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Syphilis

Nature Reviews Disease Primers volume 3, Article number: 17073 (2017) | Download Citation

Abstract

Treponema pallidum subspecies pallidum (T. pallidum) causes syphilis via sexual exposure or via vertical transmission during pregnancy. T. pallidum is renowned for its invasiveness and immune-evasiveness; its clinical manifestations result from local inflammatory responses to replicating spirochaetes and often imitate those of other diseases. The spirochaete has a long latent period during which individuals have no signs or symptoms but can remain infectious. Despite the availability of simple diagnostic tests and the effectiveness of treatment with a single dose of long-acting penicillin, syphilis is re-emerging as a global public health problem, particularly among men who have sex with men (MSM) in high-income and middle-income countries. Syphilis also causes several hundred thousand stillbirths and neonatal deaths every year in developing nations. Although several low-income countries have achieved WHO targets for the elimination of congenital syphilis, an alarming increase in the prevalence of syphilis in HIV-infected MSM serves as a strong reminder of the tenacity of T. pallidum as a pathogen. Strong advocacy and community involvement are needed to ensure that syphilis is given a high priority on the global health agenda. More investment is needed in research on the interaction between HIV and syphilis in MSM as well as into improved diagnostics, a better test of cure, intensified public health measures and, ultimately, a vaccine.

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References

  1. 1.

    & The endemic treponematoses. Clin. Microbiol. Rev. 27, 89–115 (2014).

  2. 2.

    , & Genetic diversity in Treponema pallidum: implications for pathogenesis, evolution and molecular diagnostics of syphilis and yaws. Infect. Genet. Evol. 12, 191–202 (2012).

  3. 3.

    , , , & Syphilis at the crossroad of phylogenetics and paleopathology. PLoS Negl. Trop. Dis. 4, e575 (2010).

  4. 4.

    Avoidance of host defences by Treponema pallidum in situ and on extraction from infected rabbit testes. J. Gen. Microbiol. 126, 69–75 (1981).

  5. 5.

    , , & Changes in the cell surface properties of Treponema pallidum that occur during in vitro incubation of freshly extracted organisms. Infect. Immun. 55, 2255–2261 (1987).

  6. 6.

    , , , & Assessment of the kinetics of Treponema pallidum dissemination into blood and tissues in experimental syphilis by real-time quantitative PCR. Infect. Immun. 75, 2954–2958 (2007).

  7. 7.

    et al. Treponema pallidum invades intercellular junctions of endothelial cell monolayers. Proc. Natl Acad. Sci. USA 85, 3608–3612 (1988).

  8. 8.

    & Biological basis for syphilis. Clin. Microbiol. Rev. 19, 29–49 (2006).

  9. 9.

    , & in Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases 8 th edn (eds Bennett, J. E., Dolin, R. & Blaser, M. J.) 2684–2709 (Saunders, 2014).

  10. 10.

    et al. Immune evasion and recognition of the syphilis spirochete in blood and skin of secondary syphilis patients: two immunologically distinct compartments. PLoS Negl. Trop. Dis. 6, e1717 (2012).

  11. 11.

    World Health Organisation. WHO guidelines for the treatment of Treponema pallidum (syphilis). WHO (2016).

  12. 12.

    & & Centers for Disease Control & Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recommen. Rep. 64, 1–137 (2015).

  13. 13.

    et al. 2014 European guideline on the management of syphilis. J. Eur. Acad. Dermatol. Venereol. 28, 1581–1593 (2014).

  14. 14.

    & The pathogenesis of syphilis: the Great Mimicker, revisited. J. Pathol. 208, 224–232 (2005).

  15. 15.

    et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N. Engl. J. Med. 337, 307–314 (1997).

  16. 16.

    , & Update on syphilis. JAMA 290, 1510 (2003).

  17. 17.

    et al. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann. Intern. Med. 109, 855–862 (1988).

  18. 18.

    , , , & in Sexually Transmitted Diseases 4th edn (eds Holmes, K. K. et al. ) 1577–1609 (McGraw-Hill Medical, 2008).

  19. 19.

    et al. Evaluation of molecular methodologies and rabbit infectivity testing for the diagnosis of congenital syphilis and neonatal central nervous system invasion by Treponema pallidum. J. Infect. Dis. 167, 148–157 (1993).

  20. 20.

    Congenital syphilis in Massachusetts. N. Engl. J. Med. 245, 634–640 (1951).

  21. 21.

    et al. Syphilis in pregnancy in Tanzania. I. Impact maternal syphilis outcome pregnancy. J. Infect. Dis. 186, 940–947 (2002). A comprehensive and well-designed study that showed the outcomes of syphilis during pregnancy.

  22. 22.

    , & The minimal infectious inoculum of Spirochaeta pallida (Nichols strain) and a consideration of its rate of multiplication in vivo. Am. J. Syph. Gonorrhea Vener. Dis. 32, 1–18 (1948).

  23. 23.

    et al. Global estimates of syphilis in pregnancy and associated adverse outcomes: analysis of multinational antenatal surveillance data. PLoS Med. 10, e1001396 (2013).

  24. 24.

    et al. Global burden of maternal and congenital syphilis in 2008 and 2012: a health systems modelling study. Lancet Glob. Health 4, e525–e533 (2016). This paper is one of three WHO studies that have provided the backbone of our data on the global burden of syphilis; it provided updated global estimates in pregnant women and of adverse pregnancy outcomes 5 years into the global programme for congenital syphilis elimination (that is, monitoring progress).

  25. 25.

    et al. Stillbirths: rates, risk factors, and acceleration towards 2030. Lancet 387, 587–603 (2016). The first paper that showed that syphilis has emerged as the leading cause of preventable stillbirths.

  26. 26.

    & Syphilis control — a continuing challenge. N. Engl. J. Med. 351, 122–124 (2004).

  27. 27.

    et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS ONE 10, e0143304 (2015).

