Asian Journal of Transfusion Science
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REVIEW ARTICLE Table of Contents   
Year : 2016  |  Volume : 10  |  Issue : 1  |  Page : 22-30
Efforts in blood safety: Integrated approach for serological diagnosis of syphilis

Department of Transfusion Medicine and Transplant Immunology, U.O.C. Immunohematology, Regional Reference Laboratory of Transplant Immunology, Azienda Ospedaliera Universitaria, Second University of Naples, Italy

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Date of Web Publication1-Feb-2016


Recent efforts in transfusion medicine are focused on improving blood safety as well as establishing effective and efficient diagnostic algorithms for donor screening. To date, syphilis is a transfusion-transmitted infection re-emerged in many countries as a public health threat especially among populations at specific risk. This task requires new diagnostic tools and hemovigilance programs. The current diagnostic methodologies are debated, since presenting limitations and unresolved issues with special regard to the clinical interpretation of serological patterns, especially in asymptomatic patients and in blood donors. Furthermore, the switch from the traditional to alternative diagnostic algorithms underlines the lack of a gold standard, which has not been supported by shared guidelines. Besides, a lot of ongoing clinical trials on the performance of diagnostic assays, on the serological response associated with different pharmacological treatments, as well as on the prevention programs are currently under investigation. Here, we review the recent literature about the diagnosis of syphilis especially for low-risk populations proposing the adoption of an algorithm for blood donor screening that should satisfy the need of increasing safety for transfusion-transmitted infections in the modern blood transfusion centers.

Keywords: Blood donors, confirmatory testing, diagnostic tests syphilis, serology

How to cite this article:
Sommese L, De Pascale MR, Capuano M, Napoli C. Efforts in blood safety: Integrated approach for serological diagnosis of syphilis. Asian J Transfus Sci 2016;10:22-30

How to cite this URL:
Sommese L, De Pascale MR, Capuano M, Napoli C. Efforts in blood safety: Integrated approach for serological diagnosis of syphilis. Asian J Transfus Sci [serial online] 2016 [cited 2023 Jan 28];10:22-30. Available from:

   Introduction Top

Syphilis is a re-emerging disease caused by the spirochete Treponema pallidum. The clinical manifestations of syphilis have been recognized for centuries and classified into four infectious stages: Primary syphilis, secondary syphilis (subdivided into early latent syphilis and late latent syphilis), and the noninfective tertiary syphilis. [1],[2] The first stage is characterized by painless sores called chancre that disappear within 6 weeks. If the disease is untreated, the secondary stage appears within 10 weeks from the onset of the first chancre and includes fever, malaise, lymphadenopathy, loss of appetite, and maculopapular rash. The tertiary stage results in the spread of the spirochete to the nervous system, heart, and bone. Historically, the disease was imported in Europe from the New World at the end of the 15 th century and reached an epidemic proportion after a few decades, spreading also to the rest of the world and becoming ubiquitous by the beginning of the 19 th century [Figure 1]. [3] During the last decades of the 20 th century, a radical decline in its prevalence was obtained through the use of penicillin. [4] In spite of this, at the start of the 1990s, an increase in the incidence of primary and secondary syphilis was observed all over the world. [5] This new epidemic peaked first among men having sex with men and bisexuals, but subsequently spread to the heterosexual population as well. [6] In Europe, surveillance data are available from most countries and periodical updates are issued: Recently, the European Centers for Disease Control reported a remarkable increase of syphilis cases. [7] According to this trend, in Italy, data by the National Institute of Health showed an eightfold increase of primary and secondary syphilis cases from 1996 to 2008. [8] Furthermore, the reappearance of syphilis has been ascribed to HIV and a new emphasis has been put on the need to promote syphilis awareness and screening in those patients. [9]
Figure 1: The natural history of untreated syphilis in immunocompetent individuals (based on data from Golden et al., 2003, ref#1)

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Both control and surveillance of syphilis require an accurate sexual risk anamnesis, a correct interpretation of clinical manifestations as well as the application of serological tests, based on reliable methods. Since laboratory tests are not equally sensitive and specific, their rational choice plays a crucial role for a correct diagnosis and a proper management of the patient. To date, there is not a generally recognized diagnostic algorithm. Since 1982, the World Health Organization (WHO) has been recommending both nontreponemal and treponemal tests for syphilis serological screening and diagnosis. [4]

Here, we provide a critical update of syphilis diagnosis through an overview of current available serological algorithms applicable especially in a low-prevalence population (blood donors) as well as in emerging categories (HIV and immunocompromised patients). Besides, the reported ongoing clinical trials emphasize the need of recognized diagnostic protocols and novel prevention programs highlighting the renovated interest in this topic.

