Syphilis

Who should be screened for syphilis?

1) Those who present with the classic signs and symptoms of syphilis, including but not limited to: a painless genital ulcer (primary syphilis); a diffuse, symmetric macular or papular eruption involving the entire trunk and extremities (secondary syphilis); general paresis; or tabes dorsalis (tertiary syphilis). 2) Any sexually active patient with an undiagnosed genital ulcer or a rash that involves the palms and soles. 3) Pregnant women should be screened for syphilis (regardless of perceived risk) to prevent in utero transmission of asymptomatic infection, which can lead to congenital syphilis. Others: -Sexually active men who have sex with men (MSM) -HIV-infected individuals -Patients currently engaging in high-risk sexual behaviors

How often are patients monitored after treatment for syphilis?

A nontreponemal titer should be obtained just before initiating therapy (ideally, on the first day of treatment) since titers can increase significantly over a few days between diagnosis of syphilis and treatment initiation. The subsequent frequency of monitoring depends upon the stage of disease and presence of HIV coinfection. ●In patients with early syphilis, serologic testing should be performed 6 and 12 months following treatment and at any time if clinical symptoms recur. In general, such patients should experience an adequate response by 12 months. ●Patients with late syphilis (including late latent syphilis) should undergo follow-up serologic testing at 6, 12, and 24 months, as some patients with late syphilis may not have an adequate response for up to two years following treatment. ●Patients with HIV are typically monitored more frequently.

How does late syphilis manifest clinically?

Approximately 25 to 40 percent of patients with untreated syphilis can develop late disease. The clinical events may appear at any time from 1 to 30 years after primary infection. It is not necessary for individuals to have experienced clinically symptomatic primary or secondary syphilis prior to developing late syphilis. The most common manifestations include: 1) Cardiovascular syphilis (especially aortitis) 2) Gummatous syphilis (granulomatous, nodular lesions which are rare, can occur in a variety of organs, usually skin and bones) 3) Central nervous system involvement (particularly general paresis and tabes dorsalis)

How are treponemal tests interpreted?

As a group, these tests are based upon the detection of antibodies directed against specific treponemal antigens and thus tend to be more specific than nontreponemal tests. Treponemal tests are qualitative only and are reported as "reactive" or "nonreactive". Once a patient has a positive treponemal test, this test usually remains positive for life.

What alternative tools can be used to diagnose syphilis?

Darkfield microscopy and direct fluorescent antibody (DFA) testing can be used to detect the organism; however, neither of these tests are routinely available in clinical settings because these methods require special equipment to perform the test, as well as considerable experience and expertise to properly interpret the results. Thus, for most clinicians, such tests are now viewed as alternative diagnostic tools.

What is early syphilis?

Early syphilis comprises primary and secondary syphilis, which typically occur within weeks to months after initial infection, as well as early latent syphilis (asymptomatic infection that was acquired within the previous 12 months). Patients can present with central nervous system manifestations (neurosyphilis) at any time during the course of infection. A detailed discussion of neurosyphilis is found elsewhere.

How is neurosyphilis diagnosed?

Examination of cerebrospinal fluid is the only way to definitively diagnose neurosyphilis. The laboratory diagnosis of neurosyphilis usually depends on various combinations of reactive serologic test results, CSF cell count and protein, and a reactive CSF-VDRL with or without clinical manifestations.

How does primary syphilis manifest clinically?

Following acquisition of T. pallidum, the initial clinical manifestation of infection is a localized skin lesion termed a chancre. The median incubation period before the chancre appears is 21 days (range 3 to 90 days). The lesion begins as a papule, which is typically (but not always) painless, appearing at the site of inoculation. This soon ulcerates to produce the classic chancre of primary syphilis, a 1 to 2 centimeter ulcer with a raised, indurated margin. The ulcer generally has a non-exudative base and is associated with mild to moderate regional lymphadenopathy that is often bilateral. Such lesions usually occur on the genitalia, but occasionally patients may develop chancres at other sites of inoculation. Chancres heal spontaneously within three to six weeks even in the absence of treatment. Since the ulcer is painless, many patients do not seek medical attention, a feature that enhances the likelihood of transmission.

What are possible outcomes of the diagnostic algorithm for syphilis?

