Syphilis is a systemic infection caused by Treponema pallidum, a spirochete bacterium that is transmitted primarily through sexual activity. In the absence of treatment, patients who acquire T. pallidum remain chronically infected and syphilis generally progresses in stages, characterized by episodes of active clinical manifestations interrupted by periods of latent infection. Chronic disease can result in significant morbidity, potentially affecting nearly every organ system, and rarely, can result in death. In addition, untreated syphilis in pregnant women can lead to fetal demise and devastating congenital infection for neonates born to an infected mother.
Disease 14. Syphilis
- Summarize the epidemiology of Treponema pallidum infections in the United States
- Describe the microbiology and transmission of Treponema pallidum.
- Discuss the clinical manifestations of the stages of syphilis in men, women, and children.
- Compare the laboratory diagnostic methods used to diagnose syphilis.
- State routine syphilis screening recommendations for different patient populations.
- List the CDC-recommended treatment regimens for syphilis infections.
- Summarize counseling and education messages for individuals with syphilis infection.
CNE/CME Continuing Education
Clinical Instructor of Medicine
Division of General Internal Medicine
University of Washington School of Medicine
Lindley A. Barbee, MD, MPH
Medical Director, STD Clinic, Public Health Seattle & King County HIV/STD Program
Assistant Professor of Medicine
Division of Infectious Diseases
University of Washington School of Medicine
- Epidemiology in the United States
- Microbiology and Pathogenesis
- Clinical Manifestations
- Laboratory Diagnosis
- Direct Detection of Treponema pallidum
- Serologic Testing for Syphilis
- Serologic Testing Algorithms
- Diagnosis of Latent Syphilis
- Laboratory Evaluation for Neurosyphilis
- Diagnosis of Syphilis in Patients with HIV Coinfection
- Diagnosis of Syphilis in Infants and Children
- Reporting and Referral to Health Departments
- Screening for Infection
- General Considerations
- Primary and Secondary Syphilis
- Latent Syphilis
- Tertiary Syphilis
- Syphilis in Persons with HIV Infection
- MISSED DOSES
- Syphilis in Pregnancy
- Infants and Children with Syphilis
- Jarisch-Herxheimer Reaction
- Treatment Failure
- Partner Management and Public Health Measures
- Patient Counseling and Education
- Summary Points
- Additional References
Epidemiology in the United States
Incidence trends in the united States
In the United States, the reporting of syphilis incidence is usually represented in terms of primary and secondary syphilis. Reported cases of primary and secondary syphilis (P & S syphilis) represent the incidence of syphilis more accurately than reported cases of latent infection, particularly late latent syphilis, which signifies infection acquired more than a year before syphilis is diagnosed. In the past 75 years the syphilis epidemic has undergone major fluctuations in the United States (Figure 1). During the 1920’s and 1930’s, syphilis rates were very high, but declined rapidly in the late 1940’s with the introduction of penicillin.[1,2] The number of reported cases rose between 1986 and 1990, but by the late 1990s, syphilis rates in the United States had declined to a point where public health authorities declared syphilis elimination a feasible goal and in 1999 the CDC developed a national plan to eliminate syphilis in the United States. In 2000, the reported rate of syphilis in the United States reached an all-time low, but unfortunately, cases of syphilis have increased since 2001, primarily due to an increase among men who have sex with men (MSM), including those co-infected with HIV. In 2015, a total of 23,872 cases of primary and secondary syphilis were reported, which corresponds to a rate of 7.5 cases per 100,000 population; the cases in 2015 represent a 19.0% increase from 2014, a 66.7% increase since 2010, and the highest rate reported since 1994.
Epidemiology by Demographics
The following summarizes syphilis epidemiology in the United States based on demographics per the 2015 CDC STD Surveillance report.
In the United States, from 2006 to 2105, the rates of primary and secondary syphilis increased in all major regions, with the most significant increases occuring in the West (Figure 2). In 2015, the West had the highest rate of reported primary and secondary syphilis, followed by the South, then the Northeast, and last by the Midwest (Figure 3). The seven states with the highest incidence of syphilis are Louisiana, Georgia, California, North Carolina, Nevada, Florida, and New York; rates are also very high in Puerto Rico and Washington DC (Figure 4). Most regions have pockets of high syphilis incidence in specific counties or cities.
Rates by Sex and Sexual Behavior
In 2015, the rate of reported primary and secondary syphilis cases among men (13.7 cases per 100,000 males) was nearly 10-fold higher than among women (1.4 cases per 100,000 females), with men accounting for 90.3% of primary and secondary syphilis cases (Figure 5). Since 2000, the rate of primary and secondary syphilis among men has increased every year and during 2014 to 2015, the P & S syphilis rate in men increased 18.1%. Men who have sex with men accounted for 59.6% of reported cases of primary and secondary syphilis in 2015, with a breakdown showing 54.0% of these cases involved MSM and 5.6% occurred among men who have sex with both men and women. Rates among women have fluctuated between 0.8 and 1.7 cases per 100,000 females since 2000, but during 2014 to 2015, the syphilis rate in women increased 27.3%.
Rates by Race/Ethnicity
Although syphilis cases declined in all racial/ethnic groups between 2000 and 2010, syphilis rates have increased in recent years in every racial/ethnic group, except Native Hawaiians/Other Pacific Islanders. In 2015, the rate among blacks was 5.2 times the rate among whites (21.4 versus 4.1 cases per 100,000); in addition, the rate among Hispanics was 2.2 times the rate among whites (Figure 6). From 2011 to 2015, the rates of syphilis increased in all racial/ethnic groups, except for American Indians/Alaska Natives.
Rates by Age
In females, the rates of reported primary and secondary cases of syphilis are highest in women aged 20 to 24 and next highest in those aged 25-29; for males, the rates were highest in those 25-29 years of age, followed by 20-24 year olds (Figure 7).
Syphilis and HIV Coinfection
Of primary and secondary syphilis cases diagnosed in men who have sex with men, approximately one-half (49.8%) of the men are co-infected with HIV. In contrast, cases of syphilis in men who have sex with women, only 10% of the men are co-infected with HIV. Among HIV-negative men who have sex with men, a diagnosis of primary or secondary syphilis is associated with a significant increased risk of subsequent HIV infection (HIV incidence, 2.8 per 100 person-years).[4,5]
Rates of Congenital Syphilis
The rate of congenital syphilis fluctuated from 2006 through 2011, but has been consistently rising since. Between 2014 and 2015, the rate increased by 6.0% for a rate of 11.7 cases per 100,000 live births in 2015. The recent increases in rate of congenital syphilis parallels the rise in primary and secondary syphilis among women. Transmission to the fetus in pregnancy can occur during any stage of syphilis, but the risk is much higher when the mother is in the primary or secondary stage of syphilis, especially if T. pallidum is acquired in the third trimester.
In the United States, for epidemiologic purposes, prevalence has not been a useful metric for syphilis due to (1) the multiple stages of the disease and (2) the vast majority of persons diagnosed with syphilis receive treatment.
The highest risk associated with syphilis infection occurs in MSM and in persons with HIV infection (men or women).[1,6] Additional risk factors include a history of incarceration, history of commercial sex work, black race, and, for males, age younger than 29 years. Among MSM, use of methamphetamine has been associated with acquisition of STDs, including syphilis. In one report, investigators evaluated MSM who used methamphetamines and had early syphilis and found multiple risk factors associated with methamphetamine use, including multiple or anonymous partners, not using a condom, and meeting sex partners at bathhouses.
