of benzathine penicillin for 3 weeks.

Neurosyphilis. CSF evaluation should be repeated every 6 months until the CSF WBC is in the normal range. If the CSF WBC has not decreased by 6 months or the CSF WBC or protein has not normalized by 24 months, retreatment should be considered. In general, patients with neurosyphilis that is adequately treated also will demonstrate appropriate declines in serum nontreponemal titers.

HIV co-infection

Children or adolescents with HIV infection and syphilis may be at increased risk for treatment failure or development of neurosyphilis, Careful clinical and serological follow-up every 3 months, with retreatment as necessary is indicated by clinical findings and test results.

Prognosis

Primary and secondary syphilis generally resolve without sequelae with prompt diagnosis and treatment. The tissue destruction manifested by gummata formation in tertiary syphilis can cause permanent morbidity depending on the location of lesions. The myriad manifestations of late acquired neurosyphilis also represent permanent damage that cannot be reversed with antibiotic treatment.

What causes this disease and how frequent is it?

T. pallidum subspecies pallidum is one of several pathogenic Treponema in the family Spirochaetaceae, which also includes genera Borrelia and Leptospira. Treponemas are 5 to 15 μm in length and 0.1 to 0.5 μm in diameter with a helical coiled shape. The microbes are motile on the basis of a corkscrew motion from the actions of endoflagella that impart the coiled shape. The T. pallidum subspecies pallidum genome is 1.14 Mb, which encodes 1041 predicted proteins and is relatively small among bacteria. Treponema cannot be cultured directly in vitro.

Close but genetically distinct relatives include T. pallidumsubspecies careteum, T. pallidum subspecies endemicum, and T. pallidum subspecies pertenue, the causes of pinta, bejel or endemic syphilis, and yaws, respectively. A number of nonpathogenic treponemal species are human oral and gastrointestinal commensals.

IgG and IgM antibodies generally are present in the bloodstream by the time a chancre appears. Antibody production, however, does not appear to aid in control of infection. T. pallidum produces few surface-exposed proteins, but the Tpr K protein, which may serve as a porin, elicits an opsonic antibody response in a rabbit model of syphilis. Cell-mediated immunity is suppressed during primary and secondary syphilis. CD4+ T cells and macrophages predominate in chancres, while CD8+ T cells predominate in lesions of secondary syphilis.

Prior syphilis infection may provide a modicum of protection upon re-exposure. Persons with untreated syphilis have relative resistance to reinfection but are not fully protected. Chancres usually do not develop upon re-infection, although these may occur with a high re-infecting inoculum. Antibody titers may rise in either case. Patients treated for syphilis during primary or secondary stages have only minor protection against reinfection and should be considered susceptible. Primary and secondary disease manifestations may not be as severe. Prior congenital syphilis does not protect against later acquired infection.

Syphilis pathologically is a systemic vasculitis. The microbes induce a perivascular cellular immune infiltration as they invade into tissues via capillaries. Immune complex deposition of anti-treponemal antibodies can lead to renal disease (acute syphilitic glomerulonephritis).

In congenital syphilis, the placenta is usually thickened. Villi are hypercellular with proliferative fetal vascular changes and acute and chronic inflammatory infiltrates. Spirochetes may be found in the walls of umbilical vessels.

Although variations in human leukocyte antigen (HLA) genes may affect individual susceptibility to syphilis, at this time there is no role for genetic testing of any type with regard to prognosis or treatment decisions for patients with syphilis.

Epidemiology

Syphilis is primarily sustained in the population through sexual contact with infected persons. Recent national trends in the United States show the highest incidence of infection in the South and in urban areas of other parts of the country. Many new cases have occurred among persons with HIV infection.

After steady declines through public health control measures during the last decades of the 1990s, syphilis rates in the United States increased annually from 2001-2014. Much of this overall increase has occurred among men who have sex with men. The proportion of cases among males has continued to increase. Unfortunately, increases in incidence have occurred also among females, with a corresponding increase in congenital syphilis rates to 11.6 per 100,000 live births in 2014 from the historical nadir of 8.2 per 100,000 live births in 2005. Highest rates occur among males 20-29 years old and among females 25-29 years old. Rates in non-Hispanic blacks are higher than among other race/ethnicity groups in the United States.

How do these pathogens/genes/exposures cause the disease?

T. pallidumattaches to host cell surfaces by a ligand-receptor type process. The microbes are only able to replicate when attached to mammalian cells. Fetal and infant cells appear to support growth more than adult cells. The microbes spread in the bloodstream after initial infection and infiltrate into perivascular spaces. This may be aided by microbial hyaluronidase production. Host fibronectin coats the microbes and actually may inhibit phagocytosis and complement-mediated lysis.