  28. 28.

    et al. Field evaluation of Standard Diagnostics’ Bioline HIV/Syphilis Duo test among female sex workers in Johannesburg, South Africa. Sex. Transm. Infect. 92, 495–498 (2016).

  29. 29.

    et al. Integrated bio-behavioural HIV surveillance surveys among female sex workers in Sudan, 2011–2012. Sex. Transm. Infect. 89, S17–S22 (2013).

  30. 30.

    et al. HIV and other sexually transmitted infections in a cohort of women involved in high-risk sexual behavior in Kampala, Uganda. Sex. Transm. Dis. 38, 316–323 (2011).

  31. 31.

    et al. Sexually transmitted infections among heterosexual male clients of female sex workers in China: a systematic review and meta-analysis. PLoS ONE 8, e71394 (2013).

  32. 32.

    et al. Sustained high prevalence of viral hepatitis and sexually transmissible infections among female sex workers in China: a systematic review and meta-analysis. BMC Infect. Dis. 16, 2 (2015).

  33. 33.

    et al. Prevalence of syphilis infection in different tiers of female sex workers in China: implications for surveillance and interventions. BMC Infect. Dis. 12, 84 (2012).

  34. 34.

    , , , & Syphilis trends among men who have sex with men in the United States and western Europe: a systematic review of trend studies published between 2004 and 2015. PLoS ONE 11, e0159309 (2016). A good review that described the alarming increase of syphilis in MSM in the developed world.

  35. 35.

    et al. State-specific rates of primary and secondary syphilis among men who have sex with men - United States, 2015. MMWR. Morb. Mortal. Wkly Rep. 66, 349–354 (2017).

  36. 36.

    et al. High incidence of diagnosis with syphilis co-infection among men who have sex with men in an HIV cohort in Ontario, Canada. BMC Infect. Dis. 15, 356 (2015).

  37. 37.

    Centers for Disease Control and Prevention. Syphilis treatment and care. Centers for Disease Control and Prevention (2015).

  38. 38.

    et al. Syphilis outbreak at a California men's prison, 2007-2008: propagation by lapses in clinical management, case management, and public health surveillance. J. Correct. Health Care 19, 54–64 (2012).

  39. 39.

    , , , & Characteristics of women reporting multiple recent sex partners presenting to a sexually transmitted disease clinic for care. Sex. Transm. Dis. 38, 210–215 (2011).

  40. 40.

    et al. Screening for syphilis infection in nonpregnant adults and adolescents. JAMA 315, 2321 (2016).

  41. 41.

    European Centre for Disease Prevention and Control. Antenatal screening for HIV, hepatitis B, syphilis and rubella susceptibility in the EU/EEA. European Centre for Disease Prevention and Control (2017).

  42. 42.

    et al. A double-edged sword: does highly active antiretroviral therapy contribute to syphilis incidence by impairing immunity to Treponema pallidum? Sex. Transm. Infect. 93, 374–378 (2017). This paper presented an interesting hypothesis to explain the twin epidemics of HIV and syphilis in MSM.

  43. 43.

    , , & The need and plan for global elimination of congenital syphilis. Sex. Transm. Dis. 34, S5–S10 (2007).

  44. 44.

    World Health Organisation. The global elimination of congenital syphilis: rationale and strategy for action. WHO (2007).

  45. 45.

    et al. Untreated maternal syphilis and adverse outcomes of pregnancy: a systematic review and meta-analysis. Bull. World Health Organ. 91, 217–226 (2013).

  46. 46.

    , , , & Lives Saved Tool supplement detection and treatment of syphilis in pregnancy to reduce syphilis related stillbirths and neonatal mortality. BMC Public Health 11, S9 (2011).

  47. 47.

    WHO. Investment case for eliminating mother-to-child transmission of syphilis. WHO (2012).

  48. 48.

    et al. The cost and cost-effectiveness of scaling up screening and treatment of syphilis in pregnancy: a model. PLoS ONE 9, e87510 (2014).

  49. 49.

    , , & Antenatal syphilis screening using point-of-care testing in sub-Saharan African countries: a cost-effectiveness analysis. PLoS Med. 10, e1001545 (2013).

  50. 50.

    , , , & Antenatal syphilis screening using point-of-care testing in low- and middle-income countries in Asia and Latin America: a cost-effectiveness analysis. PLoS ONE 10, e0127379 (2015).

  51. 51.

    et al. Cost-effectiveness of integrated routine offering of prenatal HIV and syphilis screening in China. Sex. Transm. Dis. 41, 103–110 (2014).

  52. 52.

    Pan American Health Organization. Regional initiative for the elimination of mother-to-child transmission of HIV and congenital syphilis in Latin America and the Caribbean. Concept document for the Caribbean. Pan American Health Organization (2009).

  53. 53.

    , , & Historical perspective of syphilis in the past 60 years in China: eliminated, forgotten, on the return. Chin. Med. J. (Engl.). 126, 2774–2779 (2013). Many lessons can be learnt from this account of the history of syphilis in China, which was once eliminated but has now come back with a vengeance.

  54. 54.

    et al. Elimination of mother-to-child transmission of HIV and Syphilis (EMTCT): process, progress, and program integration. PLoS Med. 14, e1002329 (2017). This paper described a success story of syphilis control and elimination, and highlighted how continuing global efforts can achieve an AIDS-free and syphilis-free generation.

  55. 55.

    , & Biology of Treponema pallidum: correlation of functional activities with genome sequence data. J. Mol. Microbiol. Biotechnol. 3, 37–62 (2001).

  56. 56.

    , & The outer membrane of Treponema pallidum: biological significance and biochemical properties. J. Gen. Microbiol. 131, 2349–2357 (1985).

  57. 57.

    Treponema pallidum and the quest for outer membrane proteins. Mol. Microbiol. 16, 1067–1073 (1995).

  58. 58.

    et al. MyD88 deficiency markedly worsens tissue inflammation and bacterial clearance in mice infected with Treponema pallidum, the agent of syphilis. PLoS ONE 8, e71388 (2013).