   Diagnostic Approaches Top

There is no an uniform screening method for syphilis. The diagnostic processes are based on direct examination in the early stage of syphilis when a lesion is present coupled to indirect treponemal and nontreponemal serological tests.

Direct identification tests: An early detection of syphilis is still a major clinical challenge. Since T. pallidum is a noncultivable bacterium, the diagnosis of syphilis is based on direct identification of the pathogen in the lesion and the identification of a specific immunological response. Dark-field microscopy and/or polymerase chain reaction (PCR) [10],[11] are useful in acute primary infection when spirochete can be detected directly. In particular, dark-field microscopy allows an immediate diagnosis of syphilis with a prompt start and a follow-up of the therapy. A principal limitation of this technique consists of the requirement for a great experience of each operators; moreover, the presence of nonpathogenic spirochetes can limit its use. Recently, PCR appears quite promising, but its routine use cannot yet be proposed. [10],[11] It is known that molecular tests for syphilis are too expensive for many clinical laboratories and cannot replace the serology. Besides, they are not suitable for blood donors. [12],[13]

Serological tests: Serological tests are still considered the most useful approach for the diagnosis. [12],[14],[15] The serological diagnosis is based on the detection of two distinct antibodies, the nontreponemal antibody (reagin), which binds to cardiolipin released from damaged host cells and the treponemal antibody directed against specific antigens.

The nontreponemal tests are rapid plasma reagin (RPR) and venereal disease research laboratory test (VDRL), derived from the first available laboratory test, the Wassermann reaction for cardiolipin. These tests are cheap and simple to perform and have a sensitivity of approximately 70-85%, which approaches 100% only in the secondary stage when, the infection is still active. Since RPR/VDRL takes 30 min, it can be performed in emergency departments and it is particularly suited for patients with a strong clinical suspicion of syphilis. [16] Nontreponemal antibodies become detectable in the early infection (7-10 days after the appearance of the primary lesion) or a few weeks after the infection. They are indicative of active infection and important for monitoring treatment; indeed, a reduction of their titer shows the efficacy of the antibiotic treatment while an increase shows a relapse or re-infection. [17]

When the incidence and prevalence of syphilis in blood donors appear elevated, it might be necessary to consider the use of a nontreponemal assay to identify those donors with the evidence of recent infections. However, one of the major disadvantages of nontreponemal tests are the biological false-positive reactions since nontreponemal antibodies can also be present in other diseases such as other spirochetal infections, mononucleosis, varicella, measles, malaria, leprosy, connective tissue diseases such as systemic lupus erythematosus and malignancy. [1],[17],[18]

Since nontreponemal tests are not-specific, treponemal specific assays have been developed and improved. Treponemal tests use native or recombinant T. pallidum antigens and allow the detection of specific anti-treponemal antibodies; anti-treponemal IgM are detectable within approximately 2 weeks postinfection, while anti-treponemal IgG appear at about 4 weeks after the postinfection. [19] Anti-treponemal IgM and nontreponemal antibodies decline following treatment of early syphilis, while anti-treponemal IgG antibodies persist longer and are usually detectable for many years after the disease has been thought to be eradicated. [19],[20] The treponemal tests evaluate the antibody reactivity against specific T. pallidum antigens and are based on different agglutination reactions: Treponema pallidum hemagglutination assay (TPHA) uses red blood cells, and the Treponema pallidum particle agglutination assay (TPPA), or the microhemagglutination assay for T. pallidum use gelatin particles. Higher titers of these tests are correlated to an active infection while they decrease in the latent phase. Clinically, TPHA reactivity may be detectable around the 4 th week of infection with an overall sensitivity in the untreated primary stage in the 70-80% range by increasing to about 100% in the secondary stage. TPPA is generally superior to TPHA for the detection of primary syphilis. [21]

Treponemal assays meet the requirements for use in blood center and contribute importantly to optimizing workflow and efficiency; on the other hand, they are technically difficult to perform and more expensive than nontreponemal tests and false positive reactions can occur. [16],[18]

Automated immunoassay: In the last decades, a number of highly sensitive and specific enzyme immunoassays (EIAs) for syphilis testing have become available as appropriate alternative to the combined RPR/VDRL and TPHA. EIAs have been often chosen for syphilis screening because they are particularly well-suited for automation. [22],[23],[24],[25],[26],[27],[28] The first treponemal EIA was initially approved for blood bank screening in the USA during the 1980s, and later on, it was approved for clinical diagnostic use by the Food and Drug Administration in 2001. A survey conducted in the USA showed that treponemal EIAs or chemiluminescent immunoassays (CIAs) tests increased from 0 in 2001 to over 3,90,000 performed in 2007, with a concomitant decrease in total RPRs and VDRLs performed from approximately 2.9-1.9 million. Furthermore, the most recent generation of automated immunoassays appear to be more sensitive (95-99%) and specific (98-99%) than the first generations of these assays. [29] Some of these recent assays can simultaneously detect syphilis IgG and IgM, [24],[30] thus shortening the seronegative window phase following infection.

