Syphilis is a sexually transmitted infection (STI) known since the late 15th century. Syphilis is the only major disease presumably transmitted from newly discovered America into Europe [Diamond, 2015].
Syphilis is caused by the bacterium Treponema pallidum. Morphologically, T. pallidum is a slender, tightly coiled, helical cell measuring only 6–15 μm long and 0.14–0.2 μm wide. It took until 1905 for T. pallidum to be isolated and subsequently confirmed as the causative agent of syphilis in 1912 [Noguchi, 1912].
Syphilis develops in four successive stages, primary, secondary, latent, and tertiary. The primary ulcer at entry site ("primary chancre", 10-90 days postinfection), is followed by spread of the treponemes to the regional lymph nodes and haematogenous dissemination to other parts of the body. The ulcer is classically indurated and painless. While the local immunity leads to ulcer healing in approximately 3-6 weeks, systemic dissemination results in intense immune response to the deposited treponemes, leading to secondary syphilis soon after healing of primary chancre. Rash is the presenting complaint in majority of patients with secondary syphilis, and it is found on physical examination in more than 90% of patients. Rash frequently covers palms and soles, it is usually maculopapular and never vesicular. Other symptoms include fever, sore throat, malaise, headache, and lymphadenopathy. Neurological symptoms (meningitis, ocular complaints), although more characteristic for tertiary syphilis, could arise already at secondary stage. Secondary syphilis resolves without treatment, followed by latent stage. Latent stage is asymptomatic, the bacteria remain dormant and are undetected by traditional methods in blood and issues. Tertiary syphilis represents an activation of dormant infection, occuring in about one-third of affected individuals several decades after primary infection. Tertiary syphilis can affect multiple organ systems, including brain, nerves, eyes, heart, blood vessels, liver, bones, and joints, and is often fatal. Symptoms of tertiary syphilis vary depending on the organ system affected.
The fundamental histological changes at all stages are vasculitis and its consequences, necrosis and fibrosis.
Syphilis could be transmitted: 1) by direct contact of skin/mucosa with infective treponema-rich ulcers; 2) vertically from infected mother to her unborn child; 3) by blood sharing. The main routes of transmission are sexual and congenital. Sexual transmission occurs by inoculation of bacteria into tiny abrasions resulting from sexual trauma. Minor routes of transmission are by blood transfusion, by needle sharing, and by fomites among medical personnel .
Persons with syphilis are infective for sexual transmission only during primary and secondary stage. On the contrary, women with syphilis could transmit the disease congenitally also during the latent stage.
T. pallidum gains access to the fetal compartment as early as 9–10 weeks after conception. Pregnancy in women with syphilis could result in spontaneous abortion, newborn death, and congenital syphilis. For women with syphilis, the probability of delivering a healthy infant is only 1/3.
Having syphilis once does not protect a person from becoming infected again. Reinfections, which occur despite high titres of antibodies in the serum, are possible because of limited antigenicity of treponemes due to a lack of proteins in their outer membrane.
In 1937, it was estimated that 10% of U.S. citizens would be infected with syphilis during their lives [Parran, 1937]. A number of prominent writers, artists and philosophers have reportedly died from syphilis in the 19th and early in the 20th century. Following the introduction of penicillin, the incidence of primary and secondary syphilis fell from 66.4 cases per 100,000 persons in 1947 to just 3.9 cases per 100,000 persons in 1956, and remain at this level until present. During 2015, 487 cases of congenital syphilis were reported in US, compared to an estimated 128 cases of perinatal HIV infection.
In developed countries, syphilis is restricted mainly to high-risk groups, especially HIV infected and men having sex with men (MSM). Coinfection of patients with syphilis with HIV is also frequent since virus of human immunodeficiency could be transmitted more readily through syphilitic lesions.
Russia and the states of the former USSR have experienced a recent strong increase in syphilis cases. After achieving a rate of 4.2 cases per 100,000 in 1988, the incidence of syphilis rose to 263 per 100,000 in 1996 [Drusin, 1996]. The incidence of syphilis is traditionally high in developing countries, especially in high risk groups. According to estimates, 1–3% of the neonates and infants in Africa are seroreactive and/or have signs of congenital infection.