Are additional laboratory studies available; even some that are not widely available?

PCR-based tests to detect T. pallidum and IgM serologic tests have been developed, but are not available commercially and are not recommended at this time.

How can syphilis be prevented?

The primary means of prevention of syphilis involves screening of at-risk groups for infection and treatment of sexual partners of persons with syphilis. All recent sexual contacts of persons with acquired syphilis should be identified. Patients with evidence of any STI or HIV infection should be tested for syphilis.

Asymptomatic persons with contact with an infected person within the past 3 months may still be seronegative and should be treated for potential early primary syphilis. Those exposed >90 days before diagnosis of syphilis in a sex partner may be tested for syphilis and treated based on the results. However, if test results are not immediately available or follow-up is not assured, treatment should be administered.

All cases of confirmed or suspected syphilis should be reported to local health authorities to allow for follow-up of patients and appropriate contact investigations.

All pregnant women should be screened early in pregnancy. Additional maternal syphilis testing should be performed at delivery. In high-risk populations, pregnant women also should be tested at 28 to 32 weeks gestation. No newborn infant should be discharged from the hospital without health care provider knowledge of the maternal serologic status for syphilis having been determined at least once during pregnancy.

Standard precautions are recommended for hospitalized patients with syphilis. Open lesions, secretions, and possibly blood from such patients are contagious. Gloves should be worn during care of patients with congenital, primary, and secondary syphilis with skin or mucous membrane lesions until 24 hours of effective therapy has been administered.

Persons, including health care workers, who have close unprotected contact with an infant with early congenital syphilis before 24 hours of effective antibiotic therapy is completed should be evaluated for evidence of syphilitic lesions 2 to 3 weeks after contact. Antibiotic prophylaxis should be considered for substantial exposures. Serologic testing should be conducted at baseline and 3 months later.

What is the evidence?

http://www.cdc.gov/std/tg2015/syphilis.htm.

(Comprehensive web site that contains guidelines on the treatment of sexually transmitted diseases. Specific information about syphilis can be found in the link above.)

Workowski, KA, Bolan, GA. "Sexually transmitted diseases treatment guidelines, 2015". MMWR Recomm Rep. vol. 64. 2015.

(This guideline provides current national recommendations for the diagnosis and management of sexually transmitted diseases including syphilis in adults, adolescents, and children. This document was developed by CDC staff and national experts using systematic literature review, and it updates the 2010 version.)

Ghanem, KG. "Management of Adult Syphilis: Key Questions to Inform the 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines". Clin Infect Dis. vol. 61. 2015. pp. S818-S836.

(This study reviews several key questions asked to experts in the field in the management of adult syphilis. To answer those questions, the authors performed a systematic review with useful tables of evidence.)

Workowski, KA, Berman, S. "Sexually transmitted diseases treatment guidelines, 2010". MMWR Recomm Rep. vol. 59. 2010. pp. 1-110.

(This guideline provides current national recommendations for diagnosis and treatment of acquired syphilis in adults and children and congenital syphilis. The guideline document was developed by CDC staff and national experts using systematic literature reviews for syphilis and other sexually transmitted diseases. It represents an update from the 2006 version of the guideline.)

Seña, AD, White, BL, Sparling, PF. "Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century". Clin Infect Dis. vol. 51. 2010. pp. 700-8.

(This study reviews the impact of reverse sequence screening for syphilis, where automated EIA/CIA-based treponemal tests are run first, followed by nontreponemal tests. The traditional approach, still recommended by the CDC, is to perform nontreponemal tests first.)

"Congenital syphilis--United States 2003-2008". MMWR Morb Mortal Wkly Rep. vol. 59. 2010. pp. 413-7.

(This report reviews the most current epidemiology of congenital syphilis in the United States., including the recent increase in cases that reflects the increased prevalence of syphilis among pregnant women. This has reversed a long-term declining trend.)

Hunter, MG, Robertson, PW, Post, JJ. "Significance of isolated reactive treponemal chemiluminescence immunoassay results". J Infect Dis. vol. 207. 2013. pp. 1416-23.

Ongoing controversies regarding etiology, diagnosis, treatment

The sequence of serologic testing is the primary controversy at this time. Performing nontreponemal tests as the first test continues to make the most sense from a clinical perspective, although performing automated treponemal tests first is reasonable from an economic perspective in some instances.

Syphilis is uncommon among international adoptees, but congenital syphilis can go undiagnosed or may be inadequately treated in some countries.

Syphilis testing, both nontreponemal and treponemal, is recommended as part of the evaluation of international children, regardless of any history of testing or treatment provided.

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