The total direct medical cost for treatment of syphilis infections in the United States has been estimated at 39.3 million dollars per year. This represents about 2.5% of the 15.6 billion dollars spent on sexually transmitted diseases and HIV infection in the United States (approximately 12.6 billion dollars is associated with the care of persons with HIV infection).
Microbiology and Pathogenesis
Organism and Classification
The etiologic agent in syphilis is Treponema pallidum (from the Greek terms trepo (“to turn”) and nema (“thread”) and the Latin term pallida (“pale”). T. pallidum belongs to the spirochete class and is a corkscrew-shaped, motile microaerophilic bacterium that requires a live rabbit-model system for growth and cannot be viewed by normal light microscopy (Figure 8). This spirochete bacterium is thin (0.1 to 0.18 micrometers in diameter), and 6 to 20 micrometers in length (Figure 9). T. pallidum has been erroneously described as gram-negative bacteria, but this organism lacks lipopolysaccharide (LPS), a hallmark of gram-negative organisms.
The major routes of transmission for T. pallidum are sexual and vertical (in utero via hematogenous spread to a fetus). T. pallidum enters the body via skin and mucous membranes through macroscopic and microscopic abrasions during sexual contact. An infected individual is contagious to sex partners during the primary and secondary stages of infection—when lesions or rash are present. Although predominantly transmitted at genital sites, primary lesions have been described at diverse sites, including mouth, anorectal areas, and chest or neck from human bites. Transmission may also occur via placenta from mother to fetus during pregnancy. Transfusion-associated syphilis was well-recognized prior to the 1940’s, but has been eliminated in the United States blood supply; this mode of transmission now occurs only in resource-limited countries.
Syphilis has often been called "the great imitator" because so many of the signs and symptoms may be difficult to differentiate from those of other diseases.[12,13,14,15] Before clinical signs or symptoms appear T. pallidum accesses the circulatory system, including the lymphatic system and regional lymph nodes. Invasion of the central nervous system can occur during any stage of syphilis. Early clinical manifestations (primary and secondary stages) predominantly involve the skin and mucosal surfaces, although secondary syphilis may be accompanied by systemic manifestations. Latent disease has no clinical signs or symptoms, but late manifestations (seen after years of infection) may affect virtually any organ system. Neurosyphilis and ocular syphilis can occur at any stage of infection. Obtaining a detailed history is critical for determining the duration of infection and assessing for the possibility of reinfection. When obtaining the patient’s history, the healthcare professional should assess whether the patient has had:
- A history of syphilis (if yes, obtain results of previous serologic tests for comparison)
- Known contact with someone with primary or secondary syphilis
- Signs or symptoms of syphilis in the past 12 months.
Following the inoculation of T. pallidum at the entry site, organisms proliferate, sensitize lymphocytes, and activate macrophages, causing the formation of a primary lesion or "chancre" at the site of inoculation. The initial manifestation of the chancre typically occurs about 3 weeks (range 10 to 90 days) after the acquisition of the infection. Chancres progress from a papule to an ulcer, which is typically painless, indurated, well circumscribed, round to oval in shape, with a clean base. The most common sites where chancres develop include the penis (Figure 10), labia, perianal region, or mouth (Figure 11). Regional firm, non-tender, lymphadenopathy often develops in proximity to primary syphilitic lesions (inguinal adenopathy with genital lesions and cervical adenopathy with oral lesions); in most patients, the lymphadenopathy is bilateral.[18,19] Syphilitic chancres are highly infectious and heal spontaneously within 1 to 6 weeks; untreated patients may go on to develop other manifestations of syphilis. Less typical lesions often develop, with one study reporting only 42.7% had a “classic” single lesion. Atypical features may include painful lesions or multiple lesions; in some instances chancres can mimic herpes simplex infection or chancroid. Evaluation of patients with genital ulcers should include serologic testing for syphilis and a diagnostic evaluation for genital herpes. In addition, if available, suspected primary syphilis should be evaluated with darkfield microscopy or a polymerase chain reaction (PCR) test for T. pallidum. In geographic regions where chancroid is endemic (Asia, Africa, and the Caribbean), testing for Haemophilus ducreyi should also be performed.
Secondary lesions reflect hematogenous dissemination of T. pallidum and generally appear 4 to 8 weeks after the onset of the primary chancre; patients with secondary syphilis may develop a wide array of cutaneous lesions. Signs and symptoms of secondary syphilis often are the first observed clinical manifestation of syphilis in those practicing receptive vaginal, oral, or anal intercourse because primary lesions may occur in the vagina, mouth, or anus and may not be recognized by the patient. In some patients, primary and secondary stages may overlap. Relapses of secondary symptoms may occur in up to 25% of untreated patients, usually within the first year of infection.
- Rash: A rash occurs in 75% to 100% of patients with secondary syphilis. The rash can be macular, papular, squamous, pustular (rarely), or a combination. Rash with secondary syphilis is usually nonpruritic, and characteristically involves the chest (Figure 12), back (Figure 13), palms (Figure 14), and soles (Figure 15). Any new onset of macular, papular, or squamous rash should be evaluated to rule out secondary syphilis.
- Lymphadenopathy: In 50% to 86% of cases, patients will develop lymphadenopathy. Epitrochlear lymphadenopathy should prompt consideration of secondary syphilis.
- Systemic Symptoms: Patients often present with malaise, fever, and other nonspecific constitutional symptoms.
- Mucous Patches: The development of mucous patches occurs in 6% to 30% of patients and manifest as flat patches located in the oral cavity (Figure 16), pharynx, larynx, or genital region.
- Condylomata Lata: Approximately 10% to 20% of patients will have condylomata lata lesions, which appear as moist, heaped-up, wart-like papules in warm intertriginous areas (most commonly gluteal folds, perineum, and perianal) (Figure 17); these lesions are highly contagious.
- Alopecia: About 5% of patients develop patchy alopecia, most often in the occipital or bitemporal scalp region, but some patients will have loss of the lateral region of the eyebrows.
- Visceral Organ Involvement: In some cases, syphilis may involve one or more visceral organs, including liver, kidney, lungs, gastrointestinal tract, and spleen.
- Neurologic Symptoms: Patients with secondary syphilis can develop neurosyphilis, characterized by either asymptomatic infection of the central nervous system, or acute syphilitic meningitis, a basilar meningitis that typically causes headache and stiff neck and may involve cranial nerves, which may result in hearing loss, facial weakness, or visual disturbances. Strokes may also occur. Patients may also develop ocular or otic syphilis without basilar meningitis.
Latent syphilis is a stage of syphilis characterized by the persistence of T. pallidum organisms in the body without causing signs or symptoms. Periods of clinical latency may occur between the primary and secondary stages, between secondary relapses, and after the secondary stage. The diagnosis of latent syphilis is made when an individual has (1) seroreactivity indicating infection with T. pallidum, (2) no past diagnosis of syphilis, and, and (3) no evidence of active primary, secondary, or tertiary syphilis. Latent syphilis is classified into three subcategories based on duration of the infection: early latent, late latent, and latent of unknown duration. It is often difficult to determine the duration of infection in a patient with latent syphilis. Individuals with latent syphilis should have HIV testing at the time of syphilis diagnosis (and at a 3-month follow-up if high risk for HIV acquisition), unless they are already known to have HIV infection. When evaluating an individual with latent syphilis, the health care provider should ask the patient whether they recall having symptoms of primary or secondary syphilis, and whether they had sex with someone with primary or secondary syphilis within the past year. A careful physical examination, with an emphasis on mucosal surfaces, and review of prior serology results are also useful tools for clarification of the duration of infection.
