research paper about syphilis

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Rosanna W. Peeling

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

David Mabey

Mary l. kamb.

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

Xiang-Sheng Chen

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

Justin David Radolf

4 Department of Medicine, UConn Health, Farmington, Connecticut, USA

Adele Schwartz Benzaken

5 Department of Surveillance, Prevention and Control of STI, HIV/AIDS and Viral Hepatitis, Ministry of Health, Brasília, Brazil

Treponema pallidum subspecies pallidum ( T. pallidum ) causes syphilis via sexual exposure or vertical transmission during pregnancy . T. pallidum is renowned for its invasiveness and immune-evasiveness; its clinical manifestations result from local inflammatory responses to replicating spirochetes and often imitate those of other diseases. The spirochete has a long latent period during which patients 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 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 is needed to ensure that syphilis is given high priority on the global health agenda. More investment in research is needed 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.

Introduction

Syphilis is a sexually and vertically transmitted infection (STI) caused by the spirochaete Treponema pallidum subspecies pallidum (order Spirochaetales) ( Fig. 1 ). Three other organisms within this genus are causes of nonvenereal or endemic treponematoses. T. pallidum subspecies pertenue is the causative agent of yaws, T. pallidum subspecies endemicum causes endemic (non-venereal) syphilis and T. carateum causes pinta. These pathogens are morphologically and antigenically indistinguishable. They can, however, be differentiated by their age of acquisition, principal mode of transmission, clinical manifestations, capacity for invasion of the central nervous system and placenta, and genomic sequences, although the accuracy of these differences remains a subject of debate 1 . Analyses based on the mutation rates of genomic sequences suggest that the causative agents of yaws and venereal syphilis diverged several thousand years ago from a common progenitor originating in Africa 2 . These estimates argue against the so-called Columbian hypothesis — the notion that shipmates of Christopher Columbus imported a newly evolved spirochete causing venereal syphilis from the New World into Western Europe in the late 15 th century 3 .

A | Like all spirochetes, T. pallidum consists of a protoplasmic cylinder and cytoplasmic membrane bounded by a thin peptidoglycan sacculus and outer membrane 239 , 240 . Usually described as spiral-shaped, T. pallidum is actually a thin planar wave similar to Borrelia burgdorferi , the agent of Lyme borreliosis 239 . The bacterium replicates slowly and poorly tolerates desiccation, elevated temperatures and high oxygen tensions 55 . B | Periplasmic flagellar filaments, a defining morphological feature of spirochetes, originate from nanomotors situated at each pole and wind around the cylinder atop the peptidoglycan, overlapping at mid-cell. Force exerted by the rigid filaments against the elastic peptidoglycan deforms the sacculus to create the flat wave morphology of the spirochete 100 . Panel B used with permission from Ref. 239 C | Ultra-thin section of T. pallidum showing the outer and cytoplasmic membranes and flagellar filaments (endoflagella) within the periplasmic space 9 . D | Surface rendering of a flagellar motor based on cryoelectron tomograms. Panel D used permission from Ref. 240 . E | Darkfield micrograph showing the flat-wave morphology of Tpallidum . The arrow and arrowhead indicate segments that are oriented 90° from each other. The different appearances of the helical wave at 90° to the viewer can be explained only by a flat wave morphology; a corkscrew would appear the same from any angle. Panel E used permission from Ref 239 .

T. pallidum is an obligate human pathogen renowned for its invasiveness and immunoevasiveness 4 – 7 ; clinical manifestations result from the local inflammatory response elicited by spirochetes replicating within tissues 8 – 10 . Infected individuals typically follow a disease course divided into primary, secondary, latent and tertiary stages over a period of ≥10 years. Different guidelines define early latency as starting 1–2 years after exposure. Typically, ‘early syphilis’ refers to infections that can be transmitted sexually (including primary, secondary and early latent infections) and is synonymous with active (infectious) syphilis; the WHO defines ‘early syphilis’ as infection of <2 years duration 11 , whereas the guidelines from the United States 12 and Europe 13 define it as infection <1 year in duration. These differences in definition can affect interpretation of results and in therapeutic regimens used in some circumstances.

Owing to its varied and often subtle manifestations that can mimic other infections, syphilis has earned the names of the Great Imitator or Great Mimicker 14 . Patients with primary syphilis present with a single ulcer (chancre) or multiple lesions on the genitals or other body sites involved in sexual contact and regional lymphadenopathy ~3 weeks post-infection; these are typically painless and resolve spontaneously. Resolution of primary lesions is followed 6–8 weeks later by secondary manifestations, which can include fever, headache and a maculopapular rash on the flank, shoulders, arm, chest or back and that often involves the palms of the hands and soles of the feet. As signs and symptoms subside, patients enter a latent phase, which can last many years. A patient in the first 1–2 years of latency are still considered infectious owing to a 25% risk of secondary syphilis-like relapses 15 . Historical literature suggests that 15–40% of untreated individuals will develop tertiary syphilis, which can manifest as destructive cardiac or neurological conditions, severe skin or visceral lesions (gummas) or bony involvement 9 . More-recent data suggest tertiary syphilis may be less common today, perhaps owing to wide use of antibiotics. Numerous case reports and small series suggest that HIV infection predisposes to neuro-ophthalmological complications in those with syphilis 16 . Importantly, neurosyphilis is typically described as a late manifestation but can occur in early syphilis. Indeed, T. pallidum can be frequently identified in the cerebral spinal fluid (CSF) of patients with early disease 9 , 15 , 17 . However, the majority of patients with early syphilis who have CSF abnormalities do not demonstrate central nervous system symptoms and do not require therapy for neurosyphilis 12 . Symptomatic manifestations of neurosyphilis include chronic meningitis, meningovascular stroke-like syndromes and manifestations common in the neurological forms of tertiary syphilis (namely, tabes dorsalis and general paresis, a progressive dementia mimicking a variety of psychotic syndromes) 9 .

Sexual transmission of syphilis occurs during the first 1–2 years after exposure (that is, during primary, secondary and early latent stages of infection) 9 . The risk of mother-to-child transmission (MTCT) is highest in primary and secondary stages, followed by early latent syphilis. However, transmission risk continues during the first 4 years after exposure, after which vertical transmission risk declines over time 18 . The rate of fetal infection depends on stage of maternal infection, with approximately 30% of pregnancies resulting in fetal death in utero , stillbirth (late second and third trimester fetal death) or death shortly after delivery 19 – 21 . Infants born to infected mothers are often preterm, of low birth weight or with clinical signs that mimic neonatal sepsis (that is, poor feeding, lethargy, rash, jaundice, hepatosplenomegaly and anaemia).

Given that T. pallidum has a relatively long generation time of 30–33 hours 22 , long-acting penicillin preparations such as benzathine penicillin G is the preferred therapy for most patients with syphilis. Since the 1940s (when penicillin became widely available), syphilis prevalence continued decline in regions able to appropriately test and treat the infection. However, syphilis outbreaks continue to occur throughout the world. In particular, with declining AIDS-related mortality related to effective HIV treatment over the past two decades, syphilis has re-emerged in urban settings among men who have sex with men (MSM). High-income and middle-income countries have observed rises in syphilis case rates as well as increased case rates of neurosyphilis (such as ocular syphilis) and, in some countries, congenital syphilis. In low income countries where syphilis prevalence remains high, MTCT of syphilis continues to be the most common cause of STI-related mortality outside of HIV 23 , 24 , with perinatal deaths owing to untreated syphilis exceeding those of HIV or malaria 25 . Syphilis is now the second leading cause of preventable stillbirths worldwide, following malaria 25 .

Syphilis should be an ideal disease for elimination as it has no known animal reservoir, can usually be diagnosed with simple inexpensive tests and can be cured 9 , 16 . Nevertheless, syphilis remains a continuing public health challenge globally 26 . In this Primer, we describe recent discoveries that have improved our understanding of the biological and genetic structure of the pathogen, novel diagnostic tests and testing approaches that can improve disease detection, as well as current, evidence-based management recommendations. We also draw attention to the call for global elimination of MTCT of syphilis and HIV and recent success in elimination in in low and middle income countries (LMICs), particularly through fundamental public health strategies such as ensuring quality antenatal care that includes testing for syphilis early in pregnancy and providing prompt treatment of women and their partners. We also report on the rising numbers of syphilis cases in MSM, ongoing work supporting improved interventions against syphilis in marginalized populations and, ultimately, development of an effective vaccine.

Epidemiology

According to the most recent estimation of the WHO, approximately 17.7 million individuals 15–49 years of age globally had syphilis in 2012, with an estimated 5.6 million new cases every year 27 ( Fig. 2 ). The estimated prevalence and incidence of syphilis varied substantially by region or country, with the highest prevalence in Africa and >60% of new cases occurring in LMICs 27 . The greatest burden of maternal syphilis occurs in Africa, representing >60% of the global estimate 23 , 24 .

The WHO estimates of incident cases of syphilis by region in 2012 are shown for the different geographical regions. Data from Ref. 27

Prevalence and incidence

In LMICs, heterosexual spread of syphilis has declined in the general population but remains problematic in some high-risk sub-populations, such as female sex workers (FSWs) and their male clients. A recent study of FSWs in Johannesburg, South Africa, showed that 21% of participating women had antibodies that suggested past or current infection and 3% had active (infectious) infection 28 . Another study of FSWs in 14 zones in Sudan showed high seroprevalence (median 4.1%), with the highest value of 8.9% in the eastern zone of the country 29 . A large study of >1,000 FSWs in Kampala, Uganda, showed 21% were seropositive for syphilis and 10% had active infection 30 . Studies in emerging economies, such as China, indicate that syphilis is increasing among ‘mobile men with money’ 31 . Although syphilis case rates are low in the general population in China, syphilis prevalence is ~5% among FSWs and 3% among their male clients 31 , 32 . Risk of infection varies among FSWs working in different venues, with the highest prevalence (~10%) among street-based FSWs and lower prevalence (~2%) among venue-based FSWs 33 .

By contrast, higher-income countries have had declining syphilis prevalence among heterosexual men and women. However, a resurgence of syphilis that disproportionately affects MSM has been noted. Syphilis is associated with high-risk sexual behaviours and substantially increased HIV transmission and acquisition. Indeed, the numbers and rates of reported cases of syphilis among MSM in the United States and Western Europe have been increasing since 1998 (Ref. 34 ). In 2015, the case rates for primary and secondary syphilis among MSM (309 per 100,000) in the United States were 221-times the rate for women (1.4 per 100,000) and 106 times the rate for heterosexual men (2.9 per 100,000) 35 . In Canada, compared with reported cases in the general male population, the incidence of syphilis was >300-times greater among HIV-positive MSM 36 . Syphilis infection has been associated with certain behavioural and other factors, including incarceration; multiple or anonymous sex partners; sexual activity connected with illicit drug use; seeking sex partners through the internet and other high-risk sexual network dynamics 37 – 41 . Risk factors for syphilis are frequently overlapping 40 . Reports of unusual presentations and rapid progression of syphilis in patients with concurrent HIV infection has led to the hypothesis that infection with or treatment for HIV alters the natural history of syphilis 42 .