In the search for a possible confirmation strategy for an initial positive screening result, the fluorescent antibody absorption test (FTA-Abs) has also been employed for several years as a confirmatory assay. [31],[32] FTA-Abs is technically more complex than the agglutination assays. This treponemal test performs quite well when used for sera found to be positive on screening, less well to confirm the presence of negative sera; indeed, false negative results have been reported in HIV infection. [24] Due to all these reasons and after reevaluation of assay performances, [14] FTA-Abs is not recommended anymore for syphilis confirmation [7],[29] although some laboratories decided to continue its use. In the United States, Pope et al., [27] reported that TPPA was an appropriate substitute for the TPHA as a confirmatory assay. Another report found that TPPA was significantly more sensitive than FTA-Abs and TPHA [21] making TPPA very suitable as a confirmatory test.

Recently, immunoblots for specific treponemal antibodies, as well as for reagin-directed antibodies, have gained importance. [33] Treponemal Western blot assays have proved a valid alternative choice to the FTA-Abs because of their high sensitivity and specificity together with their simplicity. [34] In addition, the LIA syphilis score immunoblot assay, which uses recombinant and synthetic polypeptide T. pallidum antigens (Fujirebio), has been evaluated satisfactory as a confirmatory testing for syphilis. [35],[36],[37]

A major breakthrough in syphilis serology has been allowed by the sequencing of the complete genome of T. pallidum and the subsequent recognition of some major protein antigens Treponema. pallidum proteins-15 (TpN15), (TpN17, TpN47, TpN44) which have strong immunogenicity and thus, considered important candidate targets for the serological diagnosis of syphilis. [17],[30],[38],[39],[40],[41],[42] The serological response to these antigens might be related to the different phases of the infection. Antibodies directed against TpN47 are usually present in phases of the disease, anti-TpN17 is more frequently observed in patients with early syphilis (primary, secondary, and early latent), while patients with other clinical forms of disease show reactivity against TpN15. Furthermore, in tertiary syphilis the reactivity of TpN15 is reported to be stronger than that of TpN47. [43],[44] Recently, new specific chimeric antigens have been described that may enhance the diagnostic accuracy of syphilis. [45] Fully automated treponemal assays employ a combination of recombinant antigens on the solid phase and this feature has contributed to their enhanced sensitivity due to the selection of immune-dominant epitopes coupled with a higher specificity in comparison with previous EIAs employing spirochetal lysates.

The use of one treponemal test for screening purpose is not without limitations which include the potential risk for false-negative and false-positive results. [23],[27],[28] The use of a nontreponemal assay for routine screening is not suitable for high-volume testing and brings the risk of an elevated number of false negative due to its low sensitivity compared to specific treponemal tests even when the infection is recent [28],[46] or due to the prozone phenomenon. [47],[48] Besides, false-positive reactions, which almost certainly occur with nontreponemal tests and with treponemal EIAs, create clinical management dilemmas (e.g., other infections) [1],[17],[18] that prompt either to repeat the test or to an unnecessary treatment. This problem will be greatest in routine screening of low-risk populations, such as blood donors. [25],[46],[49] In addition, it should also be considered that the interpretation of manual method results such as the RPR/VDRL and TPHA/TPPA assays can vary significantly among different laboratories and operators. However, all these methods require confirmatory testing with a different treponemal assay almost with a similar sensitivity and with a greater specificity compared to that used for the first screening. [15]

Many syphilis rapid point-of-care (POC) tests have been extended in the last 20 years. Their use is fundamental in the WHO strategy (syphilis control programs) for reducing syphilis especially in countries where high rates of syphilis and HIV co-infections are observed. [9],[50] At first, POC tests detected only the presence of treponemal antibodies presenting low sensitivity compared to traditional methods, even if most recent, they have improved the sensitivity. [51],[52] Moreover, dual rapid tests for treponemal antibodies and reagin have been developed [53] although they cannot distinguish among active, historical, or treated cases. [54] Syphilis POC rapid tests have also been coupled with tests for other sexually transmitted infections as HIV. [55] These multi-infection tests have showed a good sensitivity and specificity for HIV and for treponemal antibodies with a poor sensitivity for nontreponemal antibodies making it difficult to discriminate between an active case and a treated case of syphilis. For this reason, rapid POC tests are suitable in resource-limited settings and are not useful for the screening.