Early Latent Syphilis (Infection of Less than 1 Year in Duration)
Persons with latent syphilis are classified in the subcategory of early latent syphilis if they have no past diagnosis of syphilis, no clinical signs or symptoms of syphilis, and at least one of the following:
- A documented seroconversion or fourfold or greater increase in titer of a nontreponemal test during the prior 12 months
- Documented seroconversion of a treponemal test during the previous 12 months
- A history of symptoms consistent with primary or secondary syphilis during the prior 12 months
- A history of sexual exposure to a partner within the prior 12 months who had documented primary, secondary, or early latent syphilis (documented independently as duration less than 12 months)
- Sexual debut occurred in the prior 12 months and only possible sexaul contact occurred in the prior 12 months
Late Latent Syphilis (Infection Greater than 1 Year in Duration)
Persons with latent syphilis are classified in the subcategory of late latent syphilis when there is no evidence that T. pallidum was acquired in the prior 12 months, no clinical signs or symptoms of syphilis, and at least one of the following:
- No past diagnosis of syphilis and reactive nontreponemal and treponemal tests
- A past history of syphilis therapy and a current nontreponemal test titer demonstrating fourfold or greater increase from the last nontreponemal test titer
Latent Syphilis of Unknown Duration
In the situation when it is not possible to determine likely the duration of infection in a person with latent syphilis, they are categorized as having latent syphilis of unknown duration. From a practical standpoint, individuals with latent syphilis of unknown duration are effectively managed the same as persons with late latent syphilis.
Tertiary Syphilis (other than neurosyphilis)
Tertiary syphilis, also referred to as late syphilis, is rare because of widespread availability and use of antibiotics. Without treatment, however, approximately 30% of patients eventually progress to the tertiary stage of syphilis within 1 to 20 years of the original infection. Gummatous lesions can occur in skeletal, spinal, and mucosal areas, eyes, and viscera (lung, stomach, liver, genitals, breast, brain, and heart). The destructive lesions can clinically mimic carcinoma. The average onset is 10 to 15 years after infection. Cardiovascular syphilis is indicated by pathologic lesions of the aortic vasa vasorum. It clinically presents as ascending aortic aneurysm, aortic insufficiency, or coronary ostial stenosis. The average appearance is about 20 to 30 years after infection.
Neurosyphilis occurs when T. pallidum invades the central nervous system and this may occur at any stage of syphilis. In addition, cerebrospinal fluid (CSF) abnormalities can occur in early syphilis and are of unknown significance in the absence of neurologic signs or symptoms; these inflammatory CSF changes are likely due to invasion of the central nervous system by T. pallidum, as up to 25% of CSF samples taken during early syphilis can reveal T. pallidum DNA via PCR.[23,24] Experts have postulated that several decades of widespread use of antibiotics active against T. pallidum underlies the notable shift in clinical presentation from paresis and tabes dorsalis to meningeal and meningovascular syndromes; this change has been particularly evident among persons with HIV infection.[25,26]
- Early Neurosyphilis: Early forms of neurosyphilis usually occur a few months to a few years after initial infection. Clinical manifestations include acute syphilitic meningitis, a basilar meningitis that typically involves cranial nerves III, VI, VII and VIII; or meningovascular syphilis, an endarteritis that presents as a stroke-like syndrome with seizures.
- Late Neurosyphilis: Late forms of neurosyphilis usually occur decades after infection, and they are rarely seen. Clinical manifestations include general paresis and tabes dorsalis but can present with a wide variety of neurologic symptoms. Serologic treponemal tests are usually reactive. Ocular involvement can occur in early or late neurosyphilis.
Since T. pallidum can potentially infect any part of the eye, the range of manifestations associated with ocular syphilis is broad and patients may present with an array of symptoms.[27,28,29,30] Ocular syphilis can develop at any stage of syphilis and patients can present with acute or chronic symptoms. Ocular complications of syphilis have been reported in clusters in recent years.[30,31] Several recent studies have analyzed molecular strain type and found no clear evidence of a predominant strain trophic for the eye.[31,32] Ocular syphilis can be seen in isolation with other neurologic symptoms—it can present with anterior, posterior, or pan-uveitis and can occur at any stage of syphilis.[28,29] Other described manifestations include lid involvement, episcleritis, vitritis, retinitis, papillitis, interstitial keratitis, acute retinal necrosis, and retinal detachment. Primary optic atrophy is unique to late syphilis (classically described with tabes dorsalis). The clinical presentations can have significant overlap with eye disease caused by tuberculosis, toxoplasmosis, histoplasmosis, and ocular Toxocara canis infections. Non-infectious causes such as rheumatoid arthritis and sarcoidosis must also be considered. Patients with syphilis and ocular complaints should undergo prompt ophthalmologic evaluation and have a lumbar puncture performed for cerebrospinal fluid evaluation.[22,30] Improvement of symptoms (including vision) may significantly improve after treatment for syphilis, but this depends on the type of pathology and timing of initiating antimicrobial therapy; if scarring is present, it is unlikely to significantly change following treatment.
Congenital syphilis occurs when T. pallidum is transmitted from a pregnant woman with syphilis to her fetus. Untreated syphilis during pregnancy may lead to stillbirth, neonatal death, and infant disorders such as deafness, neurologic impairment, and bone deformities.[33,34] Transmission to the fetus in pregnancy can occur during any stage of syphilis, but the risk is much higher when a pregnant woman is in the primary or secondary stage of syphilis. Fetal infection can occur during any trimester of pregnancy and may range from mild to severe, with only severe cases manifesting clinically at birth. Congenital syphilis is traditionally classified as either early or late disease. Early manifestations occur within the first two years of life, and late manifestations occur after two years of age. Early manifestations are the most common.
Early Congenital Syphilis
Early congenital syphilis is usually defined as manifestations of syphilis in infants and children younger than 2 years of age, with abnormalities that include the following:
- Hepatosplenomegaly is very common but is a non-specific finding.
- Bone involvement is the most common specific manifestation and is seen in 60% to 80% of infected infants.
- Skin (bullous or exudative lesions) or mucous membranes lesions may be seen.
- Alopecia, generalized lymphadenopathy, meningitis, osteitis or osteochondritis can also occur.
- Hematologic abnormalities such as thrombocytopenia and anemia manifest in some cases.
Late Congenital Syphilis
Late congenital syphilis is generally defined as manifestations of syphilis in children older than 2 years of age, with disorders that include the following:
- Tend to be immunologic and destructive. These findings frequently result from scarring after chronic inflammatory changes from early systemic disease.
- Bone lesions including frontal bossing, shortened maxilla, high palatal arch are most common.
- Interstitial keratitis is seen in about 40% of cases.
- Perforation of the hard palate (Figure 18).
