Table of Contents
I. Introduction
• Description of Treponema pallidum subsp pallidum, the bacterium that causes syphilis
• History of syphilis and its treatment
• Increase in new cases of syphilis
II. Syphilis Transmission and Risk Factors
• Mode of transmission
• Incubation period and disease progression
• Increased risk of HIV infection
III. Syphilis Research
IV. Syphilis Screening and Diagnosis
V. Direct Detection of T. pallidum
VI. Treatment and Prevention
• Treatment options for syphilis
• Prevention methods, including screening and safe sex practices
VII. Conclusion
• Summary of syphilis and the importance of early detection and treatment.
Treponema pallidum subsp pallidum, a highly invasive pathogen, is responsible for this venereal disease that disseminates soon after inoculation. T. pallidum belongs to a family of spiral-shaped bacteria varying from 6 to 15 µm in length and dark field microscopy is used to detect it. T.pallidum has an unusually small genome, very sensitive to environmental conditions and can survive in the host for several decades. Syphilis was the first identified sexually transmitted infections (STIs) and since its recognition as a new disease in Europe in the 15th century, its origin was under the subject of great debate. The therapy used for the disease over centuries included prolonged injections of arsenicals, the use of mercury and bismuth salts. For the affected individuals, if the disease did not kill them, the cure most certainly did. The use of penicillin after 1940 for all stage of syphilis reduced the incidence of the disease and the rate of mortality. From 1944 to 1954, the cases of syphilis decreased by more than 75% and by 1975, the rate of syphilis had declined by 90%. However, the Centers for Disease Control and Prevention data from 2014 indicate an increase in the new cases of syphilis.
After the World War II, and in the late 1980s and early 1999s, the most affected population changed from heterosexual epidemic to MSM (men having sex with men). According to the health officials, 50,000 cases of syphilis were reported in the United States in 2013 of which 17,000 cases are of a primary and secondary stage and 75% were detected among men with same-sex partner.
Syphilis also increases the risk of HIV infection with some evidence suggesting the direct involvement of T.pallidum in facilitating its progression. The study also indicates that the genital sores serve as an easy passage for the transmission of HIV infection. This makes it vulnerable particularly for the high-risk population such as MSM with syphilis to also become infected with HIV easily. With the increasing rates of newly diagnosed cases, the need for syphilis screening for at-risk individuals was reaffirmed by the United States Preventative Health Services Task Force. However, the primary care physicians were unable to accurately determine which individuals belong to that category due to the highly personalized nature of discussing sexuality and sexual behavior of patients.
Mode of action
Syphilis is transmitted by direct contact with a syphilitic sore at anogenital, rarely oral and other nongenital sites. The transmission is possible during sexual contact with an average incubation period from 10 days to 3 months and the disease lasting through months or years progressing in different stages. Even with the lack of metabolic capabilities, T.pallidum is capable of invading and surviving in different tissues and organs. Progression to the latent stage may present no visible symptom and tertiary syphilis can appear after 10 – 30 years after affecting multiple organ system.
Syphilis as a study project
The research on syphilis historically has been considered a special disease as a STD with no effective treatment available for years. The syphilis study post-second world war II continued without any ethical standards for several decades. Beginning in 1946, in violation of medical ethics and human rights, more than 5,000 unconsenting Guatemala people were intentionally infected with the aim of monitoring the natural course of the disease when left untreated. Another syphilis study at Tuskegee involved 600 black men that started in 1932, actually continued for 40 years. Even when the use of penicillin became the choice of drug for syphilis in 1947, the participants of the research were not administered the treatment until the 1970s. After the Tuskegee study, the research practice changed and regulations were passed in 1974 that required voluntary informed consent from all individuals participating in studies. In 1995, National Bioethics Advisory Commission was created and in 2009 the President commission for the study of Bioethical Issues was established. And also, any of the studies supported by the Department of Health Education and Welfare (DHEW) was to be reviewed so they meet the ethical standards.
Screening
The initial serologic test for syphilis was the Wassermann test developed in 1906 and classified as nontreponemal (NTT). Decades later venereal disease research laboratory (VDRL) and Rapid Plasma Reagin (RPR) developed and the sensitivities of these tests depend on the stage of the disease and usually shows positive only after several weeks of infection. The RPR and VDRL show sensitivity of 86% and 78% respectively during primary syphilis and are 100% during secondary syphilis.
Treponemal tests (TT) detect specific anti-treponemal antibodies and have higher sensitivity than the NTT and are used as a confirmatory test for syphilis.
For the diagnostic purpose, nontreponemal tests can show false-positive results and hence, individuals with reactive nontreponemal tests should receive a treponemal test to confirm the diagnosis. The treponemal antibodies can appear sooner than the nontreponemal antibodies and can be reactive for years among individuals either with or without treatment.
T.pallidum immobilization test (TPI) was a specific test for antitreponemal antibodies followed by more sensitive fluorescent treponemal antibody (FTA) test and later the FTA-ABS test which detects the antibodies bound to T.pallidum.
The direct detection of Treponema pallidum uses various methods for the direct detection of the microorganisms or their DNA which includes Darkfield microscopy, direct fluorescent antibody test for T.pallidum (DFA-TP) in the blood fluids, direct test for T.pallidum in tissue sections, Rabbit infectivity Test (RIT) and Polymerase chain reaction (PCR).
Penicillin and alternatives
Even after decades, the use of penicillin continues to be the preferred treatment for all stage of the disease. However, the guidelines published by the Centers for Disease Control and Prevention indicate the administration of oral doxycycline or tetracycline as the alternative form of treatment in the case of allergic reaction to penicillin.
In an effort to develop a single-oral dose medication, a clinical trial in 2010 found azithromycin as an alternative for penicillin to treat early stage syphilis. The clinical trials also showed efficacy in relation to penicillin.
Macrolide resistance
When the treatment of syphilis with azithromycin proved to be promising, another study of T.pallidum samples derived from different locations identified a macrolide-resistant strain which was shown to be associated with the single base mutation in the 23S rRNA gene. The macrolide-resistance appeared to be predominantly high in San Fransisco and Dublin. Hence, among cities presenting high rates of macrolide-resistance strains, the treatment option for syphilis should continue to remain as penicillin. However, it is essential that patients administered azithromycin require to be reevaluated with serological testing.
Vaccine on the horizon
For the development of an effective vaccine against syphilis, several key milestones need to be taken into consideration such as the need for the vaccine candidate to be effective in generating a TH1 response and opsonic antibodies. Because of the complex pathogenesis at play during the infection, it may be likely that a mixture of T.pallidum antigens is essential for protection through vaccination. According to an article on the American Society for Microbiology, the objective of a vaccination is to develop a mono or multivalent vaccine that is based on outer membrane proteins (OMP) alleles from T. pallidum subsp.pallidum strains.
Summary of Key findings and proposed mechanisms
The study also provides evidence that the T.pallidum lipocalin domain –containing Tp0751 shows a promising syphilis vaccine candidate as this protein reduces treponemal dissemination. This subunit vaccine candidate may be the solution to help curb the increased rise of syphilis cases.
References
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http://cdn.intechopen.com/pdfs/23788/InTech-Laboratorial_diagnosis_of_syphilis.pdf
https://www.cdc.gov/std/tg2015/syphilis.htm
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https://cvi.asm.org/content/22/2/137
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