  59. 59.

    , & Infectivity tests in syphilis. Sex. Transm. Infect. 45, 183–195 (1969).

  60. 60.

    & Current Protocols in Microbiology (John Wiley and Sons, Inc., 2007).

  61. 61.

    & The biology, pathology, and immunology of syphilis. Int. Rev. Exp. Pathol. 24, 203–276 (1983).

  62. 62.

    Scientific monogamy: thirty years dancing with the same bug. Sex. Transm. Dis. 35, 2–7 (2008).

  63. 63.

    et al. Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen. Nat. Rev. Microbiol. 14, 744–759 (2016). The review provided a very informative summary of the interaction of T. pallidum and its human hosts.

  64. 64.

    & in Pathogenic Treponema: Molecular and Cellular Biology (eds Radolf, J. D. & Lukehart, S. A.) 9–18 (Horizon Scientific Press, 2006).

  65. 65.

    Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science 281, 375–388 (1998).

  66. 66.

    et al. Characterization of outer membranes isolated from Treponema pallidum, the syphilis spirochete. Infect. Immun. 63, 4244–4252 (1995).

  67. 67.

    , , , & Treponema pallidum in gel microdroplets: a novel strategy for investigation of treponemal molecular architecture. Mol. Microbiol. 15, 1151–1164 (1995).

  68. 68.

    , & in Pathogenic Treponemes: Cellular and Molecular Biology (eds Radolf, J. D. & Lukehart, S. A.) 197–236 (Horizon Scientific Press, 2006).

  69. 69.

    , & The immune response to infection with Treponema pallidum, the stealth pathogen. Microbes Infect. 4, 1133–1140 (2002).

  70. 70.

    , , , & Major integral membrane protein immunogens of Treponema pallidum are proteolipids. Infect. Immun. 57, 2872–2877 (1989).

  71. 71.

    , & Lipid modification of the 15 kiloDalton major membrane immunogen of Treponema pallidum. Mol. Microbiol. 4, 1371–1379 (1990).

  72. 72.

    , , , & Lipid modification of the 17-kilodalton membrane immunogen of Treponema pallidum determines macrophage activation as well as amphiphilicity. Infect. Immun. 61, 1202–1210 (1993).

  73. 73.

    , , & Identification and localization of integral membrane proteins of virulent Treponema pallidum subsp. pallidum by phase partitioning with the nonionic detergent triton X-114. Infect. Immun. 56, 490–498 (1988).

  74. 74.

    , , & The outer membrane, not a coat of host proteins, limits antigenicity of virulent Treponema pallidum. Infect. Immun. 60, 1076–1083 (1992).

  75. 75.

    et al. Crystal structure of the Tp34 (TP0971) lipoprotein of Treponema pallidum: implications of its metal-bound state and affinity for human lactoferrin. J. Biol. Chem. 282, 5944–5958 (2006).

  76. 76.

    , , & Defining the interaction of the Treponema pallidum adhesin Tp0751 with laminin. Infect. Immun. 73, 7485–7494 (2005).

  77. 77.

    , , , & Activation and proteolytic activity of the Treponema pallidum metalloprotease, pallilysin. PLoS Pathog. 8, e1002822 (2012).

  78. 78.

    et al. The multifunctional role of the pallilysin-associated Treponema pallidum protein, Tp0750, in promoting fibrinolysis and extracellular matrix component degradation. Mol. Microbiol. 91, 618–634 (2014).

  79. 79.

    et al. The structure of Treponema pallidum Tp0751 (pallilysin) reveals a non-canonical lipocalin fold that mediates adhesion to extracellular matrix components and interactions with host cells. PLOS Pathog. 12, e1005919 (2016).

  80. 80.

    et al. Heterologous expression of the Treponema pallidum laminin-binding adhesin Tp0751 in the culturable spirochete Treponema phagedenis. J. Bacteriol. 190, 2565–2571 (2008).

  81. 81.

    et al. A defined syphilis vaccine candidate inhibits dissemination of Treponema pallidum subspecies pallidum. Nat. Commun. 8, 14273 (2017).

  82. 82.

    et al. Treponema pallidum lipoprotein TP0435 expressed in Borrelia burgdorferi produces multiple surface/periplasmic isoforms and mediates adherence. Sci. Rep. 6, 25593 (2016).

  83. 83.

    et al. The transition from closed to open conformation of Treponema pallidum outer membrane-associated lipoprotein TP0453 involves membrane sensing and integration by two amphipathic helices. J. Biol. Chem. 286, 41656–41668 (2011).

  84. 84.

    et al. TP0326, a Treponema pallidum β-barrel assembly machinery A (BamA) orthologue and rare outer membrane protein. Mol. Microbiol. 80, 1496–1515 (2011).

  85. 85.

    et al. A homology model reveals novel structural features and an immunodominant surface loop/opsonic target in the Treponema pallidum BamA ortholog TP_0326. J. Bacteriol. 197, 1906–1920 (2015).

  86. 86.

    , , & Outer membrane protein biogenesis in Gram-negative bacteria. Phil. Trans. R. Soc. B Biol. Sci. 370, 20150023 (2015).

  87. 87.

    et al. Treponema pallidum major sheath protein homologue Tpr K is a target of opsonic antibody and the protective immune response. J. Exp. Med. 189, 647–656 (1999).

  88. 88.

    et al. The Tprk protein of Treponema pallidum is periplasmic and is not a target of opsonic antibody or protective immunity. J. Exp. Med. 193, 1015–1026 (2001).

  89. 89.

    et al. Gene conversion: a mechanism for generation of heterogeneity in the tprK gene of Treponema pallidum during infection. Mol. Microbiol. 52, 1579–1596 (2004).

  90. 90.

    , , , & TprK sequence diversity accumulates during infection of rabbits with Treponema pallidum subsp. pallidum Nichols strain. Infect. Immun. 74, 1896–1906 (2006).