- Hutchinson’s triad is the classic association of eighth cranial nerve deafness, interstitial keratitis, and Hutchinson teeth (Figure 19) and is described in 75% of patients.
The laboratory diagnosis of syphilis is challenging and requires using a combination of clinical and laboratory criteria to differentiate active infection, prior infection, and absence of infection.[37,38] T. pallidum cannot be cultivated on artificial medium, but the organism can be grown using special techniques that involve inoculation in rabbits. In clinical samples, spirochetes can occasionally be visualized in specimens taken from cutaneous lesions using dark-field microscopy techniques. In addition, silver staining and immunohistochemical (IHC) staining of tissue samples can demonstrate characteristic spirochetes on clinical biopsy specimens. Use of dark-field microscopy or IHC staining on oral specimens is not recommended due to the extremely poor specificity caused by abundant non-syphilitic oral Treponema species. Serologic testing remains the primary tool for diagnosis in most patients with syphilis and these tests include “nontreponemal” and “treponemal” tests. Although PCR testing is sometimes used for research purposes, there is no FDA-approved PCR test for syphilis at present. Research use of PCR detection of T. pallidum DNA has expanded the clinical sites from which T. pallidum can be detected.
Direct Detection of Treponema pallidum
Dark-field microscopy of lesion exudate or tissue is the definitive method for diagnosing early syphilis.[22,37] T. pallidum cannot be viewed by normal light microscopy. Dark-field microscopy can identify T. pallidum with its spiral shape, 10 to 14 coils, corkscrew motion, and a total length of 6 to 20 micrometers (Figure 20) . Dark-field microscopy is rarely used in clinical practice because most facilities do not have dark-field microscopy and most clinicians do not know how to appropriately obtain specimens. Dark-field microscopy has the potential advantage of making a definitive and rapid diagnosis of primary or secondary syphilis. Several disadvantages exist with dark-field microscopy, including (1) requirement for specialized, expensive equipment, (2) need for clinician training on how to appropriately collect and prepare a specimen for dark-field microscopy, (3) need for experienced microscopist who can correctly identify T. pallidum with dark-field microscopy, (4) potential false-positive results in oral specimens (from nonpathogenic spirochetes in the oral cavity), (5) potential false-negative results if topical agents have been applied by the patient or the specimen is not collected appropriately, and (6) need to immediately view any collected specimen. Clinicians need to take special precautions to protect themselves from inoculation when collecting specimens for dark-field microscopy, since the lesions contain abundant viable organisms.
Direct Fluorescent Antibody Test
The direct fluorescent antibody test can detect T. pallidum antigens in tissue samples. The test uses antibodies specific to pathogenic treponemes and can generally identify T. pallidum in samples—such as oral or rectal lesions—that may have background non-pathogenic spirochetes.
Serologic Testing for Syphilis
In the absence of dark-field microscopy, a probable diagnosis of syphilis is possible with the use of two types of serologic tests: nontreponemal and treponemal. Use of only one type of serologic test is insufficient for diagnosis since each test used alone has major limitations, including false-positive tests in persons without syphilis and the inability for treponemal tests to distinguish between recent and distant infection. Both types of tests have several advantages and disadvantages as well as differing test characteristics.
Nontreponemal Serologic Tests
The nontreponemal tests include Venereal Disease Research Laboratory (VDRL), Rapid Plasma Reagin (RPR), Toluidine Red Unheated Serum Test (TRUST), and Unheated Serum Reagin (USR). These tests measure IgM and IgG antibody and are not specific for T. pallidum. Nontreponemal test results are reported with a qualitative result and a quantitative titer, which usually correlates with disease activity. A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:16 to 1:4 or from 1:8 to 1:32) is considered necessary to demonstrate a clinically significant difference. Sequential serologic tests in individual patients should be performed using the same testing method, preferably by the same laboratory. The VDRL and RPR are equally valid assays, but quantitative results from the two tests cannot be compared directly because RPR titers are often slightly higher than VDRL titers. TRUST is similar to RPR whereas USR is similar to VDRL, though in the United States TRUST and USR are not often used. The nontreponemal tests have several drawbacks, including (1) they are labor intensive to perform, (2) results are typically not available for at least 7 days, (3) the tests have low sensitivity in certain stages, particularly early primary, late latent, and tertiary, and (4) false-positive reactions can occur. Nontreponemal tests usually become nonreactive with time after treatment. In some patients, however, nontreponemal antibodies can persist at a low titer (the definition “low” titer is dependent on laboratory and clinical context, but less than 1:8 is generally consider “low”) for a long period of time, sometimes for the life of the patient. This response is referred to as the "serofast reaction." In addition, in some patients, nontreponemal tests may, with time, become nonreactive in the absence of therapy.
Treponemal Serologic Tests
The treponemal serologic tests include T. pallidum particle agglutination (TP-PA), fluorescent treponemal antibody absorption (FTA-ABS), and various enzyme immunoassays (EIAs) and chemiluminescence immunoassays. These tests measure antibody directed against T. pallidum antigens by particle agglutination (TP-PA), immunofluorescence (FTA-ABS), or enzyme immunoassay (EIA) (Figure 21); some detect IgG only whereas others detect both IgM and IgG. These qualitative tests most often remain reactive for life, even after adequate treatment, but 15% to 25% of patients treated during the primary stage revert to being serologically nonreactive after two to three years. Treponemal antibody titers correlate poorly with disease activity, and they should not be used to assess treatment response.
Patterns of Serologic Reactivity and Sensitivity of Tests
The common patterns for serologic reactivity with syphilis tests depend on the specific test used, the stage of syphilis, and whether the patient has received treatment. The sensitivity of serologic testing also varies based on the test used and stage of syphilis .[38,41] Serologic testing for syphilis has the highest yield during secondary syphilis. Serologic tests for syphilis may be negative during very early primary syphilis. Thus, when serologic tests do not correspond with clinical findings suggestive of primary syphilis, presumptive treatment is recommended if the patient has known risk factors for syphilis; in this setting, use of other tests, such as dark-field microscopy, biopsy, or PCR, should be considered.
Prior Serologic Testing for Syphilis
The healthcare professional should determine the date and results of the patient’s most recent serologic test for syphilis, even if the patient reports no history of the disease. Prior results, if available, are particularly helpful when evaluating a patient that has a low titer serologic test for syphilis, no signs or symptoms that suggest a clinical diagnosis of syphilis, and no known contact with an early case of syphilis. Local health departments can often provide information on whether the patient has been reported as having had syphilis in the past, including reported serologic test results and treatment history.
Serologic Testing Algorithms
Given that treponemal and nontreponemal tests each have significant advantages and disadvantages, these lab tests are used together as part of a screening algorithm in order to maximize sensitivity and specificity for the detection of syphilis infection. Clinicians should be aware of their institution’s chosen method in order to most efficiently use serologic tests to screen for, diagnose, and monitor syphilis disease.
Standard (Traditional) Screening Algorithm
Traditionally, the syphilis screening algorithm has consisted of initial screening with a nontreponemal test (VDRL or RPR), with further testing on a positive initial test with a treponemal test (TP-PA or EIA) (Figure 22). Patients with a negative screening test were relegated to periodic repeat screening whereas patients with positive results required a treponemal test to confirm a diagnosis of syphilis. The major limitations with using a nontreponemal test for initial screening include the personnel time required to perform a labor-intensive test, biologic false positives (i.e. pregnancy, medication use, and other conditions) and, as with all diagnostic tests for syphilis, the inability to detect early primary or latent infection.