For those without a known history of syphilis, a diagnosis is made when both nontreponemal and treponemal tests are reactive. In laboratories using the nontreponemal test for screening, patients who have a positive nontreponemal test followed by a negative treponemal test are generally considered to have a false positive syphilis result.

How does neurosyphilis manifest clinically?

Headache - Invasion of the cerebrospinal fluid is common in early untreated disease, especially secondary syphilis. Meninges and vascular manifestations - Patients may present with meningitis, cranial nerve deficits, meningovascular disease, or stroke. Ocular findings - Patients can develop anterior uveitis, posterior uveitis, or panuveitis, which is often granulomatous.

What are treatment options for patients who are allergic to penicillin?

If a patient is allergic to penicillin, the choice of agent is less clear. Options include: ●Testing for penicillin allergy and/or rechallenging with penicillin ●Desensitizing to penicillin if allergy testing is positive ●Using an alternative agent with close post-treatment monitoring For patients with a documented history of a penicillin allergy, we typically initiate an alternative regimen if the patient has early disease or late latent syphilis and can be closely monitored after treatment. Alternative antimicrobial agents include tetracyclines and cephalosporins.

How are nontreponemal tests interpreted?

In general, these assays are semi-quantitative in that the amount of antibody present (both IgM and IgG) generally reflects the activity of the infection. Positive nontreponemal tests are reported as a titer of antibody (eg, 1:32, which represents the detection of antibody in serum diluted 32-fold). Titers tend to wane over time even without treatment, but successful therapy accelerates the pace of antibody decline. Changes in titer are followed after treatment to detect a therapeutic response.

What is the epidemiology of syphilis?

In the United States, syphilis has been a nationally notifiable disease since 1944. From 2000 to 2018, the rise in the rate of reported primary and secondary syphilis cases was primarily attributable to increased cases in men who have sex with men (MSM). The rate of reported primary and secondary syphilis cases remains highest among the black population, with the overall rate of syphilis being highest in black men. A report from the United States Centers for Disease Control and Prevention suggests that the increased rate of syphilis in women may be due in part to increased drug use. With the increased number of cases in women, there has also been an increase in the number of cases of congenital syphilis.

What is the treatment for late syphilis?

Late syphilis includes tertiary syphilis and late latent syphilis, and such patients require a longer duration of treatment compared with those who have early syphilis. Penicillin G benzathine (2.4 million units intramuscularly [IM] once weekly for three weeks) is standard therapy for tertiary and late latent syphilis as it provides adequate and persistent serum levels of penicillin. While it has the advantage of not requiring daily patient adherence, it does require that the patient follow up consistently over the entire span of treatment to receive the full course of therapy. If a patient misses a dose, and if more than 14 days have elapsed since the prior dose, the course should be reinitiated.

What is latent syphilis?

Latent syphilis refers to the period when a patient is infected with T. pallidum (as demonstrated by serologic testing) but has no symptoms. Patients with late latent disease are not considered infectious to their recent sexual contacts since they do not have lesions that can transmit disease. In contrast, patients with early latent syphilis may have transmitted T. pallidum to their sexual partners through lesions that were recently active, but are no longer present.

What is the appropriate follow-up for syphilis treatment?

Nontreponemal (rapid plasma reagin [RPR] or Venereal Disease Research Laboratory) titers should be monitored after treatment. -A fourfold decline in the nontreponemal titer, equivalent to a change of two dilutions (eg, from 1:16 to 1:4 or from 1:32 to 1:8), is considered to be an acceptable response to syphilis therapy.

What are nontreponemal tests?

Nontreponemal tests (also known as tests for reagin antibodies) are based upon the reactivity of serum from infected patients to a cardiolipin-cholesterol-lecithin antigen. Although these screening tests are nonspecific, and therefore not definitive, they have traditionally been used for initial syphilis screening due to their relatively low cost, ease of performance, and ability to be quantified for the purpose of following response to therapy. Nontreponemal tests include: 1) Rapid plasma reagin (RPR) 2) Venereal Disease Research Laboratory (VDRL) 3) Toluidine Red Unheated Serum Test (TRUST)

What is the treatment for syphilis?

Parenterally-delivered penicillin G is the treatment of choice for all stages of syphilis. For patients without neurosyphilis, the appropriate formulation of parenteral penicillin is penicillin G benzathine, which is marketed under the trade name Bicillin L-A. This agent should only be given via the intramuscular (IM) route since IV administration has been associated with cardiopulmonary arrest and death.

