After years of declining incidence in many developed countries, syphilis infection has re-emerged as a major public health problem in the past decade. The secondary stage of syphilis epitomizes the capacity of the infection to present in myriad ways. The skin, lymph glands and mucosal membranes are the most commonly affected tissues.
EcclestonK, CollinsL, HigginsSP. Primary syphilis. Int J STD AIDS2008;19:145–51
2.
StonerBP. Current controversies in the management of adult syphilis. CID2007;44(Suppl. 3):S130–46
3.
ZetolaNM, KlausnerJD. Syphilis and HIV infection: an update. CID2007;44:1222–8
4.
SimmsI, FentonKA, AshtonM, The re-emergence of syphilis in the United Kingdom: the new epidemic phases. Sex Transm Dis2005;32:220–6
5.
Health Protection Agency. Health Protection Report: HIV and Sexually Transmitted Infections. 2008;44:31 Oct
6.
HutchinsonCM, RompaloAM, ReichartCA, HookEWIII. Characteristics of patients with syphilis attending Baltimore STD clinics. Arch Intern Med1991;151:511–16
7.
HutchinsonCM, HookEWIII, ShepherdM, VerleyJ, RompaloAM. Altered clinical presentation of early syphilis in patients with human immunodeficiency virus infection. Ann Intern Med1994;121:94–9
8.
JaffeHW. The laboratory diagnosis of syphilis. New concepts. Ann Intern Med1975;83:846–50
RadolfJD, NorgardMV, SchulzWW. Outer membrane ultrastructure explains the limited antigenicity of virulent Treponema pallidum. Proc Natl Acad Sci USA1989;86:2051–5
11.
RadolfJD. PCR detection of Treponema pallidum. In: PersingDH, SmithTF, TenoverFC, WhiteTJ, eds.Diagnostic Molecular Microbiology. Principles and Applications. Washington, DC: American Society for Microbiology, 1993:224–9
12.
RadolfJD, LukehartSA. Immunology of syphilis. In: RadolfJD, LukehartSA, eds.Pathogenic Treponema: Molecular and Cellular Biology. Norfolk, UK: Caister Academic Press, 2006:285–322
RompaloAM, JoesoefMR, O'DonnellJA, Clinical manifestations of early syphilis by HIV status and gender: results of the syphilis and HIV study. Sex Transm Dis2001;28:158–65
17.
GjestlandT. The Oslo study of untreated patients: an epidemiological investigation of the natural course of syphilitic infection based on a re-study of the Boeck-Bruusgaard material. Acta Derm Venereol1955;35(Suppl. 34):3–368; Annex I–LVI
18.
NorgardMV, ArndtLL, AkinsDR, Activation of human monocytic cells by Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides proceeds via a pathway distinct from that of lipopolysaccharide but involves the transcriptional activator NF-kB. Infect Immun1996;64:3845–52
19.
SellatiTJ, BouisDA, KitchensRL, Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytic cells via a CD14-dependent pathway distinct from that used by lipopolysaccharide. J Immunol1998;160:5455–64
20.
LienE, SellatiTJ, YoshimuraA, Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products. J Biol Chem1999;274:33419–25
21.
WootenRM, MorrisonTB, WeisJH, The role of CD14 in signaling mediated by outer membrane lipoproteins of Borrelia burgdorferi. J Immunol1998;160:5485–92
22.
BrightbillHD, LibratyDH, KrutzikSR, Host defense mechanisms triggered by microbial lipoproteins through Toll-like receptors. Science1999;285:732–6
23.
AlexopoulouL, ThomasV, SchnareM, Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med2002;8:878–84
24.
WootenRM, WeisJJ. Host-pathogen interactions promoting inflammatory Lyme arthritis: use of mouse models for dissection of disease processes. Curr Opin Microbiol2001;4:274–9
25.
SalazarJ, HazlettKRO, RadolfJ. The immune response to infection with Treponema pallidum, the stealth pathogen. Microbes Infect2002;4:1133
26.
Van VoorhisWC, BarrettLK, NasioJM, Lesions of primary and secondary syphilis contain activated cytolytic T cells. Infect Immun1996;64:1048–50
27.
Van VoorhisWC, BarrettLK, KoelleDM, Primary and secondary syphilis lesions contain mRNA for Th1 cytokines. J Infect Dis1996;173:491–5
28.
TramontEC. Treponema pallidum (syphilis). In: MandellGL, BennettJE, DolinR, eds.Principles and Practice of Infectious Diseases. 5th edn.New York: Churchill Livingstone, 2000:24–74
29.
LukehartSA. Immunology and pathogenesis of syphilis. In: QuinnTC, ed.Advances in Host Defense Mechanisms: Sexually Transmitted Diseases. New York: Raven Press, 1992:141
McBroomRL, StylesAR, ChiuMJ, Secondary syphilis in persons infected with and not infected with HIV-1: a comparative immunohistological study. Am J Dermatopathol1999;21:432
32.