  91. 91.

    et al. Antigenic variation in Treponema pallidum: TprK sequence diversity accumulates in response to immune pressure during experimental syphilis. J. Immunol. 184, 3822–3829 (2010).

  92. 92.

    et al. Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variation. Nat. Microbiol. 2, 16190 (2016).

  93. 93.

    et al. TprC/D (Tp0117/131), a trimeric, pore-forming rare outer membrane protein of Treponema pallidum, has a bipartite domain structure. J. Bacteriol. 194, 2321–2333 (2012).

  94. 94.

    et al. Bipartite topology of Treponema pallidum repeat proteins C/D and I: outer membrane insertion, trimerization, and porin function require a C-terminal β-barrel domain. J. Biol. Chem. 290, 12313–12331 (2015).

  95. 95.

    et al. TP0262 is a modulator of promoter activity of tpr subfamily II genes of Treponema pallidum ssp. pallidum. Mol. Microbiol. 72, 1087–1099 (2009).

  96. 96.

    & Treponema pallidum, the stealth pathogen, changes, but how? Mol. Microbiol. 72, 1081–1086 (2009).

  97. 97.

    et al. A novel Treponema pallidum antigen, TP0136, is an outer membrane protein that binds human fibronectin. Infect. Immun. 76, 1848–1857 (2008).

  98. 98.

    , , , & Treponema pallidum fibronectin-binding proteins. J. Bacteriol. 186, 7019–7022 (2004).

  99. 99.

    , , & Treponema pallidum subsp. pallidum TP0136 protein is heterogeneous among isolates and binds cellular and plasma fibronectin via its NH2-terminal end. PLoS Negl. Trop. Dis. 9, e0003662 (2015).

  100. 100.

    , , & Viscous dynamics of Lyme disease and syphilis spirochetes reveal flagellar torque and drag. Biophys. J. 105, 2273–2280 (2013).

  101. 101.

    , , , & Virulent Treponema pallidum activates human vascular endothelial cells. J. Infect. Dis. 165, 484–493 (1992).

  102. 102.

    & Skin homing of Treponema pallidum in early syphilis: an immunohistochemical study. Appl. Immunohistochem. Mol. Morphol. 17, 47–50 (2009).

  103. 103.

    , , & Dendritic cells phagocytose and are activated by Treponema pallidum. Infect. Immun. 69, 518–528 (2001).

  104. 104.

    et al. Phagocytosis of Borrelia burgdorferi and Treponema pallidum potentiates innate immune activation and induces gamma interferon production. Infect. Immun. 75, 2046–2062 (2007).

  105. 105.

    et al. Treponema pallidum elicits innate and adaptive cellular immune responses in skin and blood during secondary syphilis: a flow-cytometric analysis. J. Infect. Dis. 195, 879–887 (2007).

  106. 106.

    et al. Host defense mechanisms in secondary syphilitic lesions. Am. J. Pathol. 177, 2421–2432 (2010).

  107. 107.

    et al. Primary and secondary syphilis lesions contain mRNA for Th1 cytokines. J. Infect. Dis. 173, 491–495 (1996).

  108. 108.

    , , , & Lesions of primary and secondary syphilis contain activated cytolytic T cells. Infect. Immun. 64, 1048–1050 (1996).

  109. 109.

    et al. Secondary syphilis in persons infected with and not infected with HIV-1: a comparative immunohistologic study. Am. J. Dermatopathol. 21, 432 (1999).

  110. 110.

    & in Pathogenic Treponemes: Cellular and Molecular Biology (eds Radolf, J. D. & Lukehart, S. A.) 285–322 (Horizon Scientific Press, 2006).

  111. 111.

    , & Subpopulation of Treponema pallidum is resistant to phagocytosis: possible mechanism of persistence. J. Infect. Dis. 166, 1449–1453 (1992).

  112. 112.

    et al. Surface immunolabeling and consensus computational framework to identify candidate rare outer membrane proteins of Treponema pallidum. Infect. Immun. 78, 5178–5194 (2010).

  113. 113.

    & Immobilization of Treponema pallidum in vitro by antibody produced in syphilitic infection. J. Exp. Med. 89, 369–393 (1949).

  114. 114.

    & Humoral immunity in experimental syphilis. II. The relationship of neutralizing factors in immune serum to acquired resistance. J. Immunol. 117, 197–207 (1976).

  115. 115.

    , & Length of guanosine homopolymeric repeats modulates promoter activity of subfamily II tpr genes of Treponema pallidum ssp. pallidum. FEMS Immunol. Med. Microbiol. 51, 289–301 (2007).

  116. 116.

    et al. Transcription of TP0126, Treponema pallidum putative OmpW Homolog, is regulated by the length of a homopolymeric guanosine repeat. Infect. Immun. 83, 2275–2289 (2015).

  117. 117.

    , & Common strategies for antigenic variation by bacterial, fungal and protozoan pathogens. Nat. Rev. Microbiol. 7, 493–503 (2009).

  118. 118.

    & Fetal syphilis in the first trimester. Am. J. Obstet. Gynecol. 124, 705–711 (1976).

  119. 119.

    et al. Reported estimates of adverse pregnancy outcomes among women with and without syphilis: a systematic review and meta-analysis. PLoS ONE 9, e102203 (2014). Together with Ref. 45, these two large systematic reviews estimated the extent of adverse pregnancy outcomes caused by untreated maternal syphilis and provided our best evidence on adverse pregnancy outcomes associated with syphilis.

  120. 120.

    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. 44, 1335–1341 (2006).

  121. 121.

    et al. Dried tube specimens: a simple and cost-effective method for preparation of HIV proficiency testing panels and quality control materials for use in resource-limited settings. J. Virol. Methods 163, 295–300 (2010).

  122. 122.

    , Sabidó, M., , & External quality assessment in the voluntary counseling and testing centers in the Brazilian Amazon using dried tube specimens: results of an effectiveness evaluation. Rev. Soc. Bras. Med. Trop. 48, 87–97 (2015).