Adverse birth outcomes caused by fetal exposure to syphilis are preventable if women are screened for syphilis and treated before the end of the second trimester of pregnancy 21 . However, MTCT of syphilis continued to cause such perinatal and infant mortality that, in 2007, the WHO and partners launched a global initiative to eliminate it as a public health problem 43 – 45 . At the time of the campaign launch, an estimated 1.4 million pregnant women had active syphilis infections, of whom 80% had attended at least one antenatal visit — suggesting missed opportunities for testing and treatment 23 . At that time, untreated maternal syphilis infection was estimated to have resulted in >500,000 adverse pregnancy outcomes, including more than 300,000 perinatal deaths (stillbirths and early neonatal deaths).

Syphilis testing and treatment during pregnancy is highly effective and was included in the Lives Saved Tools of effective maternal–child health interventions 46 . Furthermore, studies have shown that prenatal syphilis screening, treatment support testing and treatment during pregnancy are highly cost-effective in most countries regardless of prevalence or availability of resources, and can even be cost-saving in LMICs with syphilis prevalence ≥3% in pregnant women 47 – 50 . In China, where syphilis and HIV prevalence in pregnant women is low but rising, integration of prenatal syphilis and HIV screening was found to be highly cost-effective 51 .

Since 2007, an increasing number of countries have implemented regional and national initiatives to prevent MTCT of syphilis 52 , improving guidance documents, using point-of-care (POC) tests as a means of improving access to testing and treatment and integrating behavioural and medical interventions into HIV prevention and control programmes 53 . By 2012, these efforts had contributed to a reduction in global adverse pregnancy outcomes due to MTCT of syphilis to 350,000, including 210,000 perinatal deaths, and decreased the rates of maternal and congenital syphilis decreased by 38% and 39%, respectively 23 , 24 . In 2015, Cuba became the first country to be validated for having achieved elimination of MTCT of HIV and syphilis 54 . Subsequently, Thailand, Belarus and four United Kingdom Overseas Territories (Bermuda, the Cayman Islands, Montserrat and Antigua) was validated for elimination of MTCT of HIV and syphilis, Moldova was validated for elimination of MTCT of syphilis, and Armenia was validated for elimination of MTCT of HIV. However, these gains were mostly in Asia and the Americas — maternal prevalence in Africa has remained largely unchanged 23 , 24 .

Mechanisms/pathophysiology

Although a local inflammatory response elicited by spirochetes is thought to be the root cause of all clinical manifestations of syphilis 9 , the mechanisms that cause tissue damage, as well as the host defences that eventually gain a measure of control over the bacterium, are ill defined. The recalcitrance of T. pallidum to in vitro culture and the consequent inability to harness genetic techniques to delineate its virulence determinants remains the primary obstacle to progress 55 . Additionally, the fragility and low protein content of its outer membrane have confounded efforts to characterize surface-exposed molecules 56 , 57 . Finally, facile murine models to dissect the host response and the components of protective immunity are also lacking 58 . Outbred rabbits are essential for isolating T. pallidum strains from clinical specimens 59 and routine propagation in the laboratory 60 . Because rabbits are highly susceptible to T. pallidum infection, develop lesions grossly and histopathologically resembling chancres following intradermal inoculation and generate antibody responses similar to those in humans, the rabbit is the model of choice for studying endogenous and exogenous protective immunity 61 , 62 . However, the rabbit model poorly recapitulates many clinical and immunological facets of human disease 63 . Not surprisingly, even in the post-genomics era, our understanding of pathogenic mechanisms in syphilis lags well behind other common bacterial diseases 63 .

Molecular Features

The morphological features of T. pallidum are described in Figure 1 . Because of its double-membrane structure, the spirochete is often described as a Gram-negative bacterium. However, this analogy is phylogenetically, biochemically and ultrastructurally inaccurate 63 , 64 . The T. pallidum outer membrane lacks lipopolysaccharide 65 and has a markedly different phospholipid composition than the outer membranes of typical Gram-negative bacteria 66 . Although T. pallidum expresses abundant lipoproteins, these molecules reside predominantly below the surface 5 , 63 , 67 . Accordingly, this paucity of surface-exposed pathogen-associated molecular patterns (PAMPs) enables the spirochete to avoid triggering host innate surveillance mechanisms, facilitating local replication and early dissemination. Its limited surface antigenicity promotes evasion of adaptive immune responses (that is, antibodies), facilitating persistence 5 , 56 , 68 , 69 . Collectively, these attributes have earned T. pallidum its designation as ‘the stealth pathogen’ 63 , 69 . Understanding events unfolding at the host–pathogen interface requires a detailed knowledge of the T. pallidum repertoire of surface-exposed proteins. However, characterization of the protein constituents of the outer membrane has been, and continues to be, daunting 8 , 55 , 57 , 63 .

Lipoproteins

In the 1980s, investigators screened E. coli recombinant libraries with syphilitic sera and murine monoclonal antibodies based upon the unproven (and, as it turned out, immunologically incorrect) assumption that immunoreactive proteins ought to be surface-exposed in T. pallidum 57 . Biochemical and genetic analyses subsequently revealed that most of the antigens identified by these screens are lipoproteins 70 – 72 tethered by their N-terminal lipids to the cytoplasmic membrane (hence, the protein moieties are in the periplasmic space) 67 , 73 – 75 . However, convincing evidence now shows that the spirochete displays small amounts of lipoproteins on its surface that have the potential to enhance infectivity ( Fig. 3 ). For example, TP0751 (also known as pallilysin) is a laminin-binding lipoprotein and zinc-dependent metalloproteinase capable of degrading clots and extracellular matrix 76 – 78 . Although expressed by T. pallidum in minute quantities, surface exposure of TP0751 has been demonstrated by knock-in experiments in Borrelia burgdorferi (the spirochete that causes Lyme borreliosis 79 ), and the cultivatable commensal treponeme T. phagedenis 80 , opsonophagocytosis assays in T. pallidum 77 and, most recently, protection of immunized rabbits against dissemination of spirochetes following intradermal challenge 81 . The X-ray structure of TP0751, demonstrating an unusual lipocalin fold, should inform efforts to clarify its multi-functionality 79 . Additionally, the lipoprotein Tpp17 (also known as TP0435) has been shown to be at least partially surface-exposed and can function as a cytadhesin 82 . The structurally characterized lipoprotein TP0453 attaches to the inner leaflet of the outer membrane via its N-terminal lipids and two amphipathic helices within its protein moiety 83 .

Shown in the outer membrane are TP0751 (as known as pallilysin) 79 , 81 and Tpp17 (also known as TP0435) 82 , 241 — two surface-exposed lipoproteins; TP0453, a lipoprotein attached to the inner leaflet of the outer membrane 83 ; BamA (also known as TP0326) 84 , 94 ; a full-length T. pallidum repeat (Tpr) attached by its N-terminal portion to the peptidoglycan 93 , 94 ; and a generic β-barrel that represents other non-Tpr outer-membrane proteins identified by computational mining of the T. pallidum genome 112 . Substrates and nutrients present in high concentration in the extracellular milieu (such as, glucose) traverse the outer membrane through porins, such as TprC. At the cytoplasmic membrane, prototypic ABC-like transporters (such as RfuABCD, a riboflavin transporter) use a periplasmic substrate-binding protein (SBP), usually lipoproteins, and components with transmembrane and ATP-binding domains to bind nutrients that have traversed the outer membrane for transport across the cytoplasmic membrane. The energy coupling factor (ECF)-type ABC transporters use a transmembrane ligand-binding protein in place of a separate periplasmic SBP for binding of ligands (BioMNY is thought to transport biotin) 242 . Symporter permeases (for example, TP0265) use the chemiosmotic or electrochemical gradient across the cytoplasmic membrane to drive substrate transport 243 . The tripartite ATP-independent periplasmic (TRAP)-type transporters also use transmembrane electrochemical gradients to drive substrate transport; the periplasmic component protein TatT (also known as TP0956) likely associates with the SBP TatP (also known as TP0957) that binds ligands (perhaps hydrophobic molecules, such as long chain fatty acids), uptake of which is probably is facilitated by the permease TatQ-M (also known as TP0958) 244 , 245 . Figure adapted from Ref. 63 with permission.

With the publication of the T. pallidum genome in 1998 (Ref. 65 ), only one protein with sequence relatedness to an outer membrane protein of Gram-negative bacteria was identified: TP0326 (also known as β-barrel assembly machinery A; BamA) 84 , 85 . BamA has a dual domain architecture consisting of a 16-stranded, outer membrane-inserted, C-terminal β-barrel and five tandem polypeptide transport-associated (POTRA) repeats within the periplasm 84 , 85 . The opening of the channel is covered by a ‘dome’ comprising three extracellular loops, one of which contains an opsonic target that is sequence variable among T. pallidum strains 85 . BamA is the essential central component of the molecular machine that catalyses insertion of newly exported outer membrane proteins to the outer membrane 86 .

Tpr proteins

The T. pallidum repeat (Tpr) proteins, a 12-member paralogous family with sequence homology to the major outer sheath protein of the oral commensal T. denticola, were also identified by the T. pallidum genomic sequence 65 . Of these, TprK (TP0897) has received the greatest attention because of its presumed role in immune evasion by the spirochete 87 , 88 ; it has been shown to undergo antigenic variation in seven regions believed to be extracellular loops harbouring B-cell epitopes 89 – 92 . DNA sequence cassettes that correspond to V-region sequences in an area of the T. pallidum chromosome located away from the tprK gene have been proposed to serve as unidirectional donor sites for the generation of variable regions by nonreciprocal gene conversion 89 . Two other Tpr proteins, TprC and TprI, have met stringent experimental criteria for rare outer membrane proteins. They form trimeric β-barrels when refolded in vitro , cause large increases in permeability upon insertion into liposomes and are surface-exposed opsonic targets in T. pallidum 93 , 94 . Unlike classic porins, for which the entire polypeptide forms a β-barrel, TprC and TprI are bipartite. As with BamA, the C-terminal domain forms the surface-exposed β-barrel, whereas the N-terminal half anchors the barrel to the peptidoglycan sacculus. These results collectively imply that Tprs serve as functional orthologs of Gram-negative porins, using variations in substrate specificities of their channel-forming β-barrels, probably along with differential expression, to import the spirochete’s nutritional requirements into the periplasmic space from blood and body fluids 95 , 96 . These proteins also furnish a topological template for efforts to understand how antibody responses to Tprs promote bacterial clearance.