   Testing Guidelines and Algorithms Top

The different guidelines recognize that there are a number of available tests with different performance characteristics. [21],[28],[46],[44],[49],[56] The Centers for Diseases Control (CDC) recommend serologic screening with an inexpensive nontreponemal test to identify subjects with an untreated active infection followed by a more specific treponemal test to confirm syphilis infection in positive patients. [57] Syphilis guidelines in the United Kingdom recommend screening with either EIAs when early primary syphilis is suspected or a combination of VDRL and TPHA tests in other cases. [15],[21] Other European guidelines for syphilis recommend either EIA or TPPA as a screening test. [58] Furthermore, in Italy and in many other countries, blood transfusion services are forced by law to screen for syphilis.

Due to the high variability of syphilis antibodies, the results of a single test are not always sufficient for an accurate screening, and there is no evidence on which algorithm should be preferred. No standardized protocols and approved screening or confirmatory testing of an initial reactivity have been established yet for this setting. [59] This contributes to generate high discrepancies both in clinical laboratories and in blood transfusion centers stressing the need to generate an efficient algorithm. [60]

Two possible algorithms for serological screening have been proposed : t0 he traditional algorithm and the reverse algorithm, as reported in [Figure 2]. The traditional algorithm recommends the use of nontreponemal tests such as RPR/VDRL followed by treponemal agglutination assays or EIA/CIA as confirmatory treponemal testing. While this algorithm is suitable for the diagnosis of active syphilis, it does not allow identifying past infections and thus, is not useful for donor screening and for specialized settings such as blood centers where high sensitivity for all stages of T. pallidum infection is required. The reverse algorithm starts with treponemal tests such as TPHA/TPPA or EIA/CIA followed by a quantitative nontreponemal assay on positive samples. [23],[25],[61] If the latter results are negative or discordant (e.g., EIA reactive, RPR nonreactive) it would be necessary to perform a third test with a different treponemal assay [Figure 2]. [56],[62] The reverse algorithm detects active, latent, and past syphilis, and then it could be more useful for donor screening and population surveys.
Figure 2: The actual testing algorithms for diagnosis of syphilis (modified from Tong et al., 2014, ref #63)

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As recommended by CDC, [5] the protocol for syphilis screening should include not only the utilization of two different treponemal assays with the same sensitivity, but also a successive step with another sensitive treponemal test in case of discordant results. Taking this into account, our Immunohematology Laboratory at the Second University of Naples has adopted an European Centre for Disease Prevention and Control (ECDC) modified algorithm, [63] considering a treponemal test, such as the chemiluminescent microparticle immunoassay, for screening followed directly by two different treponemal assays (TPHA and INNO-LIA immunoblot assay) as confirmatory test [Figure 2]. (Sommese et al., [64] syphilis detection : e0 valuation of serological screening and confirmatory assays in blood donors, submitted). This procedure has resulted to be more suitable and more sensitive than TPHA. A potential drawback of the use of an immunoblot for confirmation of a positive screening result and the resolution of discrepancies among different treponemal assays is the occurrence of "indeterminate" results (i.e., reactivity patterns that do not fulfill the criteria for a confirmed positivity, according to the manufacturers' recommendations) as also reported in literature. [51],[65],[66],[67],[68],[69],[70] Nevertheless, the reverse screening algorithm presents several significant benefits. It allows to achieve a higher sensitivity for all stages of T. pallidum infection including resolved cases with a consequent reduction of false positive results among blood donors; furthermore, it provides a more objective interpretation of screening results. [6],[43]

It is impossible to conclude if the reverse algorithm causes a higher number of false results than traditional since RPR screening is not provided in the reverse algorithm. Different evidence and specific clinical settings that may favor the traditional or the reverse algorithm have been nicely summarized in a recent point-counterpoint discussion. [71] Some factors support the persistent use of a traditional algorithm, particularly in small clinical laboratories, to consent a more rapid screening assay without expensive instrumentations and clinicians should be vigilant that alternative testing algorithms exist. Nevertheless, since the screening tests of syphilis cannot distinguish between treated and untreated disease, the anamnesis of the patient will continue to be crucial for a correct diagnosis and for a blood safety. [25]

   Ongoing Clinical Trials Top

The relevance of continuous interest on syphilis is well documented by several ongoing clinical trials, as reported in [Table 1]. We searched on the web for studies and clinical trials selected from the USA National Institutes of Health using the following keywords (also combining them) : s0 yphilis, diagnosis, and sexually transmitted diseases. We got back 18 interventional and five observational studies. Some of these studies considered patients with also other sexually transmitted infections as HIV [Table 1]. We found eight studies on the performance and relevance of diagnostic tests; seven investigations on the serological response associated to different pharmacological treatments also in the presence of co-infections, and eight clinical trials on the implementation of prevention programs. All these ongoing projects are aimed to control the real impact of this ancient disease.
Table 1: Ongoing clinical studies on syphilis from

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   Conclusions Top

While a consolidated practice and clinical guidelines are available for symptomatic cases, the screening for asymptomatic infections is still a challenge. Many issues remain to be investigated to definitively establish the gold standard for diagnostic algorithm. Nevertheless, serologic testing remains the principal tool for syphilis diagnosis. Indeed, the most recent evidence suggests that an algorithm based on the ECDC model, as performed in our center, could guarantee an adequate sensitivity and a good overall accuracy and may then be adopted for blood donor screening.