JordaanHF. Secondary syphilis: a clinicopathological study. Am J Dermatopathol1988;10:399
33.
BjerkeJR, KroghHK, MatreR. In situ identification of mononuclear cells in cutaneous infiltrates in discoid lupus erythematosus, sarcoidosis and secondary syphilis. Acta Dermatologica Venereologica1981;61:371
34.
EngelkensHJ, ten KateFJ, VuzevskiVD, Primary and secondary syphilis: a histopathological study. Int J Std AIDS1991;2:280–4
35.
SalazarJC, CruzAR, PopeCD, Treponema pallidum elicits innate and adaptive cellular immune responses in skin and blood during secondary syphilis: a flow-cytometric analysis. JID2007;195:879–87
36.
WuL, PaxtonWA, KassamN, CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro. J Exp Med1997;185:1681–91
37.
GeijtenbeekTB, KwonDS, TorensmaR, DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell2000;100:587–97
38.
GeijtenbeekTB, van VlietSJ, van DuijnhovenGC, DC-SIGN, a dendritic cell-specific HIV-1 receptor present in placenta that infects T cells in trans-a review. Placenta2001;22(Suppl. A):S19–23
SchöferH, ImhofM, Thoma-GeberE, Active syphilis in HIV infection: a multicentre retrospective survey. Genitourin Med1996;72:176–81
46.
AmonRB, ColeGW, RussellPS. Pruritic secondary syphilis. Br J Ven Dis1976;52:355
47.
PangalisGA, VassilakopoulosTP, BoussiotisVA, Clinical approach to lymphadenopathy. Semin Oncol1993;20:570–82
48.
LewisDA, YoungH. Syphilis. In: RossJ, IsonC, CarderC, LewisD, MerceyD, YoungH, eds.Sexually Transmitted Infections: UK National Screening and Testing Guidelines. London (UK): British Association for Sexual Health and HIV (BASHH), 2006:33–9
49.
SchaudinnF, HoffmannE. Ueber Spirochätenbefunde im Lymphdrüsensaft Syphilitischer. Deutsch Med Wochenschr1905;31:711–14
50.
LarsenSA, SteinerBM, RudolfAH. Laboratory diagnosis and interpretation of tests for syphilis. Clin Microb Rev1995;8:1–21
51.
OrleKA, GatesCA, MartinDH, Simultaneous PCR detection of Haemophilus ducreyi, Treponema pallidum, and herpes simplex virus types 1 and 2 from genital ulcers. J Clin Microbiol1996;34:49–54
52.
PalmerHM, HigginsSP, HerringAJ, Use of PCR in the diagnosis of early syphilis in the United Kingdom. Sex Transm Infect2003;79:479–83
53.
RodionovaEN, GushchinAE, ShipulinGA, Detection of Treponema pallidum DNA and RNA in clinical material from patients with syphilis at different stages. Zh Mikrobiol Epidemiol Immunobiol2003;3:43–50
54.
Gayet-AgeronA, NinetB, Toutous-TrelluL, Assessment of a real-time PCR test to diagnose syphilis from diverse biological samples. Sex Transm Infect2009;85:264–9
55.
MabeyD, PeelingRW, BallardR, Prospective, multi-centre clinic-based evaluation of four rapid diagnostic tests for syphilis. Sex Transm Infect2006;82(Suppl. V):v13–6
56.
EgglestoneSI, TurnerAJ. Serological diagnosis of syphilis. PHLS Syphilis Serology Working Group. Commun Dis Public Health2000;3:158–62
57.
GeislerWM. The prozone phenomenon in syphilis testing. South Med J2004;97:327–8
58.
SmithG, HolmanRP. The prozone phenomenon with syphilis and HIV-1 co-infection. South Med J2004;97:379–82
59.
GregoryN, SanchezM, BuchnessMR. The spectrum of syphilis in patients with human immunodeficiency virus infection. J Am Acad Dermatol1990;22:1061–7
60.
HicksCB, BensonPM, LuptonGP, Seronegative secondary syphilis in a patient infected with the human immunodeficiency virus (HIV) with Kaposi's sarcoma. A diagnostic dilemma. Ann Intern Med1987;107:492–5
61.
LeverWF. Histopathology of the Skin. 4th edn.Philadelphia: Lippincott, 1967:322
HoangM, HighW, MolbergK. Secondary syphilis: a histologic and immunohistochemical evaluation. J Cutan Pathol2004;31:595–9
64.
BeckettJ, BigbecJ. Immunoperoxidase localisation of Treponema pallidum.Arch Pathol Lab Med1979;103:135–8
65.
PhelpsRG, KnispelJ, TuES, Immunoperoxidase technique for detecting spirochaetes in tissue sections: comparison with other methods. Int J Dermatol2000;39:609–13
LukehartSA, GodornesC, MoliniBJ, Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med2004;351:154–8
68.
MartinIE, GuW, YangY, TsangRSW. Macrolide resistance and molecular types of Treponema pallidum causing primary syphilis in Shanghai, China. CID2009;49:515–21
69.