Biosynthetic machinery

T. pallidum has evolved to dispense with a vast amount of the biosynthetic machinery found in other bacterial pathogens 55 , 63 – 65 . To compensate for its loss of biosynthetic capacity, the spirochete maintains a complex assortment of ABC transporters and symporters (totalling ~5% of its 1.14 MB circular genome) to transfer the broad spectrum of molecules essential for viability from periplasm to cytosol ( Fig. 3 ). T. pallidum relies on an optimized conventional glycolytic pathway as its primary means for generating ATP. By dispensing with oxidative phosphorylation, the spirochete has no need for cytochromes and the iron required to synthesize them. Accordingly, the spirochete maintains a complex, yet parsimonious, assortment of ABC transporters and symporters (totalling ~5% of its 1.14 MB circular genome) to transfer essential molecules from the periplasmic space to the cytosol ( Fig. 3 ). Whereas many pathogens have highly redundant systems for uptake of transition metals across the cytoplasmic membrane, T. pallidum accomplishes this task with just two ABC transporters (Tro, which imports zinc, manganese and iron, and Znu, which is zinc-specific). A small, but powerful arsenal of enzymes neutralize superoxides and peroxides to fend off host responses to infection. Lastly, the spirochete possesses novel and surprisingly intricate mechanisms ostensibly to redirect transcription and fine-tune metabolism in response to environmental cues and nutrient flux 63 .

Transmission and dissemination

Transmission of venereal syphilis occurs during sexual contact with an actively infected partner; exudate containing as few as 10 organisms can transmit disease 8 , 68 . Spirochetes directly penetrate mucous membranes or enter through abrasions in skin, which is less heavily keratinized in peri-genital and peri-anal areas than skin elsewhere 8 , 68 . To establish infection, T. pallidum must adhere to epithelial cells and extracellular matrix components; in vitro binding studies suggest that fibronectin and laminin are key substrates for these interaction 76 , 97 – 99 . Once below the epithelium, organisms multiply locally and begin to disseminate through the lymphatics and bloodstream. Spirochetes penetrate extracellular matrix and intercellular junctions by ‘stop and go’ movements that coordinate adherence with motility, powered by front-to-back undulating waves generated by flagellar rotation and presumably assisted by the proteolytic activity of TP0751 77 , 100 . Ex vivo studies using cultured human umbilical vein endothelial cells ( Fig. 4A ) suggest that spirochetes invade tissues using direct motility to negotiate their way through intercellular junctions, so-called inter-junctional penetration 7 , 101 . The infection rapidly becomes systemic 9 , 16 , 100 . Profuse spirochetes within the epidermis and superficial dermis in secondary syphilitic lesions ( Fig. 4B ) enable tiny abrasions created during sexual activity to transmit infection 10 , 102 . Penetration of the blood–brain barrier, occurring in as many as 40% of individuals with untreated early syphilis, can cause devastating neurological complications 9 , 16 .

A | Transmission electron micrograph of T. pallidum (arrowheads) penetrating the junctions between cultured umbilical vein endothelial cells. ‘Inter-junctional invasion’ following attachment to vascular endothelium is thought to provide T. pallidum access to tissue parenchyma during haematogenous dissemination. Reprinted with permission from Reference 101 . B | Immunohistochemical staining (using commercial anti- T. pallidum antibodies) of a secondary syphilis skin lesion reveals abundant spirochetes embedded within a mixed cellular inflammatory infiltrate in the papillary dermis. The inflammatory response elicited by spirochetes replicating in tissues is widely thought to be the cause of clinical manifestations in all stages of syphilis. Reprinted with permission from 10 . C | Human syphilitic serum (HSS) dramatically enhances opsonophagocytosis of T. pallidum by purified human peripheral blood monocytes compared with D | normal human serum (NHS). Arrowheads indicate treponemes being degraded within phagolysosomes.

Adaptive immune response and inflammation

Although the paucity of PAMPs in the T. pallidum outer membrane enables the bacterium to replicate locally and undergo repeated bouts of dissemination, pathogen sensing in the host is eventually triggered. The organisms are taken up by dendritic cells 103 , which then traffic to draining lymph nodes to present cognate treponemal antigens to naive B cells and T cells. The production of opsonic antibodies markedly enhances the uptake and degradation of spirochetes by phagocytes ( Fig. 4C,D ), liberating lipopeptides and other PAMPs for binding to Toll-like receptors lining the interior of the phagosome and antigenic peptides for presentation to locally recruited T cells 62 , 104 , 105 . Activated lesional T cells secrete IFN-γ, promoting clearance by macrophages, but also bolstering the production of tissue-damaging cytokines, such as tumor necrosis factor (TNF) and IL-6 10 , 106 , 107 . Immunohistochemical analysis has identified CD4+ and CD8+ T cells 10 , 106 , 108 , 109 , natural killer cells 10 and activated macrophages in early syphilis lesions 10 , 109 . Perivascular infiltration of lymphocytes, histiocytes (phagocytic cells in connective tissues) and plasma cells with endothelial cell swelling and proliferation are characteristic histopathological findings in all stages of syphilis and can progress to frank endarteritis obliterans (leading to occlusion of arteries and severe clinical manifestations, such as the stroke syndromes of meningovascular syphilis) 9 , 110 .

Antibody avoidance

T. pallidum is widely regarded as an extracellular bacterium 61 . Thus, a question of paramount importance is why, unlike ‘classic’ extracellular pathogens, syphilis spirochetes not only fail to be cleared rapidly but can replicate and circulate in the midst of a prolific antibody response 8 , 68 , 69 . Immunolabelling, opsonophagocytosis, and complement-dependent neutralization assays have shown that T. pallidum populations consist of antibody-binding and non-binding subpopulations; the minority of organisms that bind antibodies do so in minute amounts and with delayed kinetics 10 , 111 – 114 . Accordingly, one can envision a scenario whereby nonbinders replenish the spirochetes that bind and are cleared 63 .

Understanding the basis for the heterogeneity of T. pallidum ’s surface antigenicity is critical to unravelling its strategy for antibody avoidance. The picture emerging from our evolving concepts of the spirochete’s molecular architecture is multi-factorial and likely involves copious production of antibodies against subsurface lipoprotein ‘decoys’ 57 , 110 ; poor target availability owing to low copy numbers of outer membrane proteins and surface-exposed lipoproteins 67 , 77 , 82 , 84 , 93 ; in the case of bipartite outer membrane proteins, limited production of antibodies against surface-exposed epitopes along with skewed production of antibodies against periplasmic domain 84 , 93 ; organism-to-organism variation in the levels of expression of outer membrane proteins and outer surface lipoproteins through a variety of mechanisms, including phase variation 82 , 92 , 115 , 116 ; and, in the case of TprK, antigenic variation as a result of intra-genomic recombination 89 , 92 , 117 . Additionally, the ability of motile spirochetes to ‘outrun’ infiltrating phagocytes and reach sequestered locations, including the epidermis, could be an under-appreciated aspect of immune evasion 10 , 102 . As infection proceeds, the antibody repertoire possibly broadens and intensifies to the point where the antigen-poor surface of the spirochete is overwhelmed and its capacity for antigenic variation is exhausted, ushering in the asymptomatic period called latency. Once in the latent state, the organism can survive for years in untreated individuals, establishing niduses of inflammation in skin, bones, the thoracic aorta, the posterior uveal tract and the central nervous system, that set the stage for recrudescent disease — collectively referred to as tertiary syphilis. How immune containment mechanisms decline and enable the balance to shift back in favour of the pathogen in tertiary syphilis is inclear 9 , although a hyper-intense cellular response to the spirochete is generally believed to be the cause of the highly destructive lesions of tertiary syphilis 9 . Numerous case reports and small series suggest that HIV infection predisposes to neuro-ophthalmological complications in those with syphilis 16 . Cardiovascular syphilis, typically involving the aortic arch and leading to aneurysmal dilatation, usually occurs 10–30 years after the initial infection 9 .

Congenital infection

Although MTCT of syphilis can occur at the time of delivery, the overwhelming majority of cases are caused by to in utero transmission. Studies have shown spirochetes in placenta and umbilical cord samples, supporting transplacental passage of the organism to the fetus, as early as 9–10 weeks of gestation 118 . Although fetal syphilis infection was not thought to occur prior to the second trimester, the fetus can indeed be infected very early in pregnancy but may be unable to mount a characteristic immune response until development of the embryonic immune system at 18–20 weeks gestation.

Transmission risk is directly related to stage of syphilis in the pregnant woman (that is, the extent and duration of fetal exposure to spirochetes). Small case series have found highest MTCT risk in primary and secondary stages, during which transmission probability may be ≥80%. In latent (asymptomatic) infections during pregnancy, probability of transmission to the fetus is highest during the first 4 years after infection, after which risk declines 18 , 45 . Systematic reviews assessing women with predominantly asymptomatic infections are consistent in showing that delayed or lack of adequate treatment results in stillbirth, early neonatal death, prematurity, low birth weight or congenital infection in infants (more than half of syphilis-exposed pregnancies); syphilitic stillbirth was the most commonly observed adverse outcomes in syphilis-exposed pregnancies 21 , 45 , 119 .

Diagnosis, screening and prevention

Syphilis has varied and often subtle manifestations that make clinical diagnosis difficult and lead to many infections being unrecognized. The classically painless lesions of primary syphilis can be missed, especially in hidden sites of exposure such as the cervix or rectum. The rash ( Fig. 5 ) and other symptoms of secondary syphilis can be faint or mistaken for other conditions. A syphilis diagnosis is often based on a suggestive clinical history and supportive laboratory 9 , 16 (that is, serodiagnostic) tests. Serological testing has become the most common means to diagnose syphilis whether in people with symptoms of syphilis, or in those who have no symptoms but are detected through screening. A limitation of all syphilis serological tests is their inability to distinguish between infection with T. pallidum subsp. pallidum and the non-venereal T. pallidum subspecies that cause yaws, pinta or bejel.