By considering the most recent studies, the diagnosis and the monitoring of this infection are still intensely examined especially in patients with HIV considering their increased risk of severe complications. [72],[73] Therefore, further researches need to be performed and the ongoing clinical trials could shed light on unresolved issues.


We thank Dr. Carmela Fiorito for her help in literature research.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA 2003;290:1510-4.  Back to cited text no. 1
Merritt HH, Adams RD, Solomon HC. Neurosyphilis. New York: Oxford University Press; 1940.  Back to cited text no. 2
Peeling RW, Mabey DC. Syphilis. Nat Med 2004;2:448-9.  Back to cited text no. 3
World Health Organization. Treponemal Infections. Geneva, Switzerland: World Health Organization; 1982.  Back to cited text no. 4
Centers for Disease Control and Prevention (CDC). Sexually Transmitted Disease Surveillance 2012. Atlanta, GA: US Department of Health and Human Services, CDC; 2014.  Back to cited text no. 5
Koedijk FD, van Benthem BH, Vrolings EM, Zuilhof W, van der Sande MA. Increasing sexually transmitted infection rates in young men having sex with men in the Netherlands, 2006-2012. Emerg Themes Epidemiol 2014;11:12.  Back to cited text no. 6
Janier M, Hegyi V, Dupin N, Unemo M, Tiplica GS, Potocnik M, et al. 2014 European guideline on the management of syphilis. J Eur Acad Dermatol Venereol 2014;28:1581-93.  Back to cited text no. 7
Salfa MC, Regine V, Ferri M. Suligoi B and the Sentinel Network of Clinical Centres and Clinical Microbiology Laboratories for Sexually Transmitted diseases: Data from the two active sentinel surveillance systems in Italy. Not Ist Super Sanità 2014;27:4-39.   Back to cited text no. 8
Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009;58:1-207.  Back to cited text no. 9
Glatz M, Juricevic N, Altwegg M, Bruisten S, Komericki P, Lautenschlager S, et al. A multicenter prospective trial to asses a new real-time polymerase chain reaction for detection of Treponema pallidum, herpes simplex-1/2 and Haemophilus ducreyi in genital, anal and oropharyngeal ulcers. Clin Microbiol Infect 2014;20:O1020-7.  Back to cited text no. 10
Liu H, Rodes B, Chen CY, Steiner B. New tests for syphilis: Rational design of a PCR method for detection of Treponema pallidum in clinical specimens using unique regions of the DNA polymerase I gene. J Clin Microbiol 2001;39:1941-6.  Back to cited text no. 11
Ferreira SC, de Almeida-Neto C, Nishiya AS, Di-Lorenzo-Oliveira C, Ferreira JE, Alencar CS, et al. Prevalence of Treponema pallidum DNA among blood donors with two different serologic tests profiles for syphilis in São Paulo, Brazil. Vox Sang 2014;106:376-8.  Back to cited text no. 12
Orton SL, Liu H, Dodd RY, Williams AE; ARCNET Epidemiology Group. Prevalence of circulating Treponema pallidum DNA and RNA in blood donors with confirmed-positive syphilis tests. Transfusion 2002;42:94-9.  Back to cited text no. 13
Müller I, Brade V, Hagedorn HJ, Straube E, Schörner C, Frosch M, et al. Is serological testing a reliable tool in laboratory diagnosis of syphilis? Meta-analysis of eight external quality control surveys performed by the German infection serology proficiency testing program. J Clin Microbiol 2006;44:1335-41.  Back to cited text no. 14
Egglestone SI, Turner AJ. Serological diagnosis of syphilis. PHLS Syphilis Serology Working Group. Commun Dis Public Health 2000;3:158-62.  Back to cited text no. 15
Tiwari AK, Pandey PK, Dara RC, Rawat GS, Raina V, Bhargava R. Evaluation of a new serological test for syphilis based on chemiluminescence assay in a tertiary care hospital. Asian J Transfus Sci 2015;9:65-9.  Back to cited text no. 16
[PUBMED]  Medknow Journal  
Larsen SA, Steiner BM, Rudolph AH. Laboratory diagnosis and interpretation of tests for syphilis. Clin Microbiol Rev 1995;8:1-21.  Back to cited text no. 17
Naidu NK, Bharucha ZS, Sonawane V, Ahmed I. Comparative study of Treponemal and non-Treponemal test for screening of blood donated at a blood center. Asian J Transfus Sci 2012;6:32-5.  Back to cited text no. 18