  123. 123.

    et al. External quality assurance with dried tube specimens (DTS) for point-of-care syphilis and HIV tests: experience in an indigenous populations screening programme in the Brazilian Amazon. Sex. Transm. Infect. 90, 14–18 (2013).

  124. 124.

    et al. The development and validation of dried blood spots for external quality assurance of syphilis serology. BMC Infect. Dis. 13, 102 (2013).

  125. 125.

    in Sexually Transmitted Diseases 3rd edn (eds Holmes, K. K., Sparling, P. F. & Mardh, P. A.) 473–478 (McGraw-Hill Medical, 1999).

  126. 126.

    Centre for Disease Control and Prevention & Pan American Health Organization. Syphilis testing practices in the Americas region: results of the 2014 survey. Pan American Health Organization (2016).

  127. 127.

    et al. Molecular differentiation of Treponema pallidum subspecies in skin ulceration clinically suspected as yaws in Vanuatu using real-time multiplex PCR and serological methods. Am. J. Trop. Med. Hyg. 92, 134–138 (2014).

  128. 128.

    , , & 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. 39, 1941–1946 (2001).

  129. 129.

    , , , & Sensitivity, specificity and likelihood ratios of PCR in the diagnosis of syphilis: a systematic review and meta-analysis. Sex. Transm. Infect. 89, 251–256 (2013).

  130. 130.

    et al. Detection of Treponema pallidum sp. pallidum DNA in cerebrospinal fluid (CSF) by two PCR techniques. J. Clin. Lab. Anal. 30, 628–632 (2016).

  131. 131.

    et al. Detection of Treponema pallidum by semi-nested PCR in the cerebrospinal fluid of asymptomatic HIV-infected patients with latent syphilis. Clin. Lab. 60, 2051–2054 (2014).

  132. 132.

    et al. An evaluation of the relative sensitivities of the venereal disease research laboratory test and the Treponema pallidum particle agglutination test among patients diagnosed with primary syphilis. Sex. Transm. Dis. 34, 1016–1018 (2007).

  133. 133.

    , , & The VDRL slide test in 322 cases of darkfield positive primary syphilis. South. Med. J. 64, 633–634 (1971).

  134. 134.

    , , & Rapid tests for sexually transmitted infections (STIs): the way forward. Sex. Transm. Infect. 82 (Suppl. 5), 1–6 (2006).

  135. 135.

    et al. Robust pro-inflammatory immune response is associated with serological cure in patients with syphilis: an observational study. Sex. Transm. Infect. 93, 11–14 (2016).

  136. 136.

    & A Manual of Tests for Syphilis: Diagnostic Tests 9th edn (1998).

  137. 137.

    Diagnosis and treatment of syphilis. N. Engl. J. Med. 284, 642–653 (1971).

  138. 138.

    Posttreatment serological response of biologic false-positive reactors. JAMA 247, 817–818 (1982).

  139. 139.

    , & Syphilis detection using the Siemens ADVIA Centaur Syphilis treponemal assay. Clin. Chim. Acta 433, 84–87 (2014).

  140. 140.

    , , & Evaluation of the Bio-Rad BioPlex 2200 syphilis multiplex flow immunoassay for the detection of IgM- and IgG-class antitreponemal antibodies. Clin. Vaccine Immunol. 17, 966–968 (2010).

  141. 141.

    et al. Western immunoblotting with five Treponema pallidum recombinant antigens for serologic diagnosis of syphilis. Clin. Vaccine Immunol. 8, 534–539 (2001).

  142. 142.

    et al. Evaluation of an IgM/IgG sensitive enzyme immunoassay and the utility of index values for the screening of syphilis infection in a high-risk population. Sex. Transm. Dis. 38, 528–532 (2011).

  143. 143.

    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. 60, 133–137 (2011).

  144. 144.

    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. 57, 872–875 (2008).

  145. 145.

    & Diagnostic tools for preventing and managing maternal and congenital syphilis: an overview. Bull. World Health Organ. 82, 439–446 (2004).

  146. 146.

    et al. Field performance of a rapid point-of-care diagnostic test for antenatal syphilis screening in the Amazon region. Int. J. STD AIDS 22, 15–18 (2011).

  147. 147.

    et al. Prospective, multi-centre clinic-based evaluation of four rapid diagnostic tests for syphilis. Sex. Transm. Infect. 82 (Suppl. 5), 13–16 (2006).

  148. 148.

    et al. Point-of-care tests to strengthen health systems and save newborn lives: the case of syphilis. PLoS Med. 9, e1001233 (2012).

  149. 149.

    , , , & Performance of rapid syphilis tests in venous and fingerstick whole blood specimens. Sex. Transm. Dis. 31, 557–560 (2004).

  150. 150.

    et al. Diagnostic accuracy of a point-of-care syphilis test when used among pregnant women in Bolivia. Sex. Transm. Infect. 82 (Suppl. 5), 17–21 (2006).

  151. 151.

    Performance of the rapid plasma reagin and the rapid syphilis screening tests in the diagnosis of syphilis in field conditions in rural Africa. Sex. Transm. Infect. 78, 282–285 (2002).

  152. 152.

    et al. Performance and costs of a rapid syphilis test in an urban population at high risk for sexually transmitted infections. J. Prev. Med. Hyg. 48, 118–122 (2007).

  153. 153.

    , , , & Maternal and congenital syphilis in two Mexican hospitals: evaluation of a rapid diagnostic test [Spanish]. Rev. Invest. Clin. 58, 119–125 (2006).

  154. 154.

    et al. Evaluation of rapid diagnostic tests for the detection of human immunodeficiency virus types 1 and 2, hepatitis B surface antigen, and syphilis in Ho Chi Minh City. Am. J. Trop. Med. Hyg. 62, 301–309 (2000).

  155. 155.

    et al. Safety of benzathine penicillin for preventing congenital syphilis: a systematic review. PLoS ONE 8, e56463 (2013).