A | Primary chancre. B | Primary chancre with rash of secondary syphilis. C | Secondary syphilis in a pregnant woman, who has palmar rash. D | Secondary syphilis as palmar rash. E | 3-month old baby with congenital syphilis, showing hepatosplenomegaly and desquamating rash. The child also presented with nasal discharge. F | Typical palmar desquamating rash in baby with congenital syphilis.

Ensuring accuracy and reliability of syphilis testing is important, especially in nonspecialized laboratories where most patients are tested 120 . Syphilis-specific quality assurance strategies include training of technologists on specific techniques, internal quality control systems; test evaluation; and interassay standardization of commercially available test kits on a regular basis 37 , 120 . It is especially important to provide adequate training and regular external quality assessment or proficiency testing with corrective action to ensure the quality of tests and testing for health care providers who perform rapid tests in clinic based or outreach settings 121 – 124 . Because many parts of the world lack laboratory capacity for accurate diagnosis, the requirement for laboratory testing has greatly constrained syphilis control and congenital syphilis elimination. However, development of inexpensive rapid tests that can be performed at the POC has greatly increased access to prenatal screening and diagnosis, even in low-resourced and remote settings.

Definitive diagnosis by direct detection

The choice of method for diagnosing syphilis depends on the stage of disease and the clinical presentation 125 . In patients presenting with primary syphilitic ulcers, condyloma lata (genital lesions of secondary syphilis) or lesions of congenital syphilis, direct detection methods — which include darkfield microscopy, fluorescent antibody staining, immunohistochemistry and PCR — may be used to make a microbiological diagnosis. However, with the exception of PCR, these methods are insensitive and require fresh lesions from which swab or biopsy material can be collected as well as well-experienced technologists ( Table 1 ).

Direct detection methods for Treponema pallidum

Microscopy had been used for direct detection and diagnosis since 1920, but is now used infrequently. A 2014 survey of national reference and large clinical laboratories in Latin America and the Caribbean found that only two of 69 participating facilities, of which half were reference laboratories, still performed darkfield or direct fluorescent antibody staining for T. pallidum (DFA-TP) 126 . The most recent European guidelines recommended against DFA-TP testing in clinical settings, and the reagents are no longer available 13 . PCR techniques are increasingly used; however, there is as yet no commercially available or internationally approved test for T. pallidum 13 . Species-specific and subspecies-specific T. pallidum PCR testing is a developing technology that is still primarily available in research laboratories 127 , 128 , although these tests are anticipated to be more widely available in the near future. A systematic review and meta-analysis concluded that T. pallidum PCR was more efficient for confirmation than to exclude syphilis diagnosis in lesions 129 . Recent research indicates that this technology may be helpful for the diagnosis of neurosyphilis by the detection of T. pallidum DNA in the cerebrospinal fluid (CSF) of patients with syphilis, particularly among HIV-infected individuals 130 , 131 .

Diagnosis using serology

Serodiagnostic tests are the only means for screening asymptomatic individuals and are the most commonly used methods to diagnose patients presenting with signs and symptoms suggestive of syphilis. Serodiagnostic tests for syphilis can be broadly categorized into non-treponemal tests (NTTs) and treponemal tests (TTs).

NTTs measure immunoglobulins (IgM and IgG) produced in response to lipoidal material released from the bacterium and/or dying host cells. The most commonly used NTTs — the Rapid Plasma Reagin (RPR) test, the Toluidine Red Unheated Serum Test (TRUST) and the Venereal Disease Research Laboratory (VDRL) test — are flocculation (precipitation) tests that detect antibodies to a suspension of lecithin (including phosphatidylcholine and phosphatidylethanolamine), cholesterol and cardiolipin. NTTs are useful in detecting active syphilis. However, because they do not become positive until 10–15 days after onset of the primary lesion, 25–30% of primary syphilis cases may be missed ( Fig. 6 ) 132 , 133 . Although relatively simple and inexpensive, NTTs must be performed manually on serum, and rely on subjective interpretation ( Table 2 ). These tests also require trained laboratory personnel and specialized reagents and equipment and, therefore, do not fulfil the ASSURED (Affordable, Sensitive, Specific, User-friendly, Rapid and robust, equipment-free and Deliverable to those who need them) criteria for tests that can be used at the point of care 134 .

Diagnosis of syphilis can be made by measuring a patient’s serological response to infection. IgM antibodies against Treponema pallidum proteins are the first to appear, followed a few weeks later by IgG antibodies. Both IgM and IgG antibodies can be measured using treponemal tests such as the T. pallidum Haemagglutination Assay (TPHA), T. pallidum Particle Assay (TPPA), Fluorescent Treponemal Antibody Absorption assay (FTA-ABS), enzyme immunoassays (EIA) and Chemilluminescent immunoassays (CIA). IgM and IgG antibodies against proteins that are not specific to T. pallidum (non-treponemal antibodies) can be detected using the Rapid Plasma Reagin (RPR), Venereal Disease Research Laboratory (VDRL) or toluidine red unheated serum (TRUST) tests and usually appear 2–3 week after treponemal antibodies. With effective treatment (which is arbitrarily shown here at 6 months), the non-treponemal antibody levels decline whereas the treponemal antibodies remain high for many years. In ~20% of patients, non-trepnemal antibodies persist 6 months after treatment; these individuals are labelled as having a serofast status. Despite repeated treatment, ~11% of patients remain serofast 187 . Here, we show early syphilis (including primary, secondary and early latent infections; infectious syphilis) and late syphilis (including late latent and tertiary infections) as being ≤1 year in duration and >1 year in duration, respectively, in line with US and European guidelines. However, the WHO guidelines place this demarcation at 2 years. Beyond primary and secondary syphilis, the pattern of serological response over time is less well defined and is accordingly not shown.

Serological tests for Treponema pallidum

The data on sensitivity and specificity of each test with respect to disease stage are reported in the WHO Manual on Laboratory Diagnosis of Sexually Transmitted Infections, including HIV 252 .

Without treatment, titres peak at 1–2 years after infection and remain positive even in late disease (usually at a low titre). After treatment, titres generally decline and in most immunocompetent individuals become nonreactive within 6 months. However, up to 20% of syphilis-infected individuals have a persistently reactive (albeit low-titre) NTT even after treatment, possibly related to a less robust pro-inflammatory immune response 135 . These patients are labelled as having a serofast status and are observed more commonly with treatment for late latent than early syphilis 37 , 136 . Biologic false positive results can occur in ~2–5% of the population, regardless of the NTT test used— although the proportion is difficult to estimate with certainty because it is influenced by the population studied 137 . These low-titre reactions might be of limited duration if related to acute factors (such as febrile illness, immunization or pregnancy) or longer duration if related to chronic conditions (such as autoimmune diseases, hepatitis C infection or leprosy) 136 , 138 . By contrast, false-negative results can occur in sera with very high titres (such as those with secondary syphilis) that are not diluted before testing, a phenomenon known as a Prozone effect. Pre-dilution of sera re-establishes the concentration needed for optimal antibody–antigen interaction and avoids this problem.

In contrast to NTTs, TTs detect antibodies directed against T. pallidum proteins and are theoretically highly specific. However, as most syphilis-infected individuals develop treponemal antibodies that persist throughout life, TTs cannot be used to distinguish an active from a past or previously treated infection and are not useful in evaluating treatment efficacy. TTs are used as confirmatory assays following a positive NTT result.

TTs become positive 6–14 days after the primary chancre appears (~5 weeks after infection) and, therefore, may be useful to detect early syphilis missed by NTT testing. These tests are usually laboratory based and include the fluorescent treponemal antibody absorbed (FTA-ABS) test, the microhaemagglutination assay for antibodies to T. pallidum (MHA-TP), the T. pallidum passive particle agglutination (TPPA) and T. pallidum haemagglutination (TPHA) assays ( Table 2 ). These tests also require trained personnel in a laboratory setting, are more expensive and technically more complex than NTTs and involve specialized reagents and equipment. For these reasons, in the developing world, laboratory-based TTs are not widely available in primary care settings, hence limiting their utility as confirmatory assays for NTTs.

In recent years, TTs using recombinant T. pallidum antigens in enzyme and chemiluminescence immunoassay (EIA and CIA, respectively) formats have been commercialized. These assays are useful for large-scale screening as they are automated or semi-automated and, because they are read spectrophotometrically, are not subjective 13 , 139 – 142 . In higher income countries, many health care institutions depend upon high throughput screening and have adopted ‘reverse’ algorithms that screen with an automated treponemal EIA or CIA and confirm with a NTT rather than the opposite, traditional approach ( Fig. 7 ). Few studies as yet have addressed the accuracy of these ‘reverse testing’ algorithms 40 , 143 . The traditional and reverse approaches should theoretically produce the same result. However, the reverse alogorithm results in the detection of early syphilis cases (TT-positive, NTT-negative) that would not detected by the conventional approach 144 . As this pattern of serological reactivity occurs in very early primary syphilis, in previously treated disease and late infection, considerable attention should be given to a thorough physical examination of the patient, previous history and recent sexual risk before initiating any treatment and partner notification activities.

A | The traditional algorithm begins with a qualitative non-treponemal test (NTT) that is confirmed with a treponemal test (TT). This algorithm has a high positive predictive value when both tests are reactive, although early primary and previously treated infections can be missed owing to the lower sensitivity of NTTs 136 . Importantly, this algorithm is less costly than reverse screening algorithms, and does not require highly specialized laboratory equipment, but is limited by subjective interpretation of the technologist. Additionally, false negative NTT results can arise from the prozone effect (when there is an excess of antibody). Finally, because the traditional algorithm is not always followed by a confirmatory TT, previously treated, early untreated and late latent cases can be missed and biologically false-positive cases can be overtreated. B | The reverse screening algorithm uses a TT with recombinant T. pallidum antigens in enzyme immunoassay (EIA) or chemiluminescence immunoassay (CIA) formats that, when reactive, is followed by an NTT. This approach is associated with higher initial setup costs and ongoing operational costs than the traditional algorithm, but the algorithm permits treatment of 99% of syphilis cases, compared to the traditional algorithm in a low-prevalence setting 246 . Also, because TTs are not flocculation assays, false negative tests due to the Prozone effect do not occur. However, in high-risk populations, screening with a TT can result in a high rate of positive results due to previously treated infections, leading to increased clinician workload needed to review cases and determine appropriate management. Some guidelines recommend further evaluation of reactive TT with a quantitative NTT and, if results of the latter are nonreactive, a second (different) TT to help resolve the discordant results 143 , 247 , 248 . The European Centre for Disease Prevention and Control uses a variation of this approach: a reactive TT immunoassay is followed by a second (different) TT of any kind (that is, not followed by an NTT) 249 . Ideally, a positive TT should be supplemented by another TT or an NTT. However, in most developing countries, and in particular given the serious consequences of syphilis in pregnancy, treatment is recommended in a patient with a positive TT result.