[PUBMED]  Medknow Journal  
Luger A. Serological diagnosis of syphilis: Current methods. In: Young H, McMillan A, editors. Immunological Diagnosis of Sexually Transmitted Diseases. New York: Marcel Dekker; 1988. p. 249-74.  Back to cited text no. 19
Hunter MG, Robertson PW, Post JJ. Significance of isolated reactive treponemal chemiluminescence immunoassay results. J Infect Dis 2013;207:1416-23.  Back to cited text no. 20
Young H. Guidelines for serological testing for syphilis. Sex Transm Infect 2000;76:403-5.  Back to cited text no. 21
Sommese L, Iannone C, Cacciatore F, De Iorio G, Napoli C. Comparison between screening and confirmatory serological assays in blood donors in a region of South Italy. J Clin Lab Anal 2014;28:198-203.  Back to cited text no. 22
Binnicker MJ, Jespersen DJ, Rollins LO. Treponema-specific tests for serodiagnosis of syphilis: Comparative evaluation of seven assays. J Clin Microbiol 2011;49:1313-7.  Back to cited text no. 23
Maple PA, Ratcliffe D, Smit E. Characterization of Treponema pallidum particle agglutination assay-negative sera following screening by treponemal total antibody enzyme immunoassays. Clin Vaccine Immunol 2010;17:1718-22.  Back to cited text no. 24
Seña AC, White BL, Sparling PF. Novel Treponema pallidum serologic tests: A paradigm shift in syphilis screening for the 21 st century. Clin Infect Dis 2010;51:700-8.  Back to cited text no. 25
Rodríguez I, Alvarez EL, Fernández C, Miranda A. Comparison of a recombinant-antigen enzyme immunoassay with Treponema pallidum hemagglutination test for serological confirmation of syphilis. Mem Inst Oswaldo Cruz 2002;97:347-9.  Back to cited text no. 26
Pope V, Fears MB, Morrill WE, Castro A, Kikkert SE. Comparison of the Serodia Treponema pallidum particle agglutination, Captia Syphilis-G, and SpiroTek Reagin II tests with standard test techniques for diagnosis of syphilis. J Clin Microbiol 2000;38:2543-5.  Back to cited text no. 27
Schmidt BL, Edjlalipour M, Luger A. Comparative evaluation of nine different enzyme-linked immunosorbent assays for determination of antibodies against Treponema pallidum in patients with primary syphilis. J Clin Microbiol 2000;38:1279-82.  Back to cited text no. 28
Park Y, Park Y, Joo SY, Park MH, Kim HS. Evaluation of a fully automated treponemal test and comparison with conventional VDRL and FTA-ABS tests. Am J Clin Pathol 2011;136:705-10.  Back to cited text no. 29
Young H, Pryde J, Duncan L, Dave J. The Architect Syphilis assay for antibodies to Treponema pallidum: An automated screening assay with high sensitivity in primary syphilis. Sex Transm Infect 2009;85:19-23.  Back to cited text no. 30
Choi SJ, Park Y, Lee EY, Kim S, Kim HS. Comparisons of fully automated syphilis tests with conventional VDRL and FTA-ABS tests. Clin Biochem 2013;46:834-7.  Back to cited text no. 31
Aktas G, Young H, Moyes A, Badur S. Evaluation of the fluorescent treponemal antibody absorption test for detection of antibodies (immunoglobulins G and M) to Treponema pallidum in serologic diagnosis of syphilis. Int J STD AIDS 2007;18:255-60.  Back to cited text no. 32
Franken AA, Oliver JH, Litwin CM. Comparison of a combined nontreponemal (VDRL) and treponemal immunoblot to traditional nontreponemal and treponemal assays. J Clin Lab Anal 2015;29:68-73.  Back to cited text no. 33
Backhouse JL, Nesteroff SI. Treponema pallidum western blot: Comparison with the FTA-ABS test as a confirmatory test for syphilis. Diagn Microbiol Infect Dis 2001;39:9-14.  Back to cited text no. 34
Lam TK, Lau HY, Lee YP, Fung SM, Leung WL, Kam KM. Comparative evaluation of the INNO-LIA syphilis score and the MarDx Treponema pallidum immunoglobulin G Marblot test assays for the serological diagnosis of syphilis. Int J STD AIDS 2010;21:110-3.  Back to cited text no. 35
Hagedorn HJ, Kraminer-Hagedorn A, De Bosschere K, Hulstaert F, Pottel H, Zrein M. Evaluation of INNO-LIA syphilis assay as a confirmatory test for syphilis. J Clin Microbiol 2002;40:973-8.  Back to cited text no. 36