NandwaniR, FisherM. Clinical standards for the screening and management of acquired syphilis in HIV-positive adults. MSSVD HIV Special Interest Group. Int J STD AIDS2006;17:588–93
70.
VeraJH, ParkesR, GoldmeierD. Current management of syphilis infection. Int J STD AIDS2009;20:810
71.
DowellD, PolgreenPM, BeekmannSE, Dilemmas in the management of syphilis: a survey of infectious diseases experts. CID2009;49:1526–9
72.
MarraCM, MaxwellCL, SmithSL, Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis2004;189:369–76
73.
LiboisA, De WitS, PollB, HIV and syphilis: when to perform a lumbar puncture. Sex Transm Dis2007;34:141–4
74.
CousinsDE, ThngC, RatcliffeL, Prevalence of asymptomatic neurosyphilis in HIV patients after treatment of early syphilis. HIV Medicine2010;11(Suppl. 1):9
75.
KingstonM, FrenchP, GohB, UK National Guidelines on the Management of Syphilis 2008. Int J STD AIDS2008;19:729–40
76.
FrenchP, GombergM, JanierM, SchmidtB, van Voorst VaderP, YoungH. IUSTI: 2008 European Guidelines on the Management of Syphilis. Int J STD AIDS2009;20:300–9
JarischA. Therapeutische versuche bei syphilis. Wiener Medizinische Wochenschrift1895;45:721–4
79.
HerxheimerK, KrauseDW. Ueber eine bei syphilitischen vorkommende quecksilberreaktion. Deutsche Medizinische Wochenshrift1902;28:895–7
80.
RomanowskiB, SutherlandR, FickGH, Serologic response to treatment of infectious syphilis. Ann Intern Med1991;114:1005–9
81.
BrycesonAD, CooperKE, WarrellDA, PerinePL, ParryEH. Studies of the mechanism of the Jarisch-Herxheimer reaction in louse-borne relapsing fever: evidence for the presence of circulating borrelia endotoxin. Clin Sci1972;43:343–54
82.
GelfandJA, ElinRJ, BerryFWJr, FrankMM. Endotoxemia associated with the Jarisch-Herxheimer reaction. New Engl J Med1976;295:211–13
83.
NegussieY, RemickDG, De ForgeLE, KunkelSL, EynonA, GriffinGE. Detection of plasma tumor necrosis factor, interleukins 6, and 8 during the Jarisch-Herxheimer Reaction of relapsing fever. J Exp Med1992;175:1207–12
84.
GriffinGE. Cytokines involved in human septic shock – the model of the Jarisch-Herxheimer reaction. J Antimicrob Chemo1998;41(Suppl. A):25–9
85.
BrownST, ZaidiA, LarsenSA, Serological response to syphilis treatment: a new analysis of old data. JAMA1985;253:1296–9
86.
McMillanA, YoungH. Reactivity in the Venereal Diseases Research Laboratory test and the Mercia® IgM enzyme immunoassay after treatment of early syphilis. Int J STD AIDS2008;19:689–93
87.
SchroeterAL, LucasJB, PriceEV, Treatment for early syphilis and reactivity of serological tests. JAMA1972;221:471–6
88.
FiumaraNJ. Treatment of primary and secondary syphilis: serologic response. J Am Acad Dermatol1986;14:487–91
89.
FiumaraNJ. Reinfection primary and secondary syphilis. The serologic response after treatment. Sex Transm Dis1980;7:111–15
90.
RolfsRT, JoesoefMR, HendershotEF, A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med1997;337:307–14
91.
GhanemKG, ErbeldingEJ, WienerZS, Serological response to syphilis treatment in HIV-positive and HIV-negative patients attending sexually transmitted disease clinics. Sex Transm Infect2007;83:97–101
92.
Gonzalez-LopezJJ, Fernandez GuerreroML, LujanR, Factors determining serologic response to treatment in patients with syphilis. Clin Infect Dis2009;49:1505–11
93.
KingstonMA, HigginsSP. Comparison of the serological response to treatment of early syphilis in HIV positive versus HIV negative individuals. Sex Transm Infect2004;80:152–3
94.
HopkinsS, BerginC, MulcahyF. HIV status does not contribute to response to syphilis treatment. Int J STD AIDS2009;20:593–4
95.
WarwickZ, DeanG, FisherM. Should syphilis be treated differently in HIV-positive and HIV-negative individuals? Treatment outcomes at a university hospital, Brighton, UK. Int J STD AIDS2009;20:229–30
96.
SchoberPC, GabrielG, WhiteP, FeltonWF, ThinRN. How infectious is syphilis?Br J Ven Dis1983;59:217–19
97.
von WerssowetzAJ. The incidence of infection in contacts of early syphilis. J Vener Dis Inform1948;28:132–7
98.
AlexanderLL, SchochAG. Prevention of syphilis. Arch Dermatol Syphilol1949;59:1–10