Rapid tests

POC rapid TTs are a recent technology that enable onsite screening and treatment, and are particularly useful in settings with limited laboratory capacity. Rapid syphilis use a finger-prick whole blood sample and are are typically immuno-chromatographic strip-based TT assays that can be stored at room temperature, require no equipment and minimal training, and give a result in <20 minutes 145 ( Table 2 ). Various rapid tests have been evaluated in a range of clinical and community settings and shown to fulfil the ASSURED criteria 134 , 146 – 154 . Like other TTs, most POC diagnostics have the limitation of being unable to distinguish between recent and previously treated syphilis infection and, therefore, could lead to overtreatment. Ideally, patients found to have a reactive POC TT would be further evaluated with an NTT to support management decisions; however, this is often not possible in settings with limited laboratory capacity as is the case in many antenatal care clinics and outreach programmes for high-risk populations. POC rapid tests play an important part when delayed diagnosis is problematic, such as in pregnant women in whom delayed or no treatment poses significant risks to the fetus that far outweigh the risks of overtreatment for the mother 45 , 155 . In non-pregnant individuals, treatment is recommended in those who test positive if they have no prior history of treatment, and to refer those with a prior history to have an NTT 11 .

At least one test has been developed that enables simultaneous detection of non-treponemal and treponemal antibodies in a single POC device 156 – 158 . Additionally, dual syphilis/HIV rapid tests are available to screen for HIV and treponemal antibodies using a single lateral flow immunochromatographic strip. These are an increasingly important tool in the global elimination of MTCT of HIV and syphilis in settings in which laboratory capacity is limited 159 .

Tests useful in special situations

Neurosyphilis.

The diagnosis of neurosyphilis is challenging. The CSF is frequently abnormal in patients with neurosyphilis with both pleocytosis (lymphocyte accumulation) and a raised protein concentration. The Venereal Disease Research Laboratory (VDRL) assay performed on CSF is considered the gold standard for specificity but is recognized to have limited sensitivity 160 , 161 . Other CSF tests, including serological assays — such as the Rapid Plasma Reagin (RPR) 162 , FTA-ABS 163 and TPHA 164 — and molecular assays including PCR 165 have all been assessed for CSF and have variable specificity and sensitivity for the diagnosis of neurosyphilis. Difficulties in interpretation of CSF pleocytosis in individuals co-infected with HIV and syphilis challenge the evaluation of the relationship between the two diseases. CSF pleocytosis occurs in individuals with either infection alone 37 , 165 ; thus, discerning the cause of pleocytosis in co-infected individuals is not always possible.

Congenital syphilis

Diagnosis of congenital syphilis in exposed, asymptomatic infants is another area in testing can be improved. Because maternal nontreponemal and treponemal IgG antibodies can be transferred from mother to child, treponemal testing of infant serum is difficult to interpret and is not recommended 37 . An infant with a reactive RPR or VDRL serum titre that is ≥4-times than those of the mother is highly suggestive of congenital syphilis, but its absence does not exclude the diagnosis. A clinical examination, reactive infant CSF VDRL, abnormal complete blood count or liver function tests or suggestive long-bone radiographs (that, for example, show retarded ossification or dislocation of epiphyses and radiolucencies, especially of long bones) can support a diagnosis of congenital syphilis. Use of IgM immunoblots is controversial owing to limited availability of tests and inconclusive data thus far on sensitivity; their use in diagnosing congenital syphilis is recommended in some guidelines 11 , 13 but not others 37 . Maternal syphilis infection is highly correlated with fetal loss, therefore, evaluation of a stillborn infant should include evaluation of maternal tests for syphilis 11 .

The wide availability of effective treatment and resulting decline in syphilis prevalence has led to low yield of screening in low prevalence settings; thus, screening in low-risk adults (for example, premarital adults or those admitted to hospital) has been abandoned in most places. However, systematic reviews provide convincing evidence in favour of syphilis screening in pregnant women 13 , 166 , adults and adolescents at increased risk for infection 13 , 40 and individuals donating blood, blood products or solid organs 13 , 167 – 169 . Several countries also recommend syphilis testing in people with unexplained sudden visual loss, deafness or meningitis as these may be manifestations of early neurosyphilis 13 , 37 .

Prenatal screening

Syphilis screening is universally recommended for pregnant women, regardless of previous exposure, because of the high risk of MTCT during pregnancy and the availability of a highly effective preventive intervention against adverse pregnancy outcomes 11 , 37 , 41 , 46 . Global normative authorities and most national guidelines recommend syphilis screening at the first prenatal visit, ideally during the first trimester 11 , 37 , 41 , 170 . Some countries recommend that women at high risk have repeat screening in the third trimester and again at delivery to identify new infections 37 . Women should be tested in each pregnancy, even if they have tested negatively in a previous pregnancy. When access to prenatal care is not optimal or laboratory capacity is limited, rapid tests have been found beneficial in detecting and treating syphilis in pregnancy 148 . Guidelines recommend that, post-delivery, neonates should not be discharged from the health facility unless the serological status of the mother had been determined at least once during pregnancy and preferably again at delivery 11 , 37 .

The importance of universal syphilis screening in pregnancy to prevent perinatal and infant morbidity and mortality is highlighted in the current WHO global initiative to eliminate congenital syphilis 43 , 44 and justified by the continuing high global burden of congenital syphilis, availability of an effective and affordable preventive intervention and wider availability of low cost POC rapid tests that can be used when laboratory capacity is lacking 23 , 43 , 44 , 46 , 145 . A systematic review of studies (most of which were conducted in low-income countries) reporting on antenatal programmes initiating or expanding syphilis screening, compared with various local control conditions, found that enhanced screening reduced syphilis-associated adverse birth outcomes by >50% 171 . Integration of syphilis testing with other prenatal interventions, including HIV testing, has been shown to be cost-effective across settings, even when syphilis prevalence is low 48 – 51 . Strategies that enhance screening coverage, such as increased use of POC rapid testing and integrating syphilis and HIV screening, will further support global elimination of congenital syphilis 145 , 172 – 174 .

Screening at-risk populations

Increased risk for infection can be related to personal or partner behaviours leading to syphilis infection or living in a community with high syphilis prevalence 37 , 40 . In many countries, syphilis testing is recommended for all attendees at STI or sexual health centres and as part of integrated services targeted to high-risk groups (such as HIV testing centres or drug treatment centres) 13 , 37 . The optimal screening interval for individuals at increased risk for infection is not well established; however, some guidelines suggest that MSM or people with HIV may benefit from more frequent screening than others at risk for syphilis (for example, 3 monthly rather than annual screening) 37 , 40 , 175 , 176 .

At-risk communities are often marginalized from care and experience discrimination and stigma when using traditional STI services 177 . Innovations in promoting uptake of testing and developing user-friendly services are important in the control of syphilis in these communities to reduce transmission. Social entrepreneurship and crowdsourcing approaches have been shown as innovative approaches to improve HIV and syphilis testing coverage rates and accelerate linkage to care, two fundamental elements within the cascade of STI service delivery 178 , 179 . Evaluation studies of other interventions, such as pre-exposure prophylaxis (PrEP) for syphilis, are also underway 180 . One option in the future might be to simultaneously administer PrEP for syphilis and HIV 181 .

Blood bank screening

Although syphilis was among the first identified infectious risks for blood donation and s transmission through blood has been documented 182 – 184 , reports of transfusion-transmitted syphilis have become exceedingly rare over the past 60 years as increasingly more countries adopt donor selection processes, universal serological screening of donors and use of refrigerated products rather than fresh blood components 183 , 185 . Survival of T. pallidum in different blood components has been shown to vary according to storage conditions, with fresh blood or blood components stored for <5 days more infectious than blood stored for longer periods 183 . Syphilis screening of blood, blood components or solid organs remains a recommendation in many countries 13 , 169 . Occasional cases of transfusion-transmitted syphilis are still reported in settings with high syphilis prevalence, particularly with transfusion of fresh blood 167 .

There is as yet no vaccine against syphilis, and the most effective mode of prevention is prompt treatment to avoid continued transmission of the disease sexually or vertically from mother-to-child, and treatment of all sex partners to avoid reinfection. Other prevention modalities against venereal transmission of syphilis are latex condom use, male circumcision and avoiding sex with infected partners 37 . Treatment of exposed sex partners is important to avoid reinfection 37 .

Important factors in managing syphilis are early detection, prompt treatment with an effective antibiotic regimen and treatment of sex partners of a person with infectious syphilis (primary, secondary or early latent infections). The WHO guidelines 11 ( Box 1 ) and European guidelines 13 for the management of early syphilis in adults are the same. The CDC guidelines do not offer procaine penicillin as a treatment, but are otherwise identical 12 . Patients with late syphilis are no longer infectious. Thus, the objective of treatment is to prevent complications in persons who are asymptomatic (that is, have late latent syphilis) or arrest their development if the patient has manifestations of tertiary disease. Treatment of late syphilis requires longer courses of antimicrobial therapy than early disease.

WHO guidelines for the treatment of syphilis

Early syphilis.

• Intramuscular benzathine penicillin G (single dose)
• Or intramuscular procaine penicillin (daily doses for 10–14 days)
• If penicillin-based treatment cannot be used, oral doxycycline (twice daily doses for 10–14 days)* or intramuscular ceftriaxone (daily doses for 10–14 days)

Late syphilis

• Intramuscular benzathine penicillin G (weekly doses for 3 weeks)
• Or intramuscular procaine penicillin (daily doses for 20 days)
• If penicillin-based treatment cannot be used, oral doxycycline (daily doses for 30 days)*
• Intravenous aqueous benzyl penicillin six hourly (for 10–15 days)
• Or intramuscular procaine penicillin daily (for 10–15 days)

*Contraindicated in pregnancy. From Ref. 11

Penicillin has been the mainstay of treatment for syphilis since it first became widely available in the late 1940s. Although its efficacy was never demonstrated in a randomized controlled trial, it was clearly far superior to all previous treatments, and T. pallidum resistance to penicillin has never been reported. As T. pallidum divides slower than most bacteria, it is necessary to maintain penicillin levels in the blood above the minimum inhibitory concentration (MIC) for at least 10 days; this can be achieved by giving a single intramuscular injection of long-acting benzathine penicillin G (which benefits from not requiring patient adherence to a prolonged drug regimen). The first-line treatments for early syphilis recommended by the CDC and European (authored by the International Union Against Sexually Transmitted Infections) guidelines are very similar 12 , 13 as are recommendations for treatment of exposed sex partners. Patients with late syphilis, or with syphilis of unknown duration, should receive longer courses of treatment ( Box 1 ). Those with symptoms suggestive of neurosyphilis or ocular involvement should undergo lumbar puncture to confirm or rule out the presence of neurosyphilis, which requires more intensive treatment. However, CDC and European guidelines define latent syphilis as occurring beginning at 1 year after infection, whereas the WHO defines latent syphilis to occur beginning at 2 years, resulting in some differences in management; that is, longer treatment duration is required for some patients in the United States and Europe.