Ebel A, Vanneste L, Cardinaels M, Sablon E, Samson I, De Bosschere K, et al. Validation of the INNO-LIA syphilis kit as a confirmatory assay for Treponema pallidum antibodies. J Clin Microbiol 2000;38:215-9.  Back to cited text no. 37
Wellinghausen N, Dietenberger H. Evaluation of two automated chemiluminescence immunoassays, the LIAISON Treponema Screen and the ARCHITECT Syphilis TP, and the Treponema pallidum particle agglutination test for laboratory diagnosis of syphilis. Clin Chem Lab Med 2011;49:1375-7.  Back to cited text no. 38
Sun AH, Mao YF, Hu Y, Sun Q, Yan J. Sensitive and specific ELISA coated by TpN15-TpN17-TpN47 fusion protein for detection of antibodies to Treponema pallidum. Clin Chem Lab Med 2009;47:321-6.  Back to cited text no. 39
Lafond RE, Lukehart SA. Biological basis for syphilis. Clin Microbiol Rev 2006;19:29-49.  Back to cited text no. 40
Fraser CM, Norris SJ, Weinstock GM, White O, Sutton GG, Dodson R, et al. Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science 1998;281:375-88.  Back to cited text no. 41
Norris SJ. Polypeptides of Treponema pallidum: Progress toward understanding their structural, functional, and immunologic roles. Treponema Pallidum Polypeptide Research Group. Microbiol Rev 1993;57:750-79.  Back to cited text no. 42
Sun R, Lai DH, Ren RX, Lian S, Zhang HP. Treponema pallidum-specific antibody expression for the diagnosis of different stages of syphilis. Chin Med J (Engl) 2013;126:206-10.  Back to cited text no. 43
de Lemos EA, Belém ZR, Santos A, Ferreira AW. Characterization of the Western blotting IgG reactivity patterns in the clinical phases of acquired syphilis. Diagn Microbiol Infect Dis 2007;58:177-83.  Back to cited text no. 44
Smith BC, Simpson Y, Morshed MG, Cowen LL, Hof R, Wetherell C, et al. New proteins for a new perspective on syphilis diagnosis. J Clin Microbiol 2013;51:105-11.  Back to cited text no. 45
Wang LN, Li JM. Evaluation of immunoglobulin M and G Western blot and ELISA for screening antibodies to Treponema pallidum in blood donors. Sex Transm Dis 2009;36:413-6.  Back to cited text no. 46
Liu C, Ou Q, Chen H, Chen J, Lin S, Jiang L, et al. The diagnostic value and performance evaluation of five serological tests for the detection of Treponema pallidum. J Clin Lab Anal 2014;28:204-9.  Back to cited text no. 47
Jurado RL, Campbell J, Martin PD. Prozone phenomenon in secondary syphilis. Has its time arrived? Arch Intern Med 1993;153:2496-8.  Back to cited text no. 48
Cole MJ, Perry RK, Parry V. Comparative evaluation of 15 serological assays for the detection of syphilis infection. Eur J Clin Microbiol Infect Dis 2007;26:705-13.  Back to cited text no. 49
Fu GF, Jiang N, Hu HY, Mahapatra T, Yin YP, Mahapatra S, et al. The epidemic of HIV, syphilis, chlamydia and gonorrhea and the correlates of sexual transmitted infections among men who have sex with men in Jiangsu, China, 2009. PLoS One 2015;10:e0118863.  Back to cited text no. 50
Centers for Disease Control and Prevention (CDC). Discordant results from reverse sequence syphilis screening - five laboratories, United States, 2006-2010. MMWR Morb Mortal Wkly Rep 2011;60:133-7.  Back to cited text no. 51
Herring AJ, Ballard RC, Pope V, Adegbola RA, Changalucha J, Fitzgerald DW, et al. A multi-centre evaluation of nine rapid, point-of-care syphilis tests using archived sera. Sex Transm Infect 2006;82 Suppl 5:v7-12.  Back to cited text no. 52
Castro AR, Esfandiari J, Kumar S, Ashton M, Kikkert SE, Park MM, et al. Novel point-of-care test for simultaneous detection of nontreponemal and treponemal antibodies in patients with syphilis. J Clin Microbiol 2010;48:4615-9.  Back to cited text no. 53
Jafari Y, Peeling RW, Shivkumar S, Claessens C, Joseph L, Pai NP. Are Treponema pallidum specific rapid and point-of-care tests for syphilis accurate enough for screening in resource limited settings? Evidence from a meta-analysis. PLoS One 2013;8:e54695.  Back to cited text no. 54
Buchacz K, Klausner JD, Kerndt PR, Shouse RL, Onorato I, McElroy PD, et al. HIV incidence among men diagnosed with early syphilis in Atlanta, San Francisco, and Los Angeles, 2004 to 2005. J Acquir Immune Defic Syndr 2008;47:234-40.  Back to cited text no. 55