  156. 156.

    et al. Novel point-of-care test for simultaneous detection of nontreponemal and treponemal antibodies in patients with syphilis. J. Clin. Microbiol. 48, 4615–4619 (2010).

  157. 157.

    et al. A dual point-of-care test shows good performance in simultaneously detecting nontreponemal and treponemal antibodies in patients with syphilis: a multisite evaluation study in China. Clin. Infect. Dis. 56, 659–665 (2012).

  158. 158.

    et al. An evaluation of a novel dual treponemal/nontreponemal point-of-care test for syphilis as a tool to distinguish active from past treated infection. Clin. Infect. Dis. 61, 184–191 (2015).

  159. 159.

    et al. A systematic review and meta-analysis of studies evaluating the performance and operational characteristics of dual point-of-care tests for HIV and syphilis. Sex. Transm. Infect. (2017).

  160. 160.

    & Management of adult syphilis. Clin. Infect. Dis. 53 (Suppl. 3), 110–128 (2011).

  161. 161.

    et al. UK national guidelines on the management of syphilis 2015. Int. J. STD AIDS 27, 421–446 (2016).

  162. 162.

    et al. The rapid plasma reagin test cannot replace the venereal disease research laboratory test for neurosyphilis diagnosis. Sex. Transm. Dis. 39, 453–457 (2012).

  163. 163.

    , , , & Alternative cerebrospinal fluid tests to diagnose neurosyphilis in HIV-infected individuals. Neurology 63, 85–88 (2004).

  164. 164.

    , , , & Cerebrospinal Fluid Treponema pallidum particle agglutination assay for neurosyphilis diagnosis. J. Clin. Microbiol. 55, 1865–1870 (2017).

  165. 165.

    et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J. Infect. Dis. 189, 369–376 (2004).

  166. 166.

    et al. USPSTF recommendations for STI screening. Am. Fam. Physician 77, 819–824 (2008).

  167. 167.

    , & Transfusion-transmitted syphilis in teaching hospital. Emerg. Infect. Dis. 17, 2080–2082 (2011).

  168. 168.

    Food and Drug Administration. Requirements for blood and blood components intended for transfusion or for further manufacturing use; Federal Register, Rules and Regulations. Government Publishing Office (2015).

  169. 169.

    , & Status of blood safety in the WHO African region: report of the 2010 survey. World Health Organization (2014).

  170. 170.

    , & The elimination of congenital syphilis: a comparison of the proposed World Health Organization action plan for the elimination of congenital syphilis with existing national maternal and congenital syphilis policies. Sex. Transm. Dis. 34, S22–S30 (2007).

  171. 171.

    , , & Effectiveness of interventions to improve screening for syphilis in pregnancy: a systematic review and meta-analysis. Lancet Infect. Dis. 11, 684–691 (2011). This systematic review of 10 studies showed that interventions to improve the coverage and effect of screening programmes for antenatal syphilis could reduce the syphilis-attributable incidence of stillbirth and perinatal death by 50%.

  172. 172.

    , , , & Introduction of rapid syphilis testing in antenatal care: a systematic review of the impact on HIV and syphilis testing uptake and coverage. Int. J. Gynecol. Obstet. 130, S15–S21 (2015).

  173. 173.

    , & Sífilis materna y sífilis congénita en América Latina: un problema grave de solución sencilla [Spanish]. Rev. Panam. Salud Pública 16, 211–217 (2004).

  174. 174.

    Pan American Health Organization. Update 2014: elimination of mother-to-child transmission of HIV and syphilis in the Americas. Pan American Health Organization (2014).

  175. 175.

    , , & Screening for syphilis. JAMA 315, 2328 (2016).

  176. 176.

    & Go big or go home: impact of screening coverage on syphilis infection dynamics. Sex. Transm. Infect. 92, 49–54 (2015).

  177. 177.

    et al. Adolescent patient preferences surrounding partner notification and treatment for sexually transmitted infections. Acad. Emerg. Med. 22, 61–66 (2014).

  178. 178.

    et al. Organizational characteristics of HIV/syphilis testing services for men who have sex with men in South China: a social entrepreneurship analysis and implications for creating sustainable service models. BMC Infect. Dis. (2014).

  179. 179.

    , , & Social Entrepreneurship for Sexual Health (SESH): a new approach for enabling delivery of sexual health services among most-at-risk populations. PLoS Med. 9, e1001266 (2012).

  180. 180.

    & The challenges of preexposure prophylaxis for bacterial sexually transmitted infections. Clin. Microbiol. Infect. 22, 753–756 (2016).

  181. 181.

    et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N. Engl. J. Med. 373, 2237–2246 (2015).

  182. 182.

    NIH Consensus Development Panel on Infectious Disease Testing for Blood Transfusions et al. Infectious disease testing for blood transfusions. JAMA 274, 1374–1379 (1995).

  183. 183.

    , , , & Persons with early syphilis identified through blood or plasma donation screening in the United States. J. Infect. Dis. 185, 545–549 (2002).

  184. 184.

    et al. Amplification of the DNA polymerase I gene of Treponema pallidum from whole blood of persons with syphilis. Diagn. Microbiol. Infect. Dis. 40, 163–166 (2001).

  185. 185.

    , & Transmission of syphilis by fresh blood components. Transfusion 9, 32–34 (1969).

  186. 186.

    et al. A systematic review of syphilis serological treatment outcomes in HIV-infected and HIV-uninfected persons: rethinking the significance of serological non-responsiveness and the serofast state after therapy. BMC Infect. Dis. 15, 479 (2015).

  187. 187.

    et al. Predictors of serological cure and serofast state after treatment in HIV-negative persons with early syphilis. Clin. Infect. Dis. 53, 1092–1099 (2011).

  188. 188.

    et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N. Engl. J. Med. 353, 1236–1244 (2005).

  189. 189.

    et al. A phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis. J. Infect. Dis. 201, 1729–1735 (2010).