Given that confirmation or exclusion of the presence of viable T. pallidum after treatment is not possible, treatment efficacy is measured indirectly using serology. Cure is usually defined as reversion to negative or a fourfold reduction in titre of an NTT. However, as noted earlier, a minority of patients remain seropositive, with a less than four-fold reduction in NTT titre, in spite of almost certainly having been cured and with no evidence of progressive disease — the so-called serofast state 186 . The management of these patients depends on taking a careful sexual history to exclude the possibility of reinfection, which can be challenging as patients may not recognize new infections. The serofast state more commonly occurs in patients with late syphilis and low NTT titres and in HIV-positive patients who are not on anti-retroviral treatment 187 . Because few data are available on long-term clinical outcomes in serofast patients, CDC guidelines recommend continuing clinical follow up and retreatment if follow up cannot be ensured 12 .

Second-line treatments

Patients who are allergic to penicillin should be treated with doxycycline or ceftriaxone (though allergy to cephalosporins is more common in those who are allergic to penicillin) with repeat NTT serology as follow up. Doxycycline is contraindicated in pregnancy. Two treatment trials of early syphilis in Africa showed that a single oral dose of azithromycin was equivalent to benzathine penicillin G 188 , 189 . Unfortunately, strains of T. pallidum with a mutation that confers resistance to azithromycin and other macrolide antibiotics are common in the United States, Europe, China and Australia 190 – 194 . A study in HIV-positive patients with syphilis showed that azithromycin to prevent opportunistic infections led to better serological outcomes 195 . The WHO recommends the use of azithromycin for the treatment of syphilis only in settings where the prevalence of macrolide-resistant T. pallidum is known to be very low.

HIV co-infection

In patients with early syphilis, a raised CSF cell count and protein are found more frequently in the CSF of patients with HIV infection than in HIV-uninfected patients, and there is some evidence that early symptomatic neurosyphilis is more common in HIV-positive patients 196 , 197 . As single-dose benzathine penicillin G does not reliably lead to treponemicidal levels in the CSF, some experts have suggested that HIV co-infected patients with early syphilis should receive enhanced treatment 198 . However, a randomized controlled trial ( n = 541) showed no significant difference in clinical outcomes between patients receiving standard or enhanced treatment 15 . Notably, the 101 HIV-infected patients enrolled in the trial responded less well serologically, but due to loss to follow up the study was underpowered to detect a two-fold difference in standard versus enhanced treatment in HIV co-infected patients. Furthermore, a large ( n =573) prospective observational study in Taiwan found no difference between single-dose benzathine penicillin G and enhanced treatment in a per-protocol analysis 199 . However, using a last-observed-carried-forward analysis to account for missing data, the authors concluded that 67.1% of those who received one dose responded serologically compared with 74.8%who received the enhanced treatment, a statistically significant difference ( P =0.044) 199 . Finally, a retrospective study ( n = 478) showed no difference in serological response at 13 months between those receiving single-dose benzathine penicillin G and enhanced treatment 200 . Given the inconclusive results of these studies, many clinicians continue to offer enhanced therapy to HIV co-infected patients with early syphilis.

Treatment in pregnancy

Adverse pregnancy outcomes are common in women with syphilis 45 , 119 . A study in Tanzania found that, of women with latent syphilis who had RPR titres ≥1:8, 25% delivered a stillborn, and 33% a live but preterm infant 21 . A second study showed that adverse pregnancy outcomes due to syphilis can be prevented with a single dose of benzathine penicillin G given before 28 weeks’ gestation 201 and that, in this setting, in which 5–6% of pregnant women had syphilis, this was one of the most cost-effective interventions available in terms of cost per disability-adjusted life year saved 202 .

Penicillin is the only antibiotic known to be effective in treating syphilis in pregnancy and preventing adverse birth outcomes. Since doxycycline is contraindicated in pregnancy, and macrolides such as azithromycin and erythromycin do not cross the placenta well, there are few alternatives to penicillin for the treatment of pregnant women with syphilis who are allergic to penicillin. The CDC recommends desensitization for those who are allergic to penicillin 12 .

The WHO recommends that infants with suspected congenital syphilis, including infants who are born to syphilis-seropositive mothers who were not treated with penicillin >30 days before delivery, should be treated with aqueous benzyl penicillin or procaine penicillin ( Box 1 ). All syphilis-exposed infants, including infants without signs or symptoms at birth, should be followed closely, ideally with NTT titres. Titres should decline by 3 months of age and be nonreactive by 6 months 12 . TTs are not useful in infants due to persistent maternal antibody.

Neurosyphilis and ocular syphilis

CNS involvement can occur during any stage of syphilis, but there is no evidence supporting a need to deviate from recommended syphilis regimens without presence of clinical neurological findings (such as ophthalmical or auditory symptoms, cranial nerve palsies, cognitive dysfunction, motor or sensory deficits, or signs of meningitis or stroke) 203 . With symptoms and tests indicating neurosyphilis, or any suggestion of ocular syphilis regardless of CSF testing, more-intensive treatment is recommended. For example, the CDC recommends that adults with neurosyphilis or ocular syphilis should be treated with high-dose intravenous aqueous crystalline, or intramuscular procaine penicillin plus probenecid, for 10–14 days 204 .

Quality of life

Historical reports dating from the 15 th century indicate that syphilis was perceived as a dangerous infection, and a source of public alarm via fear of contagion and dread of its manifestations and anxiety around its highly toxic ‘cures’ (heavy metal therapy with mercury, arsenicals or bismuth) 205 – 207 . Case reports through the 19 th century as well as modern re-evaluations of skeletal remains support the fact that the disease could cause severe physical stigmata, with individuals having disfiguring rashes; non-healing ulcerations; painful bony lesions that often involved destruction of the nose and palate; visceral involvement; dementia and other incapacitating neurological complications; and early death 208 . Stigmatization associated with syphilis was also evident, with symptomatic patients quarantined to specialized hospitals, and affected people hiding their symptoms — perhaps fearing societal shunning or the dubiously effective treatment regimens even more than the disease 209 . Reductions in syphilis prevalence were documented after the introduction of penicillin 210 and since that time, the most virulent manifestations of the disease have almost vanished, and today it is rare to find a patient with tertiary disease 211 . Nevertheless, continuing reports emphasize that complications of late syphilis, particularly those involving the eyes, CNS and cardiovascular system, can cause lifelong disability and even death 9 . For example, case numbers of ocular syphilis have increased with rising syphilis incidence rates in many communities 212 , with delayed treatment associated with permanently diminished visual acuity 213 . It is essential, therefore, that caregivers be cognizant of the need to screen at-risk patients for latent infection and administer therapy if previous treatment has not been documented.

Few modern studies have addressed quality of life in men and women with syphilis, whether in social, psychological or economic contexts. One study ( n = 250) showed only a minor effect on patient-reported quality of life at time of treatment, and essentially no effect 1 month after treatment 214 . The currently high case rates of syphilis infection and reinfection among MSM in urban centres throughout the world may lend support to the notion that syphilis in the modern era poses limited impact on quality of life as long as it is detected and treated. However, partner notification studies suggest STI diagnoses can lead to significant social stigma, intense embarrassment, and fear of retaliation, domestic violence or loss of relationship 177 . Public health experts have posited that syphilis is the source of more stigma than other STI diagnoses, although this is difficult to measure with certainty because STI programmes tend to focus contact tracing efforts more strongly on syphilis than other curable STIs owing to its serious consequences 215 . In one study measuring the level of shame associated with several stigmatizing skin diseases, patients assigned greatest shame to syphilis — more than to AIDS, other STIs or several disfiguring skin conditions 216 .

Untreated maternal syphilis results in severe adverse perinatal outcomes, most prominently stillbirth, in at least half of affected pregnancies 45 . While MTCT of syphilis is clearly linked to lack of prenatal care, WHO data indicate that globally, whether in wealthy or poor nations, most adverse pregnancy outcomes caused by maternal syphilis are in women who attended prenatal care but were not adequately tested or treated 24 . This suggests other factors, such as weak health systems, gender inequality, lack of political will to support quality STI and reproductive health services, or other structural influences associated with lack of screening might be at play 217 . An increasing literature supports that, as for infant loss, a stillbirth can lead to poor mental and other health outcomes for both parents and the wider family, even extending to health care providers. For example, experiencing a stillbirth has been linked to ‘unspoken grief’ and a variety of psychosocial consequences such as depression, blame, shame, social isolation, problems in future pregnancies and relationship dissolution 218 – 220 . In Haiti, pregnancy loss associated with syphilis (which had a maternal prevalence of 6%) is so common that a myth about a werewolf sucking the blood out of the unborn fetus has developed to help women with their loss and suffering 221 . Economic research suggests a stillbirth results in substantial direct and indirect costs and can sometimes require more resources than a livebirth 219 .

With syphilis continuing to be the leading cause of preventable stillbirths in the developing world and re-emerging as a public health threat in developed nations, particularly in HIV co-infected MSM, the demand for improved diagnostics, prevention strategies and treatments is growing. Here, we describe the most pressing issues and propose a call to action ( Box 2 ).

Major challenges and a call to action wish list

Eliminate mother-to-child transmission of syphilis.