What is the serofast state of syphilis?

Patients who have had an adequate (≥fourfold) decline in titers, but whose nontreponemal titers do not serorevert or continue to fall after 24 months of monitoring, are considered serofast. The serofast state is seen in approximately 15 to 20 percent of patients with early syphilis and has been reported to be as high as 35 percent in patients with late latent syphilis.

What is the treatment for neurosyphilis?

Patients with neurosyphilis should be treated with IV penicillin G (3 to 4 million units IV every four hours, or 18 to 24 million units per day by continuous infusion) for 10 to 14 days. For patients with late disease, we generally administer a single dose of penicillin G benzathine (2.4 million units IM) after completion of IV penicillin since the duration of treatment for neurosyphilis is shorter than the regimens used for late syphilis.

What is treatment failure in syphilis?

Persons with syphilis are considered to have treatment failure if nontreponemal titers do not decline fourfold or greater or if there is a documented fourfold increase after initial decline. Treatment failure should be distinguished from reinfection.

How is syphilis diagnosed?

Serologic tests provide a presumptive diagnosis of syphilis. There are two types of serologic tests for syphilis: nontreponemal tests and treponemal-specific tests.

What is syphilis?

Syphilis is an infection caused by the bacterium Treponema pallidum. Most new cases of syphilis are sexually acquired.

What are the stages of syphilis?

Syphilis is generally divided into early and late stages.

What is the pathophysiology of syphilis?

T. pallidum initiates infection when it gains access to subcutaneous tissues via microscopic abrasions. Despite a slow estimated dividing time of 30 hours, the spirochete evades early host immune responses and establishes the initial ulcerative lesion, the chancre. During the period of early local replication, some organisms establish infection in regional draining lymph nodes, with subsequent dissemination. In some respects, the immune response to T. pallidum is paradoxical. On one hand, the various immune responses during early infection appear to be efficacious, since they coincide with resolution of the primary chancre, even in the absence of therapy. However, despite this apparent immune control, widespread dissemination of spirochetes occurs at the same time, leading to subsequent clinical manifestations of secondary or tertiary syphilis in untreated patients.

What is Treponema pallidum?

T. pallidum, the causative organism of syphilis, was first identified in 1905. It is a bacterium from the order Spirochaetales and is one of several closely related treponemes which cause human disease. T. pallidum is approximately 10 to 13 microns long but only 0.15 microns in width, making it too slender to be visualized by direct microscopy. The organism can be seen with darkfield microscopy, a technique that employs a special condenser that casts an oblique light. When visualized by this method, T. pallidum is a delicate, corkscrew-shaped organism with tightly wound spirals.

How does tertiary syphilis manifest clinically?

Tertiary syphilis describes patients with late syphilis who have symptomatic manifestations involving the cardiovascular system or gummatous disease (granulomatous disease of the skin and subcutaneous tissues, bones, or viscera). Cardiovascular — Cardiovascular syphilis classically involves the ascending thoracic aorta resulting in a dilated aorta and aortic valve regurgitation. The disorder is thought to be a consequence of vasculitis in the vasa vasorum leading to a weakening of the wall of the aortic root. Gummatous syphilis — Gummatous syphilis is very uncommon. Gummas can occur anywhere, including skin, bones, or internal organs. Central nervous system — There are many forms of central nervous system (CNS) syphilis, some of which may occur as many as 25 years after the initial infection (eg, general paresis and tabes dorsalis).

What is the Jarisch-Herxheimer reaction?

The Jarisch-Herxheimer reaction (JHR) is an acute, self-limited, febrile reaction that usually occurs within the first 24 hours after the patient receives therapy for any spirochetal infection, including syphilis. This reaction occurs in approximately 10 to 35 percent of cases. It is seen most commonly after treatment of early syphilis. The fever may be accompanied by systemic symptoms, including headache, myalgias, rigors, diaphoresis, hypotension, and worsening of rash if initially present. Uncommon manifestations include meningitis, respiratory distress, renal and/or hepatic dysfunction, mental status changes, stroke, seizures, and uterine contractions in pregnancy.

What is seroreversion in syphilis?