Reverse Sequence Screening Algorithm
Another option for syphilis screening is to use T. pallidum-specific EIAs or chemiluminescence immunoassays as an initial screening test. In recent years, increasing numbers of clinical laboratories and blood banks have begun using treponemal EIA or chemiluminescence immunoassays (CIAs) as the initial screening laboratory test for syphilis. With this approach, a positive EIA or CIA test is followed by further testing with a nontreponemal test—often referred to as reverse screening (Figure 23). In the reverse screening algorithm, negative treponemal results are relegated to follow-up screening as with the standard (traditional) algorithm. Positive treponemal results undergo a confirmatory nontreponemal test (i.e. RPR) to guide management. In the event of a positive EIA and a negative nontreponemal test, a second confirmatory treponemal test (TP-PA) is performed. If either of the confirmatory tests is positive and there is no history of prior, treated syphilis, the patient is diagnosed with syphilis. This ‘reverse screening algorithm’ has several advantages and disadvantages distinguishing it from the standard (traditional) screening algorithm. Advantages of the reverse sequence algorithm include improved detection of early primary and treated infection, low cost, and reduced laboratory time and effort (much less pipetting and circumventing the manual dilutions of nontreponemal testing).
Discordant Test Results Using Reverse Screening
In the scenario where a patient has a positive treponemal screening test (EIA), a negative nontreponemal test, and a positive second treponemal test (TP-PA), there are several possible scenarios: prior treated syphilis, early syphilis, untreated latent syphilis, or false-positive test. If the patient has received prior treatment for syphilis and has no evidence by history or examination for recent infection with T. pallidum, then the patient does not require further evaluation or management. Patients without prior treatment and no evidence for recent infection are considered to have latent syphilis and require further evaluation and treatment. If recent infection possibly occurred, then repeat nontreponemal testing should take place 2 to 3 weeks later; if this repeat testing is positive the patient likely has early syphilis and if the test is negative then further evaluation is usually not needed.
Management of Positive Screening Results
Current syphilis serologic screening algorithms include a nontreponemal titer (VDRL or RPR) to help clarify disease activity. Infections can thus be differentiated based on active disease, prior treatment, and time since prior screening. Symptomatic patients should be classified by stage of syphilis based on clinical findings, including determination of whether they have evidence of neurologic or ophthalmologic disease. Patients without a history of treatment for syphilis should be offered therapy based on clinical findings and the stage of disease. Asymptomatic, previously untreated persons who have not had syphilis testing in the prior year should be considered to have late latent syphilis. All patients who have syphilis should be tested for HIV infection, and those with primary or secondary syphilis who live in areas with a high prevalence of HIV should be retested for HIV after three months (if the first HIV test result was negative). Providers should consider screening patients with syphilis for other STDs, based on risk.
Positive Titers in Patients Previously Treated for Syphilis
Although patients with early syphilis usually have a fourfold or greater decline in nontreponemal titer within 12 months after treatment, some fail to achieve seroreversion at month 12. Patients previously treated for syphilis who had a documented adequate reduction in nontreponemal titer after treatment may have a persistent low-positive nontreponemal titer that does not significantly change; this is called a serofast state and they do not require additional therapy. Patients with prior treatment and higher (but unchanged) nontreponemal titer are considered treatment failures unless there is clinical suspicion for reinfection.
With both nontreponemal and treponemal serologic tests for syphilis, false-positive reactions can occur. The following table lists causes of false-positive reactions for various serologic tests. In addition to those listed on the slide, technical errors and transient unknown causes can lead to false-positive reactions in treponemal and nontreponemal tests.
False-Negative Reaction (“Prozone Effect”)
Infrequently, patients may have a false-negative reaction with nontreponemal testing due to the “prozone effect”. The prozone effect occurs when very high serum antibodies supersaturate the antigens used in the nontreponemal assay, thereby interfering with the antigen-antibody lattice network needed to visualize a flocculation reaction.[45,46] Overall, this occurs in less than 2% of cases of syphilis.[45,47] This false-negative reaction is most likely to occur in patients with secondary syphilis and HIV infection. If clinical suspicion of secondary syphilis is high and the nontreponemal testing is negative, the clinician should alert the laboratory of a suspected prozone effect and the laboratory should reevaluate the clinical sample after diluting the serum, typically a 1/16 dilution.
Diagnosis of Latent Syphilis
Persons are diagnosed with latent syphilis when they have (1) serologic evidence of T. pallidum infection, (2) no past diagnosis of syphilis, and (3) no active syphilis-related signs or symptoms. It is often difficult to determine the duration of infection in a patient with latent syphilis.
Laboratory Evaluation for Neurosyphilis
Neurologic involvement can occur during any stage of syphilis. Cerebrospinal fluid (CSF) abnormalities have been noted in 13% of patients with untreated primary syphilis and 25% to 40% of patients with untreated secondary syphilis.[26,48] Although these CSF laboratory abnormalities are common in persons with early syphilis, no evidence exists to support variation from recommended treatment for syphilis at any stage in the absence of clinical neurologic findings, with the exception of tertiary syphilis. In addition to work-up of clinically suspected neurosyphilis, there are a number of additional indications to perform CSF evaluation .
Several studies have shown that among persons with HIV and syphilis, CSF abnormalities (mononuclear pleocytosis and elevated protein) are associated with a CD4 count of 350 cells/mm3 or less and/or a nontreponemal serologic test titer of greater than or equal to 1:32. Data are lacking regarding the benefits of a CSF examination in this setting. In general, persons with HIV infection tend to have more frequent CSF abnormalities in the absence of neurologic symptoms, and the presence of 20 or more white blood cells (WBC)/mm3 might improve the specificity of probable neurosyphilis in this patient population. When using a nontreponemal test to evaluate for neurosyphilis, the CSF VDRL is preferred over the CSF RPR. For more detailed information on the diagnosis of neurosyphilis including interpretation of CSF findings, consult the 2015 CDC STD Treatment Guidelines.
Diagnosis of Syphilis in Patients with HIV Coinfection
Syphilis and HIV infection frequently coexist. In general, the clinical course of syphilis in persons with HIV infection is similar to that in persons not infected with HIV. Although not common, unusual serologic responses among persons with HIV infection can occur. If the clinical suspicion of syphilis is high and the serologic tests for syphilis are negative, then use of other tests (e.g., biopsy of the lesion or rash) should be considered. Conventional therapy is usually effective. After appropriate therapy, persons with HIV infection more frequently demonstrate “high serofast” values of nontreponemal serologic tests (often defined as RPR greater than or equal to 1:8).
Diagnosis of Syphilis in Infants and Children
The diagnosis of congenital syphilis is often difficult since maternal nontreponemal and treponemal IgG antibodies can be transferred through the placenta to the fetus. The decision to treat a neonate (aged fewer than 30 days) is based on (1) identification of syphilis in the mother; (2) adequacy of maternal treatment; (3) clinical, laboratory, and radiographic evidence of disease in the neonate; and (4) comparison of maternal and neonatal nontreponemal serologic titer. Based on these factors, neonates are classified as (1) proven or highly probable congenital syphilis; (2) possible congenital syphilis; (3) congenital syphilis less likely; or 4) congenital syphilis unlikely.