• Requires political commitment
• Prenatal syphilis screening to be integrated into mother-to-child elimination programmes for HIV or as a component of an essential diagnostic package for prenatal care
• Develop point-of-care tests with data connectivity or data transmission capability to facilitate automated surveillance and to improve the efficiency of health systems

Address HIV and syphilis co-infection in MSM

• Requires research into potential synergies between the two infections
• Implement scientific and community involvement to reach at-risk populations
• Integrate programmes for HIV, syphilis, hepatitis and other STIs

Develop tests for active infection, neurosyphilis and congenital syphilis

• Development of biomarkers for test development
• Development of network of clinical sites for rapid validation of new tests

Develop new oral drugs to prevent transmission to fetus and to sexual partners

• Provide incentives for drug discovery programmes
• Provide incentives to evaluate drug combinations

Develop vaccines

• Requires research to better understand pathogenesis
• Requires research to identify vaccine targets and methods for validation

Elimination of MTCT of syphilis

The WHO campaign to eradicate yaws, which treated >50 million people with penicillin and reduced the number of cases by at ≥95% worldwide between 1952 and 1964, was ultimately unsuccessful. What can we learn from this heroic failure? The yaws eradication campaign was based on clinical examination and serological testing to determine prevalence by community, and mass treatment or selective mass treatment (cases and contacts) of communities with penicillin, depending on prevalence. Unfortunately, as the prevalence of yaws fell, it was no longer perceived as an important public health problem worthy of an expensive vertical programme; resources were diverted to other programmes, yaws was forgotten, and it came re-emerged 222 . To some extent the same is true of syphilis; once penicillin became available, its incidence and prevalence declined in many parts of the world, and it was no longer seen as a public health priority. Although screening of all pregnant women for syphilis has continued to be recommended in most countries, coverage has been low in many regions; for example, WHO estimates that approximately 50% of antenatal clinic attenders in Africa are not currently screened for syphilis 24 . This low coverage has resulted in a high burden of entirely preventable stillbirths and neonatal deaths 23 . Exacerbating this situation, the WHO has received reports of stock outs and shortages of injectable benzathine penicillin G in multiple countries, many with a high burden of maternal and congenital syphilis. In collaboration with international partners, the WHO has spearheaded an initiative to assess global supply, current and projected demand, and production capacity for benzathine penicillin G 223 .

Strong advocacy will be needed to ensure that the control and elimination of syphilis is given a high priority on the global health agenda. Policy makers and funders need to be made aware that syphilis is a leading cause of preventable stillbirths and neonatal death, that these deaths can be prevented with a single dose of penicillin given to the mother before 28 weeks gestation, and that this is one of the most cost-effective health interventions available 51 , 202 . Perhaps with this awareness and political will, syphilis MTCT elimination programmes — which have failed to progress in the past 10 years 224 — will witness the success of the MTCT HIV programmes in Africa. Other developments are occurring that are forging change. For example, the availability of POC tests has led to increased coverage of antenatal screening and treatment for syphilis in many settings 148 , and the WHO campaign for the elimination of MTCT of HIV and syphilis has increased the visibility of syphilis on the global health agenda. In 2014, the WHO target for the elimination of MTCT of syphilis was ≤50 cases of congenital syphilis per 100,000 live births. The process targets are antenatal care coverage (at least one visit) of ≥95% of pregnant women; coverage of syphilis testing ≥95% of pregnant women; and treatment of ≥95% of seropositive pregnant woment 225 . Additionally, the WHO has conducted a systematic review of the performance of dual HIV-syphilis rapid tests and issued an information note on testing algorithms for dual HIV-syphilis tests 226 .

The huge reduction in the number of HIV-positive infants in Africa in recent years, a more difficult undertaking than reducing MTCT of syphilis, is proof of concept that congenital syphilis elimination is achievable. Given that Cuba, Thailand, Belarus, Moldova and Armenia have eliminated MTCT of HIV, syphilis or both, elimination can be achieved with political will and a well-organized health care system. Indeed, inclusion of syphilis and HIV screening with tests for anaemia, diabetes and pre-eclampsia as a package of essential diagnostics for prenatal care should be implemented as a minimum standard to ensure safe and healthy pregnancies worldwide.

POC testing has greatly increased access to screening for pregnant women, and has the potential to increase access to screening for high-risk groups such as MSM and FSWs through outreach programmes. However, the quality of testing must be assured given these tests are conducted outside the laboratory. Strategies to ensure reliability of POC tests include use of electronic readers 227 and microfluidic assays powered by smart phones 228 for real-time monitoring of progress 229 , and routine provision of proficiency testing panels 121 , 122 . For example, one study in the Amazon region of Brazil showed that proficiency panels consisting of dried serum tubes that were assessed by each healthcare worked could be used to monitor the performance of healthcare workers in remote settings 123 .

HIV and syphilis co-infection in MSM

In developed countries, the incidence of syphilis in MSM is several hundred times higher than in the general population. Furthermore, the incidence continues to increase as condom use has fallen with increasing use of pre-exposure prophylactic anti-retroviral medications for HIV 42 , 230 . Indeed, with wider HIV treatment coverage in recent years and HIV no longer considered a ‘death sentence’, there has been a decline in safe sex practices and more risk-taking behaviours 231 . However, the alarming increase in incidence of syphilis, compared to other STIs, in HIV-infected MSM cannot be explained by behavioural factors alone. The frequent co-infection of HIV and syphilis in MSM in many countries have led researchers and policy makers to consider the hypothesis that treatment for HIV may be a double-edged sword that contributed to increased susceptibility to syphilis through impairment of the innate or acquired immunity to T. pallidum 42 , 232 .

Accordingly, research is urgently needed to understand the underlying causes of this twin epidemic. The involvement of the MSM community is critical in the design and implementation of innovative approaches to promote the uptake of testing and linkage to care, particularly as this community is still stigmatized and marginalized from care in many societies. Although self-testing for HIV and hepatitis C virus infection is now possible using highly sensitive and specific oral tests that are commercially available, syphilis does not elicit sufficient antibody for an oral test. Thus, implementation science is needed to integrate and optimize the delivery of a package of HIV, syphilis, hepatitis and other STI screening and treatment strategies and partner notification systems for MSM in different cultural, socioeconomic and political settings.

Better diagnostic tests

Research is needed to identify biomarkers that can more accurately distinguish between past, treated and active syphilis requiring treatment, identify patients who have become reinfected, and provide a test of cure. Using current serological tools, a high proportion of patients remain serofast after treatment in some settings, and the optimal management of these individuals is uncertain. Additionally, more-accurate diagnostic tests are needed to confirm the diagnosis of congenital syphilis, as serological tests based on IgG antibodies cannot distinguish between infected infants and those with passively acquired maternal antibodies. IgM tests can be highly sensitive in symptomatic infants but have suboptimal sensitivity in infants who are infected but not symptomatic at birth 12 .

The diagnosis of neurosyphilis also remains a challenge, particularly in HIV co-infected patients, in whom a raised CSF protein or cell count does not necessarily indicate that the patient has neurosyphilis. Promisingly, a POC rapid test has been adapted for the diagnosis of neurosyphilis using CSF 233 ; performance of this test is better in cell-free specimens, requiring the use of a centrifuge. Another promising assay might be measurement of macrophage migration factor (MIF); CSF levels of MIF alone was shown to have a sensitivity of 74.42% and a specificity of 67.74% for the diagnosis of neurosyphilis in one study ( n =43) 234 . By integrating all CSF parameters (pleocytosis, increased protein and MIF), the sensitivity and specificity would be improved to 100% by parallel testing. Additionally, assay of B cell attractant chemokine CXCL13 in the CSF could be used to distinguish the pleoctysosis caused by HIV from that due to neurosyphilis in HIV-infected patients 235 .

Better use of existing drugs

With penicillin, many countries still struggle with the fear of injections on the part of patients and the management of anaphylactic shock on the part of the health care providers. Oral regimens that are safe in pregnancy and effective in preventing the transmission of syphilis to the fetus are urgently needed. Furthermore, macrolide resistance is correlated with treatment failure in patients with primary syphilis 191 , lending further urgency to the need to find alternative oral therapies. Incentives for a drug discovery programme for syphilis needs to be established and, in the meantime, evaluation of existing drug combinations might be useful as alternative to reduce the threat of development of resistance.

Vaccine development

Human challenge studies have shown that people with late latent syphilis are resistant to symptomatic reinfection with heterologous strains of T. pallidum , and protective immunity has been induced in rabbits by repeated inoculation with γ-irradiated T. pallidum 236 , 237 .Accordingly, it should be possible to develop protective vaccines. However, research on virulence determinants of T. pallidum , and our understanding of protective immunity against it, have been hindered by our inability to culture the bacteria in vitro. To overcome this limitation, genome sequencing of T. pallidum directly from clinical samples is now possible 92 , 238 This advance should enable understanding of strain variation on a global scale, and help to identify outer membrane proteins and other surface antigens as possible vaccine candidates 81 . A recent study showed that immunization of rabbits with the lipoprotein TP071 prevented dissemination of T. pallidum and, hence, has become a promising vaccine candidate 81 . Integration of potential vaccine targets with diagnostic targets in discovery programmes also hold promise in accelerating progress towards improved tools for control, prevention and ultimately the elimination of this disease.

Acknowledgments

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 contributions

Competing interests

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

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Syphilis Infection: Clinical, Epidemiology, Basic science, and Behavioral Research

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Syphilis, a sexually transmitted disease caused by Treponema pallidum , has undergone a dramatic global resurgence in the past ten years. The World Health Organization estimated 2.2 million (1.3 – 3.1 million) incident cases of syphilis infection in 2020. Congenital syphilis cases are increasing in many ...

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• Research article
• Open access
• Published: 16 August 2019

Early syphilis: risk factors and clinical manifestations focusing on HIV-positive patients

• Maider Arando   ORCID: orcid.org/0000-0003-2020-4193 1 , 2 ,
• Candela Fernandez-Naval 3 , 4 ,
• Miriam Mota-Foix 5 ,
• Desi Martinez 1 ,
• Pere Armengol 1 ,
• Maria Jesús Barberá 1 ,
• Juliana Esperalba 6 &
• Martí Vall-Mayans 1  

BMC Infectious Diseases volume  19 , Article number:  727 ( 2019 ) Cite this article

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Since 2000, substantial increases in syphilis in men who have sex with men (MSM) have been reported in many cities. Condomless anal sex (CAS) is one of the factors, along with drugs for sex and sex in group. This study identified factors and clinical manifestations as well as Treponema pallidum (T.pallidum) strains that could be related to early syphilis in Barcelona.

This prospective study was conducted in a sexually transmitted infections unit in 2015. Epidemiological, behavioral, clinical and microbiological variables were collected in a structured form. Univariate and multivariate statistical analyses were performed focusing on HIV-positive patients.

Overall, 274 cases were classified as having early syphilis (27.5% primary, 51.3% secondary, and 21.2% early latent syphilis). In all, 94% of participants were MSM and 36.3% were HIV-positive. The median number of sexual contacts in the last 12 months was 10; 72.5% practiced CAS, 50.6% had sex in group, and 54.7% consumed drugs. HIV-positive cases had more anonymous sex contacts ( p  = 0.041), CAS ( p  = 0.002), sex in group ( p  < 0.001) and drugs for sex ( p  < 0.001). In the multivariate analysis, previous syphilis (adjusted odds ratio [aOR] 4.81 [2.88–8.15]), previous Neisseria gonorrhoeae infection (aOR 3.8 [2.28–6.43]), and serosorting (aOR 20.4 [7.99–60.96]) were associated with having syphilis. Clinically, multiple chancres were present in 31% of cases with no differences on serostatus, but anal chancre was most common in HIV-positive patients ( p  = 0.049). Molecular typing did not conclusively explain clinical presentation in relation to specific T.pallidum strains.