The loss of antibodies over time (seroreversion) in a patient who has been successfully treated for syphilis is considered to be consistent with clinical cure. The majority of patients who are treated for early syphilis will experience seroreversion over time.

What is the pathophysiology of the Jarisch-Herxheimer reaction?

The mechanism by which this reaction develops is not completely understood. However, it is thought to result from accelerated phagocytosis by polymorphonuclear leukocytes, followed by the release of lipoproteins, cytokines, and immune complexes from killed organisms . There is no way to prevent this reaction. Patients should be informed of the possible signs and symptoms and advised to contact their clinicians if a severe reaction occurs. Although these symptoms often resolve without intervention within 12 to 24 hours, non-steroidal anti-inflammatory drugs (NSAIDS) or other antipyretics can be used if symptoms arise and they may reduce the severity of symptoms and the duration of the reaction.

What is the diagnostic algorithm for syphilis?

Traditional serologic testing algorithms for syphilis involve initial screening with a nontreponemal test (eg, RPR). A reactive nontreponemal test is then confirmed with a treponemal test, such as the fluorescent treponemal antibody absorption (FTA-ABS). In general, for asymptomatic patients, no further testing is needed if the nontreponemal test is negative.

How is syphilis transmitted?

Transmission of T. pallidum usually occurs via direct contact with an infectious lesion during sex. In addition, T. pallidum readily crosses the placenta, thereby resulting in fetal infection. Sexual transmission requires exposure to open lesions with organisms present, features seen with the primary chancre and with some of the manifestations of secondary syphilis (mucous patches and condyloma lata). These lesions are very infectious, with an efficiency of transmission estimated at approximately 30 percent. T. pallidum can initiate infection wherever inoculation occurs.

What are treponemal tests?

Treponemal tests have historically been more complex and expensive to perform than nontreponemal tests. Thus, they have traditionally been used as confirmatory tests for syphilis when the nontreponemal tests are reactive. Specific treponemal tests include: 1) Fluorescent treponemal antibody absorption (FTA-ABS) 2) Microhemagglutination test for antibodies to T. pallidum (MHA-TP) 3) T. pallidum particle agglutination assay (TPPA) 4) T. pallidum enzyme immunoassay (TP-EIA) 5) Chemiluminescence immunoassay (CIA)

How is treatment failure approached?

We first assess the patient to see if there is a history of possible new exposure or clinical evidence of a new infection (eg, chancre, rash). In addition, we repeat testing for HIV. If there is no evidence of new infection, we then assess for evidence of potential neurosyphilis. We perform a lumbar puncture (LP) in HIV-uninfected patients with the following: •Neurologic symptoms •Signs or symptoms of syphilis that persist or recur •A fourfold or greater increase in nontreponemal test titers persisting for >2 weeks •Persons treated for late latent syphilis with an initially high titer (≥1:32) that fails to decline at least fourfold within 12 to 24 months of treatment

What is late syphilis?

When patients are untreated during the earlier stages of syphilis, they can progress to late latent disease (which is asymptomatic) or develop major complications of the infection (eg, tertiary syphilis). The clinical events occurring as a consequence of late syphilis may appear at any time from 1 to 30 years after primary infection and can involve a wide variety of different tissues. Patients can present with central nervous system manifestations (neurosyphilis) at any time during the course of infection. A detailed discussion of neurosyphilis is found elsewhere.

How does secondary syphilis manifest clinically?

Within weeks to a few months after the chancre develops, approximately 25 percent of individuals with untreated infection develop a systemic illness that represents secondary syphilis. Patients with secondary syphilis may not have a history of a preceding chancre since the primary infection may have been asymptomatic and/or gone unnoticed. Constitutional symptoms - Patients with secondary syphilis may develop systemic symptoms including fever, headache, malaise, anorexia, sore throat, myalgias, and weight loss. Adenopathy - Most patients with secondary syphilis have lymph node enlargement with palpable nodes present in the posterior cervical, axillary, inguinal, and femoral regions. The finding of epitrochlear nodes is particularly suggestive of the diagnosis. Rash - Rash is the most characteristic finding of secondary syphilis. The rash is classically a diffuse, symmetric macular or papular eruption involving the entire trunk and extremities, including the palms and soles. Individual lesions are discrete copper, red, or reddish-brown, and measure 0.5 to 2 cm in diameter.