  190. 190.

    et al. Macrolide resistance inTreponema pallidum in the United States and Ireland. N. Engl. J. Med. 351, 154–158 (2004).

  191. 191.

    et al. Azithromycin treatment failure among primary and secondary syphilis patients in Shanghai. Sex. Transm. Dis. 37, 726–729 (2010).

  192. 192.

    et al. Azithromycin-resistant syphilis-causing strains in Sydney, Australia: prevalence and risk factors. J. Clin. Microbiol. 52, 2776–2781 (2014).

  193. 193.

    Global challenge of antibiotic-resistant Treponema pallidum. Antimicrob. Agents Chemother. 54, 583–589 (2010).

  194. 194.

    et al. Molecular typing of Treponema pallidum in the Czech Republic during 2011 to 2013: increased prevalence of identified genotypes and of isolates with macrolide resistance. J. Clin. Microbiol. 52, 3693–3700 (2014).

  195. 195.

    et al. Antiretroviral therapy is associated with reduced serologic failure rates for syphilis among HIV-infected patients. Clin. Infect. Dis. 47, 258–265 (2008).

  196. 196.

    et al. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS 22, 1145–1151 (2008).

  197. 197.

    & Emerging trends and persistent challenges in the management of adult syphilis. BMC Infect. Dis. 15, 351 (2015).

  198. 198.

    & Syphilis and HIV infection: an update. Clin. Infect. Dis. 44, 1222–1228 (2007).

  199. 199.

    et al. One dose versus three weekly doses of benzathine penicillin G for patients co-infected with HIV and early syphilis: a multicenter, prospective observational study. PLoS ONE 9, e109667 (2014).

  200. 200.

    et al. A single dose of benzathine penicillin G is as effective as multiple doses of benzathine penicillin G for the treatment of hiv-infected persons with early syphilis. Clin. Infect. Dis. 60, 653–660 (2014).

  201. 201.

    et al. Syphilis in pregnancy in Tanzania. II. The effectiveness of antenatal syphilis screening and single-dose benzathine penicillin treatment for the prevention of adverse pregnancy outcomes. J. Infect. Dis. 186, 948–957 (2002).

  202. 202.

    Is antenatal syphilis screening still cost effective in sub-Saharan Africa. Sex. Transm. Infect. 79, 375–381 (2003).

  203. 203.

    & Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features. Clin. Microbiol. Rev. 12, 187–209 (1999). An excellent review that covered all aspects of syphilis.

  204. 204.

    Centers for Disease Control and Prevention. 2015 Sexually Transmitted Diseases Treatment Guidelines: Syphilis. Centers for Disease Control and Prevention (2015).

  205. 205.

    in Venereal Disease 33–44 (Methuen & Company, Limited 1917).

  206. 206.

    Syphilis — its early history and treatment until penicillin and the debate on its origins. J. Mil. Veterans Health 20, 49–28 (2012).

  207. 207.

    & From mercury to malaria to penicillin: the history of the treatment of syphilis at the Mayo Clinic — 1916–1955. J. Am. Acad. Dermatol. 32, 255–261 (1995).

  208. 208.

    , & Syphilis and cirrhosis: a lethal combination in a XIX century individual identified from the Medical Schools Collection at the University of Coimbra (Portugal). Mem. Inst. Oswaldo Cruz 105, 1050–1053 (2010).

  209. 209.

    The “rade” disease--a Norwegian tragedy [Norwegian]. Tidsskr. Nor. Laegeforen. 24, 3557–3558 (2003).

  210. 210.

    Division of STD Prevention et al. Sexually Transmitted Diseases Surveillance 2015. Centers for Disease Control and Prevention (2015).

  211. 211.

    Two centuries of neurology and psychiatry in the journal. N. Engl. J. Med. 367, 58–65 (2012).

  212. 212.

    et al. Ocular syphilis — eight jurisdictions, United States, 2014–2015. MMWR. Morb. Mortal. Wkly. Rep. 65, 1185–1188 (2016).

  213. 213.

    et al. Clinical features and incidence rates of ocular complications in patients with ocular syphilis. Am. J. Ophthalmol. 159, 334–343.e1 (2015).

  214. 214.

    , & Assessment of quality of life of patients with syphilis. Prakt. Med. Infect. Dis. 7, 1 (2014).

  215. 215.

    , , , & Strategies for partner notification for sexually transmitted infections, including HIV. Cochrane Database Syst. Rev. 3, CD002843 (2013).

  216. 216.

    , , & Disease-induced level of shame in patients with acne, psoriasis and syphilis. Postepy Dermatol. Alergol. 30, 233–236 (2013).

  217. 217.

    & Eliminating mother-to-child transmission of syphilis: the need for more consistent political commitment. J. Publ. Health Emerg. 1, 41 (2016).

  218. 218.

    et al. From grief, guilt pain and stigma to hope and pride — a systematic review and meta-analysis of mixed-method research of the psychosocial impact of stillbirth. BMC Pregnancy Childbirth (2016).

  219. 219.

    et al. Stillbirths: economic and psychosocial consequences. Lancet 387, 604–616 (2016).

  220. 220.

    et al. Stillbirths in sub-Saharan Africa: unspoken grief. Lancet 387, e16–e18 (2016).

  221. 221.

    & A piece of my mind. Beyond folklore. JAMA 288, 2791–2792 (2002).

  222. 222.

    & The endemic treponematoses: not yet eradicated. World Health Stat. Q. 45, 228–237 (1992).

  223. 223.

    et al. Estimating benzathine penicillin need for the treatment of pregnant women diagnosed with syphilis during antenatal care in high-morbidity countries. PLoS ONE 11, e0159483 (2016).

  224. 224.

    & Celebrating the decline in syphilis in pregnancy: a sobering reminder of what's left to do. Lancet. Glob. Health 4, e503–e504 (2016).

  225. 225.

    World Health Organization. Global guidance on criteria and processes for validation: elimination of mother-to-child transmission of HIV and syphilis. >WHO (2014).

  226. 226.