Reporting and Referral to Health Departments
Patients with primary, secondary or early latent syphilis, or syphilis of unknown duration with a high nontreponemal serologic test titer (greater than 1:32), should be referred to the local health department STD program for interview, partner elicitation, and partner follow-up. The follow-up of patients with early syphilis is a public health priority. Laws and regulations in all states require that persons diagnosed with syphilis be reported to public health authorities. Reporting can be provider-based or laboratory-based. Providers unsure of reporting requirements should seek advice from state or local health departments or STD Programs. To locate a state health department, see the CDC resource tool Public Health Resources: State or Territorial Health Departments.
Screening for Infection
The 2016 US Preventive Services Task Force (USPSTF) Recommendation Statement on Screening for Syphilis Infection in Nonpregnant Adults identifies men who have sex with men and persons living with HIV as the highest risk groups for acquiring syphilis.[6,50] In addition, the USPSTF lists five other risk factors associated with increased syphilis prevalence rates: history of incarceration, history of commercial sex work, certain racial/ethnic groups (highest in blacks), and being a male younger than 29 years of age. Routine screening is recommended for several other specific populations, including patients who are pregnant, persons taking preexposure prophylaxis for HIV prevention, and persons who have a sexual partner diagnosed with syphilis.
Summary of Recommendations for Routine Screening for Syphilis
- Heterosexual Women and Women who have Sex with Women: The USPSTF recommends screening for non-pregnant women, regardless of sexual orientation, who are at increased risk for infection (see above "Risk Factors" and "Screening for Infection").
- Heterosexual Men: The USPSTF recommends screening for men who are at increased risk of infection (see above "Risk Factors" and "Screening").
- Men who have Sex with Men: For sexually active MSM, at least annual screening is recommended. More frequent screening is indicated for MSM with HIV infection if risk behaviors persist, or if their sex partners have multiple partners The USPSTF guidelines recommend screening sexually active MSM every 3 months.
- Persons with HIV Infection: Routine syphilis screening should be performed at the initial HIV evaluation, at least annually in all sexually active persons with HIV infection, and more frequently if indicated based on risk behaviors. The USPSTF guidelines further recommend screening men with HIV infection and MSM every 3 months.
- Pregnancy: At the first prenatal visit, all pregnant women should be screened for syphilis. This approach is recommended by the CDC as well as the American College of Obstetrics and Gynecology (ACOG) and is mandated by most state laws.[22,51] Women who are at high risk for syphilis or live in areas of high syphilis morbidity should be screened again around 28 weeks gestation and at delivery. Any woman who delivers a stillborn infant after 20 weeks of gestation should be tested for syphilis. Screening for syphilis should occur during each pregnancy.
- Adolescents: Routine screening of adolescents for syphilis, is not generally recommended, but young men who have sex with men and pregnant adolescent females should be screened for syphilis.
- Neonates: Neonates should not be discharged from the hospital unless the syphilis serologic status of the mother has been determined at least one time during pregnancy (and again at delivery if there was ongoing risk for acquiring syphilis during pregnancy).
- Correctional Facilities: Routine screening should be performed based the local area and institutional prevalence of early (primary, secondary, and early latent) infectious syphilis. Correctional facilities should stay apprised of syphilis prevalence as it changes over time.
Penicillin G, administered parenterally, is the preferred drug for treating of all stages of syphilis. The preparation(s) of penicillin used (i.e., benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of the disease. However, neither benzathine-procaine penicillin co-formulations nor oral penicillin preparations are considered appropriate for the treatment of syphilis. Reports have identified the inappropriate use of combination benzathine-procaine penicillin (Bicillin C-R) instead of the standard G benzathine penicillin G (Bicillin L-A) product. Practitioners, pharmacists, and purchasing agents should be aware of the similar names of these two products and avoid use of the inappropriate combination therapy agent for treating syphilis. It is important to understand that benzathine penicillin G is slowly released from the intramuscular site due to extremely low solubility and is also hydrolyzed to penicillin G; the combination of slow absorption and hydrolysis results in prolonged low serum levels of penicillin. In addition, practitioners should be aware of ongoing shortages of parenteral penicillin in the United States. Updated information on penicillin shortages can be found on the FDA Drug Shortages web site.
Primary and Secondary Syphilis
Parenteral penicillin G is effective in resolving clinical symptoms associated with primary and secondary syphilis and prevents late sequelae in those who receive appropriate treatment. The recommended regimen for adults with primary and secondary syphilis is benzathine penicillin G given as 2.4 million units intramuscular (IM) in a single dose; for infants and children, the dose is 50,000 units/kg, with a maximum of 2. 4 million units . The few available studies exploring optimal dosing regimens did not find any benefit from additional doses of penicillin or with combination therapy that included other antibiotics.[23,53] Treatment of primary and secondary syphilis for patients with documented allergy to penicillin is a topic with limited available date. Small studies and clinical experience suggest that regimens of doxycycline (100 mg orally twice daily for 14 days) or tetracycline (500 mg four times daily for 14 days) are acceptable alternatives for nonpregnant, penicillin-allergic persons who have primary or secondary syphilis.[54,55] Doxycycline is preferable to tetracycline because tetracycline can cause gastrointestinal side effects and requires more frequent dosing. In addition, ceftriaxone (1–2 g daily either IM or IV for 10 to 14 days) is considered effective for treating primary and secondary syphilis, but the optimal dose and duration of ceftriaxone in this setting remains unknown. Azithromycin as a single 2 g oral dose has been effective for treating primary and secondary syphilis, but concerns for emerging macrolide resistance led the CDC to recommend avoiding azithromycin for first-line syphilis treatment and, if used, it should only be considered when treatment with penicillin or doxycycline is not feasible. Further, azithromycin to treat syphilis should not be used in any circumstance to treat MSM, persons with HIV infection, or pregnant women. Any person receiving any of the alternative therapies for the treatment of syphilis should have careful clinical and serologic follow-up. In patients with a penicillin allergy for whom concern exists with adherence or follow-up should undergo penicillin desensitization and then receive treatment with benzathine penicillin G.
What is the recommended treatment for this patient?
The treatment of patients with latent syphilis requires appropriate classification into early latent syphilis (acquired less than 1 year ago as detailed above) or late latent syphilis (acquired longer than 1 year ago) or undetermined duration). The goals of treating patients with latent syphilis are to prevent development of late manifestations of infection (tertiary/neurosyphilis), as well as to prevent transmission to the fetus by infected pregnant women. Early latent syphilis is treated with a single dose of benzathine penicillin G 2.4 million units IM; late latent syphilis is treated with benzathine penicillin G 7.2 million units total split into three weekly IM injections of 2.4 million units . There are limited data comparing the efficacy of specific regimens or duration, but available data do not suggest any added benefit of additional antibiotics. Alternative therapies for treatment of latent syphilis have not been well studied. For penicillin-allergic, non-pregnant patients with early latent syphilis, the treatment approach should be the same as penicillin-allergic patients with primary or secondary syphilis. For penicillin-allergic patients with late latent syphilis, the only acceptable treatment alternatives are doxycycline (100 mg orally twice daily) or tetracycline (500 mg orally four times daily), each for 28 days. Ceftriaxone may be a reasonable option in this setting, but the optimal number of doses or schedule has not been determined and use of ceftriaxone to treat latent syphilis should involve consultation with a syphilis expert. All patients treated with alternative regimens require close serologic and clinical follow-up, especially in persons with HIV infection. Patients for whom adherence and follow-up is a concern should be desensitized and treated with benzathine penicillin G if possible.