Classically, the serological diagnosis of syphilis requires the detection of two distinct populations of antibodies, namely heterophile or non-treponemal (NT) antibodies directed against lipoidal material released from damaged host cells and possibly from the treponemes themselves, and antibodies directed against T. pallidum - specific antigens. The earliest marker of syphilis are treponemal IgM antibodies, which could be detectable already 1 week after infection. On the contrary, the conversion of IgG antibodies, both NT and treponemal, usually occurs several days to 1 week after appearance of a chancre. The most prominent feature of NT antibodies is their gradual decline after successful therapy - fourfold after 3–6 months and eightfold after about 12 months. In latent and tertiary untreated syphilis, both treponemal (always) and NT antibodies (in most cases) remain detectable.
In recent years many immunoassays were developed, which are based on either whole-cell lysate or recombinant antigens of T.pallidum . More than 100 antigenic proteins were identified (10% of total number of proteins).
Antigens TpN47, TmpA , TpN37, TpN17, and TpN15 are believed to be major immunoreactive membrane proteins of T.pallidum cells. The majority of main immunogenic proteins are lipoproteins and components of inner cytoplasmic membrane.
Some immunogenic proteins of T.pallidum, for example, TmpA and TmpC proteins, induce a response similar in dinamics to that of NT antibodies, demonstrating a decline in titers soon after treatment. These proteins may me useful antigens for future tests which would replace outdated NT assays.
The symptoms of primary and secondary syphilis are non-specific. The lesion of primary syphilis, even if detected, could be easily misdiagnosed with genital herpes and chancroid; rash similar to that in secondary syphilis develops under number of conditions, e.g. primary HIV, psoriasis, erythema multiforme. Latent syphilis is clinically silent.
In regions where there are no diagnostic facilities or where the cost of diagnostic tests is prohibitive, empiric treatment of a genital ulcer to cover common causes such as chancroid and syphilis is recommended. Otherwise, there are two main methods utilized for diagnosis of syphilis, dark field microscopy (DFM) and detection of antibodies by serological tests. In DFM, the treponemes are identified by the morphology and characteristic movements. Although highly specific, this technique is rarely performed today. An important application area for DFM is early diagnosis of the disease, because the appearance of a chancre precedes the conversion of most serological tests by several days to 1 week.
Serodiagnosis of syphilis is classically performed by both NT and treponemal tests. The use of a NT test for screening and a treponemal test - for confirmation is termed direct diagnostic algorithm. If a treponemal test is utilized for screening and a NT test-for confirmation, this is termed reverse diagnostic algorithm. The application of either direct or reverse algorithm depends upon population tested (main factor to respect is the prevalence of past infections in a population, since treponemal, but not NT antibodies persist for life), upon cost considerations (treponemal tests could be automatized, although they are more expensive than NT tests), and upon local legislation.
Currently, the mostly used NT tests are VDRL and RPR assay. In the VDRL test, the presence of specific antibodies elicits foaming of the solution, which could be detected using a microscope. RPR assay is based upon aggregation of charcoal particles which could be assessed by the naked eye.
There are several tests that detect treponemal antibodies including T. pallidum–particle agglutination (TP-PA) assay, indirect immunofluorescence assays (FTA-ABS), enzyme immunoassays, and rapid point-of-care tests. The most sensitive and specific are ELISA tests using recombinant proteins which are superior to NT and other treponemal tests.
False-positive rates are slightly lower for treponemal than for NT tests. NT tests could be false-positive in lower (<1/8) titres under autoimmune diseases, HIV, spirochetal infections other than syphilis, and other conditions. False reactive treponemal test results can occur in connective tissue and autoimmune diseases, viral infections, pregnancy, and Lyme disease.
In most cases, patients get tested for syphilis if they have symptoms or if their sexual partner is diagnosed with syphilis. Testing for syphilis could additionally be indicated in following cases:
1) HIV patients should be tested for syphilis and vice versa;
2) Patients with a STI should be tested for syphilis and other STIs;
3) All pregnant women should have a test for syphilis during the first trimester. In areas with high prevalence of syphilis, serological screening should be performed at the beginning of third trimester and at delivery;
4) Neonates born from women positive for syphilis at prenatal screening. Congenital syphilis is diagnosed either by IgM or by 4-fold/> titres of NT antibodies relatively to mother;
5) Cerebrospinal fluid (CSF) should be tested for syphilis in patients with neurologic or ophthalmic disease, in symptomatic tertiary syphilis, and some other cases;
6) In blood donors;
7) To define treatment outcome;
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