    World Health Organization. WHO information note on the use of dual HIV/Syphilis rapid diagnostic tests (RDT). WHO (2017).

  227. 227.

    , , & Using electronic readers to monitor progress toward elimination of mother-to-child transmission of HIV and syphilis: an opinion piece. Int. J. Gynecol. Obstet. 130, S81–S83 (2015).

  228. 228.

    , , , & Smartphone dongle for simultaneous measurement of hemoglobin concentration and detection of HIV antibodies. Lab Chip 15, 3514–3520 (2015).

  229. 229.

    Diagnostics in a digital age: an opportunity to strengthen health systems and improve health outcomes. Int. Health 7, 384–389 (2015).

  230. 230.

    Syphilis. Lancet 389, 1550–1557 (2017).

  231. 231.

    & Internet-based partner selection and risk for unprotected anal intercourse in sexual encounters among men who have sex with men: a meta-analysis of observational studies. Sex. Transm. Infect. 90, 290–296 (2014).

  232. 232.

    , & Syphilis and HIV: is HAART at the heart of this epidemic? Sex. Transm. Infect. 93, 311–312 (2017).

  233. 233.

    , , , & Point-of-care treponemal tests for neurosyphilis diagnosis. Sex. Transm. Dis. 42, 48–52 (2015).

  234. 234.

    et al. Macrophage migration inhibitory factor as a novel cerebrospinal fluid marker for neurosyphilis among HIV-negative patients. Clin. Chim. Acta 463, 103–108 (2016).

  235. 235.

    , , , & CXCL13 as a cerebrospinal fluid marker for neurosyphilis in HIV-infected patients with syphilis. Sex. Transm. Dis. 37, 283–287 (2010).

  236. 236.

    & Current status of syphilis vaccine development: need, challenges, prospects. Vaccine 32, 1602–1609 (2014). This review described the progress in vaccine development for syphilis and all the challenges that need to be overcome.

  237. 237.

    Immunity in experimental syphilis. VI. Successful vaccination of rabbits with Treponema pallidum, Nichols strain, attenuated by -irradiation. J. Immunol. 110, 1206–1215 (1973).

  238. 238.

    et al. Origin of modern syphilis and emergence of a pandemic Treponema pallidum cluster. Nat. Microbiol. 2, 16245 (2016).

  239. 239.

    et al. Cryo-electron tomography elucidates the molecular architecture of Treponema pallidum, the syphilis spirochete. J. Bacteriol. 191, 7566–7580 (2009).

  240. 240.

    et al. Cellular architecture of Treponema pallidum: novel flagellum, periplasmic cone, and cell envelope as revealed by cryo electron tomography. J. Mol. Biol. 403, 546–561 (2010).

  241. 241.

    , , & Insights into the potential function and membrane organization of the TP0435 (Tp17) lipoprotein fromTreponema pallidum derived from structural and biophysical analyses. Protein Sci. 24, 11–19 (2014).

  242. 242.

    , , & Energy coupling factor-type ABC transporters for vitamin uptake in prokaryotes. Biochemistry 51, 4390–4396 (2012).

  243. 243.

    , , , & Coupling substrate and ion binding to extracellular gate of a sodium-dependent aspartate transporter. Nature 445, 387–393 (2007).

  244. 244.

    , , , & Structural and thermodynamic characterization of the interaction between two periplasmic Treponema pallidum lipoproteins that are components of a TPR-protein-associated TRAP transporter (TPAT). J. Mol. Biol. 420, 70–86 (2012).

  245. 245.

    et al. Structural, bioinformatic, and in vivo analyses of two Treponema pallidum lipoproteins reveal a unique TRAP transporter. J. Mol. Biol. 416, 678–696 (2012).

  246. 246.

    et al. Screening for syphilis with the treponemal immunoassay: analysis of discordant serology results and implications for clinical management. J. Infect. Dis. 204, 1297–1304 (2011).

  247. 247.

    , & Non-treponemal serologic tests: a supplemental, not confirmatory testing approach. Clin. Infect. Dis. 52, 274–275 (2010).

  248. 248.

    , , & Validation of reverse sequence screening for syphilis. J. Clin. Microbiol. 50, 1501 (2012).

  249. 249.

    et al. Analysis of 3 algorithms for syphilis serodiagnosis and implications for clinical management. Clin. Infect. Dis. 58, 1116–1124 (2014).

  250. 250.

    et al. Accelerating worldwide syphilis screening through rapid testing: a systematic review. Lancet Infect. Dis. 10, 381–386 (2010).

  251. 251.

    et al. 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 8, e54695 (2013).

  252. 252.

    World Health Organization. Laboratory diagnosis of sexually transmitted infections, including human immunodeficiency virus. WHO (2013).

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Acknowledgements

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the US Centers for Disease Control and Prevention.

Author information

Affiliations

  1. London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.

    • Rosanna W. Peeling
    •  & David Mabey
  2. Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

    • Mary L. Kamb
  3. National Center for STD Control, Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Dermatology, Nanjing, China.

    • Xiang-Sheng Chen
  4. Department of Medicine, UConn Health, Farmington, Connecticut, USA.

    • Justin D. Radolf
  5. Department of Surveillance, Prevention and Control of STI, HIV/AIDS and Viral Hepatitis, Ministry of Health, Brasília, Brazil.

    • Adele S. Benzaken

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Contributions

Introduction (R.W.P. and D.M.); Epidemiology (D.M. and X.-S.C.); Mechanisms/pathophysiology (J.D.R.); Diagnosis, screening and prevention (R.W.P., M.L.K., X.-S.C. and A.S.B.); Management (D.M.); Quality of life (M.K. and A.S.B.); Outlook (all authors); overview of the Primer (R.W.P.).

Competing interests

J.D.R. receives royalties for licensing of syphilis diagnostics reagents. The other authors declare no competing interests.

Corresponding author

Correspondence to Rosanna W. Peeling.

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https://doi.org/10.1038/nrdp.2017.73