Involvement of the CNS can occur during any stage of syphilis, which makes it essential that any patient receiving treatment for primary, secondary, or latent infection be evaluated for clinical evidence of neurologic involvement. If signs or symptoms of neurologic involvement are noted, a CSF examination should be performed. The recommended regimen for both neurosyphilis and ocular syphilis is aqueous crystalline penicillin G 18-24 million units per day, given as 3-4 million units intravenously (IV) every 4 hours (or as continuous infusion), for a total of 10 to 14 days . If adherence to therapy can be ensured, an acceptable alternative regimen is procaine penicillin G 2.4 million units IM once daily with probenecid 500 mg orally four times a day. Both agents are given for 10 to 14 days. It is important to note that some experts believe the duration of neurosyphilis therapy is not sufficient for treatment of late latent syphilis. Therefore, benzathine penicillin G 2.4 million units IM once per week for up to 3 weeks can be considered after completion of a neurosyphilis regimen in order to provide a comparable total duration of therapy. In addition, systemic corticosteroids have been used by some experts or specialists as adjunctive therapy for otologic syphilis, but data are insufficient to support the use of systemic corticosteroid therapy for otologic syphilis or any other form of syphilis. Limited data suggest that ceftriaxone 2 g daily either IM or IV for 10 to 14 days can be used as an alternative treatment for persons with neurosyphilis.[22,58] Other regimens have not been adequately studied for use in patients with neurosyphilis.
The recommended regimen for tertiary syphilis (not neurosyphilis) is benzathine penicillin G 7.2 million units total split into three weekly IM injections of 2.4 million units . All persons diagnosed with tertiary syphilis should undergo a CSF examination prior to starting therapy. This is done because of the high rates of clinically inapparent neurosyphilis in patients with tertiary syphilis. Patients with tertiary syphilis have potential for a wide variety of sequelae and should be managed in consultation with a syphilis expert. Patients diagnosed with tertiary syphilis who have a documented penicillin allergy also should be treated in consultation with a syphilis expert; for these patients, there is no alternative therapy suggested by the CDC.
Syphilis in Persons with HIV Infection
Available data suggest that persons with HIV infection who have early syphilis may have an increased risk of developing neurologic complications. The extent of this increased risk has not been clarified and current CDC guidelines do no recommend routinely performing CSF examination in persons with HIV infection diagnosed with syphilis, but all persons with HIV infection and syphilis should undergo careful neurologic examination and those with abnormal findings should promptly undergo lumbar puncture for CSF examination. There is no evidence that more intensive syphilis treatment improves outcomes or prevents neurosyphilis in persons with HIV infection who have early syphilis. The recommended regimens for the treatment of syphilis in persons with HIV infection are the same as for persons without HIV infection . Initiation of antiretroviral therapy for HIV infection concurrently with syphilis treatment has been shown to reduce serologic failure rates for syphilis.
The decision to restart a treatment regimen in the event of missed doses of benzathine penicillin G remains somewhat unclear. Although clinical experience suggests that an interval of 10 to 14 days between doses for late latent syphilis (or latent syphilis with unknown duration) might be acceptable, the pharmacokinetic profile of benzathine penicillin G suggests an interval of 7 to 9 days between doses would be optimal. Clinicians have differing practices within these limitations, but intervals greater that 14 days should always be restarted and pregnant women should repeat the full course if any doses are missed.[22,62]
Syphilis in Pregnancy
All pregnant women diagnosed with syphilis should receive treatment according to stage of infection and whether there is any evidence of neurologic disease. Erythromycin is no longer an acceptable alternative drug for penicillin-allergic patients. Patients who are skin-test-reactive to penicillin should be desensitized in the hospital and treated with penicillin. Some experts recommend giving a second dose of benzathine penicillin G 2.4 million units IM 1 week after the initial dose for pregnant women who have primary, secondary, or early latent infection. Treatment of the mother during the last month of pregnancy or with a drug other than penicillin is not considered adequate treatment for the fetus. Pregnant women should be informed that treatment for syphilis may precipitate early labor and that they should notify an obstetrician if problems develop.
Infants and Children with Syphilis
The regimen for proven or highly probable and possible congenital syphilis is either aqueous crystalline penicillin G 100,000–150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days or procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days. Neonates classified as possible congenital syphilis have the additional option of receiving treatment with benzathine penicillin G 50,000 units/kg IM in a single dose. The single dose regimen is only acceptable if all elements of the neonate’s lab work-up were performed and unequivocally normal. In addition, follow-up must be assured. Neonates with disease classified as “congenital syphilis less likely” should be given benzathine penicillin G 50,000 units/kg/dose intramuscularly in a single dose. Neonates for whom congenital syphilis is deemed unlikely do not require therapy but should be followed to ensure that their nontreponemal titer returns to non-reactive (as mother’s antibodies are lost). For additional details regarding the diagnosis and management of congenital syphilis, refer to the 2015 CDC STD Treatment Guidelines for information on the management of congenital and acquired syphilis in infants and children or the American Academy of Pedatrics' Red Book. Diagnosis and treatment of congenital syphilis is complex and challenging and should be done in consultation with a congenital syphilis expert. Notably, infants and children with a history of penicillin allergy or who develop signs of allergic reaction during treatment with penicillin present a unique challenge and should be managed with close follow-up and consultation with a syphilis expert.
The Jarisch-Herxheimer reaction is a self-limited reaction associated with initiation of anti-treponemal therapy that most often occurs in persons treated for early syphilis, presumably because bacterial burdens are higher during these stages. The Jarisch-Herxheimer reaction is characterized by fever, malaise, nausea, vomiting, and less frequently, chills and exacerbation of a secondary syphilis rash. This reaction almost always occurs within 24 hours after initiating antimicrobial therapy and usually resolves within 24 hours. For patients who develop a Jarisch-Herxheimer reaction, the clinician should clarify this reaction is not an allergic reaction to penicillin. It occurs more frequently after treatment with penicillin and treatment of early syphilis, especially at the secondary stage. Antipyretics can be used to manage symptoms associated with the Jarisch-Herxheimer reaction, but they do not prevent this reaction.
The follow-up of patients with syphilis is extremely important to document response to therapy and to reevaluate for reinfection. The following are general recommendations for follow-up after treatment.
- Patients treated for primary or secondary syphilis should be reexamined clinically and serologically 6 months and 12 months following treatment.
- Patients with latent syphilis should be followed up clinically and serologically at 6, 12, and 24 months.
- Persons with HIV infection should be evaluated more frequently; for primary or secondary syphilis at 3, 6, 9, 12, and 24 months and for latent syphilis at 6, 12, 18, and 24 months.
- If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the CSF cell count is normal. If the cell count has not decreased after 6 months, or if the CSF cell count or protein is not normal after 2 years, retreatment should be considered.
- Follow-up titers should be compared to the maximum or baseline nontreponemal titer obtained prior to treatment.