Jost H, Castro A, Cox D, Fakile Y, Kikkert S, Tun Y, et al. A comparison of the analytical level of agreement of nine treponemal assays for syphilis and possible implications for screening algorithms. BMJ Open 2013;3:e003347.  Back to cited text no. 56
Centers for Disease Control and Prevention (CDC). Syphilis testing algorithms using treponemal tests for initial screening: Four laboratories, New York City, 2005-2006. MMWR Morb Mortal Wkly Rep 2008;57:872-5.  Back to cited text no. 57
French P, Gomberg M, Janier M, Schmidt B, van Voorst Vader P, Young H, et al. IUSTI: 2008 European Guidelines on the Management of Syphilis. Int J STD AIDS 2009;20:300-9.  Back to cited text no. 58
Binnicker MJ. Which algorithm should be used to screen for syphilis? Curr Opin Infect Dis 2012;25:79-85.  Back to cited text no. 59
Vulcano F, Milazzo L, Volpi S, Battista MM, Barca A, Hassan HJ, et al. Italian national survey of blood donors: External quality assessment (EQA) of syphilis testing. J Clin Microbiol 2010;48:753-7.  Back to cited text no. 60
Lipinsky D, Schreiber L, Kopel V, Shainberg B. Validation of reverse sequence screening for syphilis. J Clin Microbiol 2012;50:1501.  Back to cited text no. 61
Workowski KA, Berman S. Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep 2010;59:1-110.  Back to cited text no. 62
Tong ML, Lin LR, Liu LL, Zhang HL, Huang SJ, Chen YY, et al. Analysis of 3 algorithms for syphilis serodiagnosis and implications for clinical management. Clin Infect Dis 2014;58:1116-24.  Back to cited text no. 63
Sommese L, Paolillo R, Sabia C, Costa D, De Pascale MR, Iannone C, et al. Syphilis detection: evaluation of serological screening and pilot reverse confirmatory assay algorithm in blood donors. Int J STD AIDS 2015 Jun 10. p. ii: 0956462415590723.  Back to cited text no. 64
Lam TK, Lau HY, Lee YP, Fung SM, Leung WL, Kam KM. Use of the INNO-LIA syphilis score assay in the resolution of discordant positive screening enzyme immunoassay results for the serological diagnosis of syphilis. Int J STD AIDS 2014;25:52-6.  Back to cited text no. 65
Lee K, Park H, Roh EY, Shin S, Park KU, Park MH, et al. Characterization of sera with discordant results from reverse sequence screening for syphilis. Biomed Res Int 2013;2013: 269347.  Back to cited text no. 66
Park IU, Chow JM, Bolan G, Stanley M, Shieh J, Schapiro JM. Screening for syphilis with the treponemal immunoassay: Analysis of discordant serology results and implications for clinical management. J Infect Dis 2011;204:1297-304.  Back to cited text no. 67
Binnicker MJ, Jespersen DJ, Rollins LO. Direct comparison of the traditional and reverse syphilis screening algorithms in a population with a low prevalence of syphilis. J Clin Microbiol 2012;50:148-50.  Back to cited text no. 68
Mishra S, Boily MC, Ng V, Gold WL, Okura T, Shaw M, et al. The laboratory impact of changing syphilis screening from the rapid-plasma reagin to a treponemal enzyme immunoassay: A case-study from the Greater Toronto Area. Sex Transm Dis 2011;38:190-6.  Back to cited text no. 69
Baião AM, Kupek E, Petry A. Reverse algorithm for syphilis screening more than halved false positive test results in Brazilian blood donors. Transfus Med 2014;24:64-6.  Back to cited text no. 70
Loeffelholz MJ, Binnicker MJ. It is time to use treponema-specific antibody screening tests for diagnosis of syphilis. J Clin Microbiol 2012;50:2-6.  Back to cited text no. 71
Lynn WA, Lightman S. Syphilis and HIV: A dangerous combination. Lancet Infect Dis 2004;4:456-66.  Back to cited text no. 72
Pialoux G, Vimont S, Moulignier A, Buteux M, Abraham B, Bonnard P. Effect of HIV infection on the course of syphilis. AIDS Rev 2008;10:85-92.  Back to cited text no. 73

Correspondence Address:
Linda Sommese
Department of Transfusion Medicine and Transplant Immunology, U.O.C. Immunohematology, Regional Reference Laboratory of Transplant Immunology, Azienda Ospedaliera Universitaria, Second University of Naples, Piazza Miraglia 2, 80138 Naples
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-6247.164267

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