A key reason for close follow-up of patients treated for syphilis is to monitor signs, symptoms, or serologic changes that indicate possible treatment failure. There are no well-established, definitive criteria for treatment failure. Treatment failure cannot usually be differentiated from reinfection and thus persons suspected to have treatment failure failure or reinfection should be retested for HIV and should have a CSF evaluation for neurosyphilis (regardless of symptoms or prior CSF findings). Indications of probable treatment failure or reinfection include the following:
- A patient has persistent or recurring signs or symptoms.
- Patient testing shows sustained fourfold increase in nontreponemal titer. These patients should be retreated and reevaluated for HIV infection. Because treatment failure may be a result of unrecognized central nervous system (CNS) infection, CSF examination should be considered.
- Failure of nontreponemal titers to decline fourfold within twelve months after therapy for primary or secondary syphilis may be indicative of treatment failure. Additional clinical and serological follow-up is necessary since the optimal management is unclear. Examination of CSF can be considered in these instances. If follow-up cannot be ensured, retreatment is recommended.
When patients are retreated for primary, secondary, or latent syphilis (assuming no evidence of neurosyphilis), the recommended regimen is weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks. If neurosyphilis is diagnosed, aqueous crystalline penicillin G 18-24 million units per day a given as 3 to 4 million units IV every 4 hours (or as continuous infusion), for a total of 10 to 14 days. Refer to the 2015 STD Treatment Guidelines for more detailed information on assessment and management of probable treatment failure.
Partner Management and Public Health Measures
In general, the transmission of T. pallidum between sex partners only occurs when the person with syphilis has mucocutaneous lesions. In general, all persons who have sexual contact with a person diagnosed with primary, secondary, or early latent syphilis infection should undergo evaluation and testing for syphilis. Potential treatment for syphilis depends on the circumstances, as outlined below as recommended in the 2015 CDC STD Guidelines.
- Persons who have had sexual contact with a person who receives a diagnosis of primary, secondary, or early latent syphilis within 90 days preceding the diagnosis should be treated presumptively for early syphilis, even if serologic test results are negative.
- Persons who have had sexual contact with a person who receives a diagnosis of primary, secondary, or early latent syphilis greater than 90 days before the diagnosis should be treated presumptively for early syphilis if serologic test results are not immediately available and the opportunity for follow-up is uncertain. If serologic tests are negative, no treatment is needed. If serologic tests are positive, treatment should be based on clinical and serologic evaluation and stage of syphilis.
- In some areas or populations with high rates of syphilis, health departments recommend notification and presumptive treatment of sex partners of persons with late latent syphilis who have high nontreponemal serologic test titers (i.e., greater than 1:32), because high titers might be indicative of early syphilis. These partners should be managed as if the index case had early syphilis.
- Long-term sex partners of persons who have late latent syphilis should be evaluated clinically and serologically for syphilis and treated bassed on these findings.
- Certain sex partners of persons with syphilis are considered at risk for infection and should be confidentially notified of the exposure and the need for evaluation. These include partners who have had sexual contact within (a) 3 months plus the duration of symptoms for persons who receive a diagnosis of primary syphilis, (b) 6 months plus duration of symptoms for those with secondary syphilis, and (c) 1 year for persons with early latent syphilis.
Expedited Partner Therapy
There is insufficient data to support the use of expedited partner therapy in management of syphilis contacts. Accordingly, use of expedited partner therapy is not recommended for sexual contacts of persons diagnosed with syphilis. Transmission of T. pallidum is highly unlikely in persons when more than 1 year has elapsed since the time of infection.
Patient Counseling and Education
Patient counseling and education should cover the nature of the disease, transmission, treatment, follow-up, and risk reduction.
Nature of the Disease
Syphilis may be symptomatic or asymptomatic and a wide range of symptoms and manifestations can develop with syphilis. Patients with untreated syphilis can have progressive and severe complications, including neurologic and cardiovascular disorders. Untreated syphilis in pregnancy can cause severe disability of the fetus. Treatment of syphilis is not universally effective and all patients need follow-up evaluation following treatment.
Syphilis is transmitted by having sex with someone who has syphilis, or via vertical transmission from an infected pregnant mother to her fetus. Syphilis is most infectious during the primary and secondary stages (when lesions or rashes are present) and persons infected with T. pallidum for longer than 1 year are unlikely to transmit syphilis to others. All sexual contacts of persons with syphilis need to undergo evaluation and possibly receive treatment. Syphilis is associated with increased susceptibility to HIV acquisition.
The following risk reduction plan is recommended for clinicians to assist persons in reducing their risk of reacquiring T. pallidum infection:
- Assess the patient’s potential for behavior change.
- Discuss prevention strategies such as abstinence, mutual monogamy with an uninfected partner, use of condoms, and limiting the number of sex partners.
- Discuss latex condoms, which when used consistently and correctly, can reduce the risk of syphilis transmission.
- Develop individualized risk-reduction plans.
- Syphilis is a systemic infection caused by Treponema pallidum, and in the absence of treatment, patients remain chronically infected and progress through stages of disease, characterized by episodes of active clinical manifestations interrupted by periods of asymptomatic latent infection.
- Of primary and secondary syphilis cases diagnosed in men who have sex with men, approximately one-half of the men are coinfected with HIV.
- Neurosyphilis and ocular syphilis can occur at any stage of infection.
- Untreated syphilis in pregnancy can lead to devastating consequences, including stillbirth, neonatal death, and congenital syphilis.
- The laboratory diagnosis of syphilis is challenging and requires using a combination of clinical criteria and laboratory tests (both treponemal and nontreponemal tests) to differentiate active infection, prior infection, and absence of infection.
- Screening for syphilis is recommended in all pregnant women, men who have sex with men, persons with HIV infection, and other high-risk groups.
- Penicillin G, administered parenterally, is the preferred drug for treatment of all stages of syphilis and is effective in resolving clinical symptoms associated with primary and secondary syphilis as well as preventing late sequelae.
- The Jarisch-Herxheimer reaction is a self-limited reaction associated with initiation of anti-treponemal therapy and is characterized by fever, malaise, nausea, vomiting, and less frequently chills and exacerbation of a secondary syphilis rash.
- Persons who have had sexual contact within 90 days preceding that contact's diagnosis of primary, secondary, or early latent syphilis should receive presumptive treatment for early syphilis; if serologic testing is not immediately available, presumptive treatment should be started even if the sexual contact occurred more than 90 days prior.
Check-On-Learning Questions Display Options
What is the recommended treatment for this patient?
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|Sensititivy During Stage of Infection, % (range)||Specificity, % range|
*FTA-ABS and TP-PA are generally considered equally sensitive in the primary stage of disease.
|VDRL||78 (74-87)||100||95 (88-100)||71 (37-94)||98 (96-99)|
|RPR||86 (77-99)||100||98 (95-100)||73||98 (93-99)|
|FTA-ABS||84 (70-100)||100||100||96||97 (94-100)|
|TP-PA||88 (86-100)||100||97 (97-100)||94||98 (96-99)|
- Seña AC, White BL, Sparling PF. Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century. Clin Infect Dis. 2010;51:700-8. [PubMed Abstract]
Indications for Cerebrospinal Fluid (CSF) Analysis at Initial Diagnosis of Syphilis
Indications for Cerebrospinal Fluid Analysis in Patients Following Treatment for Syphilis
Consider Cerebrospinal Fluid Analysis