Control of syphilis remains a challenge. Similar to prior studies, HIV-positive patients were found to engage more often in sexual behaviors associated with syphilis than HIV-negative patients. Clinical manifestations were rather similar in both groups, although anal chancre was most common in HIV-positive patients. Various strain types of syphilis were found, but no clinical associations were identified.

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Since 2000, substantial increases in cases of early syphilis have been reported in metropolitan areas of Western countries. These increases have been described particularly among men who have sex with men (MSM). In Europe, there were 28,701 cases of early syphilis reported in 2015, yielding a rate of 6.0 per 100,000 inhabitants [ 1 ]. Similarly, an increase has been described in our setting in Catalonia (Spain): in 2014, the rate of early syphilis was 12.4 per 100,000 inhabitants, a 231% increase over the figures for 2005 observed mainly in MSM [ 2 ].

One of the most important factors affecting syphilis transmission is the practice of condomless anal sex (CAS) [ 3 ]. Other factors, such as drug consumption, internet use for sexual contacts, and sex in group have also been reported [ 4 ]. In some studies, these risk factors are directly related to syphilis, whereas, other studies have found, indirect links with CAS [ 5 , 6 ]. HIV coinfection has been demonstrated to be strongly associated with syphilis [ 3 , 7 ].Clinically, some differences have been described between HIV-positive and HIV-negative patients, for instance, in atypical manifestations, such as multiple chancres in primary syphilis [ 8 ] or the persistence of chancres in secondary syphilis [ 9 ] in HIV-positive patients.

Molecular typing of Treponema pallidum subspecies pallidum ( T. pallidum) has been used for different purposes [ 10 , 11 , 12 ]. Epidemiologically, use of the technique has identified a wide distribution of strain types depending on geographic location, with 14d/g being the most common in Europe [ 13 , 14 ]. Some strains have been associated with clinical outcomes such as neurosyphilis in rabbits, although this has not been shown in humans [ 10 ].

The aim of this study was to provide updated information on syphilis in Barcelona by identifying factors associated with early syphilis and occurrence of these factors, focusing on HIV-positive patients. An additional aim was to describe the clinical characteristics of syphilis, exploring the role of specific strain types of T. pallidum . Altogether, the study was intended to gain an overview of the syphilis epidemic that affects MSM in particular.

This prospective study was conducted in the Sexually Transmitted Infections Unit Vall d’Hebron-Drassanes in Barcelona, Spain (STIUVD). The STIUVD is the main referral sexually transmitted infections (STIs) in Catalonia and is located in the downtown area of Barcelona. It provides care to patients for a total of 25000 visits per year (60% MSM) and reported around 50% of all syphilis cases seen in Barcelona during the study period.

All patients aged 18 years or older with early syphilis who came between 15 January and 15 October 15, 2015 were eligible to participate in the study. Syphilis diagnosis and management were based on the European syphilis guidelines [ 15 ]. Primary syphilis was defined as a typical ulcer (chancre) and/or a positive test using dark-field microscopy or as polymerase chain reaction (PCR) detection of T. pallidum and/or a positive serological test for syphilis. Secondary syphilis was defined based on typical clinical symptoms with positive treponemal and non-treponemal tests. Early latent syphilis was defined as positive serological treponemal and non-treponemal tests with no clinical evidence of infection, with a previous negative syphilis serology, or a four-fold increase in the titer of a non-treponemal test (i.e. two dilutions) within the past 12 months. Cured syphilis was defined as a four-fold decline in the titer of a non-treponemal test within 1 year of treatment.

Behavioral variables

Participants completed a self-administered questionnaire of demographic and sexual behavior information from the previous 12 months. Variables included how they met their partners and practices such as sex in group, drugs for sex, use of condoms, serosorting (sex between partners with same HIV status) and seropositioning (adapting sexual practices according to one’s HIV status). The self-administered questionnaire was based on the European MSM Internet Survey (EMIS) [ 16 ], which had been previously modified, piloted, and revised. An adapted version of this questionnaire was used for heterosexual participants. Drugs for sex was defined as substance use 2 h before or during intercourse; chemsex was defined as the use of crystal methamphetamine, gammahydroxybutrate (GHB), and/or mephedrone before or during sexual sessions; and poly drug use was defined as the consumption of three or more drugs, excluding alcohol or cannabis. CAS was defined as the absence of systematic use of a condom, even if used occasionally. Clinical and microbiological variables were completed by the attending physicians. Information on pre-exposure prophylaxis against (PrEP) HIV was not collected because it was not readily available at that time.

If patients had more than 1 episode of syphilis during the study period, the epidemiological and behavioral data were analyzed only once. To determine the risk factors for the acquisition of syphilis according to HIV status, HIV-positive patients were defined as patients who knew that they were HIV-positive at syphilis diagnosis, excluding patients whose diagnoses of HIV and syphilis infection coincided. However, in the clinical analysis, the latter (patients with coincident diagnoses) were included in the HIV coinfection group analysis because the clinical manifestations and course of syphilis could be influenced by HIV.

Microbiological tests

All patients were tested for syphilis following a reverse algorithm sequence screening algorithm. Initial screening consisted of a specific test for antibodies against T. pallidum with any positive results a subsequently confirmed by a non-treponemal test and another treponemal test. The tests used were the treponemal enzyme immunoassay (EIA, Siemens Healthcare Diagnostics, Germany), rapid plasma regain (RPR) test (Biokit, Spain), T. pallidum particle hemagglutination assay (TPHA, Biokit, Spain), and indirect immunofluorescence assay (FTA-abs, BioMérieux, France). Direct diagnoses were made using dark-field microscopy or in-house PCR for T. pallidum [ 17 ]. A swab was taken in the case of ulcer, with a second swab taken if there were lesions in more than one site. For typing purposes an extra swab was taken. Treponemal DNA was detected by means of a diagnostic real-time PCR (qPCR) and molecular typing was performed by the Enhanced CDC Typing, analyzing the arp , tpr and tp0548 genes. This typing is based on three regions of T. pallidum -2 first described in 1998 by the Centers for Disease Control and Prevention (CDC) [ 18 ] and extended with tp058 in 2010 by Marra et al. [ 10 ] Participants were offered screening for N. gonorrhoeae (NG), C. trachomatis (CT) and HIV, as well as hepatitis C virus (HCV) in MSM.

Statistical analysis

Categorical variables were expressed as percentages and comparisons were made using the chi-square test or Fisher’s exact test, as appropriate. The strength of the association was measured as the odds ratio (OR) with 95% confidence intervals (95% CI). Continuous variables were expressed as the mean (+/− SD) or median and interquartile range [IQR]. Comparisons were performed using a Student t test, Mann-Whitney U test, ANOVA, or Kruskal-Walls test with 95% CI if there were more than two groups. Variables identified as clinically significant at the univariate level ( p  < 0.01) were tested in a final regression model using the Akaike information criterion (AIC). The “R” program (R Foundation for Statistical Computing, Vienna, Austria), version 3.3.1, was used for all analyses.

Ethical approval was granted by the Hospital Vall d’Hebron Ethics Committee (PR(AG)297/2014) and all patients provided written informed consent obtained by the attending physician.

Among patients diagnosed with early syphilis during the study period, 33 patients declined to participate while another 3 were < 18 years old. In total, 270 patients with 274 episodes (4 patients had 2 episodes during this period) were included. In terms of episodes, 76 (27.7%) were primary syphilis, 140 (51.1%) were secondary syphilis and 58 (21.2%) were early latent syphilis. Most patients (257 [95%]) were MSM including bisexuals; there were 2 (0.75%) women and 11 (4.0%) heterosexual men. The median age was 36 [30–44] years, 60.5% were autochthonous, 65.0% had university-level education, 73.5% were employed, and 7.0% were students. A total of 95 (36.0%) patients knew they were HIV-positive at the time of syphilis diagnosis. Four patients had never undergone an HIV test (these patients were excluded from the comparative study). In HIV-positive patients, the median CD4 count was 653 cells/μl [517–810] and 85 (89.5%) were on antiretroviral therapy (ART). Among all patients, 42.8% (110) had a previous history of syphilis.

A total of 266 patients completed the questionnaire answering more than 85% of the questions (2 cases were excluded from the behavioral analysis due to incompleteness). Overall, in the past 12 months, the median number of contacts was 10 and CAS was practiced in 72.5% of cases. Half (50.6%) of them engaged in sex in group and 54.7% used drugs for sex- 25.0% practiced chemsex and 22.6% engaged in poly drug use. Two-thirds of patients searched for sexual partners through apps and 34.5% through the internet (Table  1 ).

Clinically, in primary syphilis, genital chancre was the most common manifestation in 73.7% (56/76) of cases followed by anal chancre in 22.4% (17/76). Others locations (such as oral or urethral) were uncommon, less than 4% (3/76). All (except 2 cases) were confirmed by positive dark-field microscopy or PCR positive for T. pallidum . Oral chancre was found in 2 patients. Notably, 31.1% had more than one chancre and 2 patients had genital and anal chancres simultaneously. Coexistent chancres in secondary syphilis were observed in 38 (28.5%) of patients. The most frequent secondary lesions were syphilides in the genital area (70.7%) and skin rash (62.1%) affecting the soles (45.0%) more often than the palms of the hands (40.7%). The most common systemic manifestations were asthenia (27.1%), sore throat (22.1%), lymph node enlargement (10.7%), and malaise (10.7%) (Table  2 ).

The median RPR titre at diagnosis was 1/32 [1/8; 1/64]. Among patients offered STI screening, 257 (94.0%) of them received NG and CT / lymphogranuloma venereum tests, with a prevalence of 9.3 and 16.0%, respectively. HIV was tested in 148 patients with 8.8% (13/148) being newly diagnosed while 5 (2.7%) of 189 patients tested positive for HCV (Table  3 ).

The majority of patients were treated with benzathine penicillin G 2.4 million units IM as a single dose (93.0%) and 14 (5.2%) were treated with oral doxycycline 100 mg twice daily for 14 days. About a year after treatment, a four-fold decrease in the non-treponemal test titre was observed in all but 14 patients (2 patients were reinfected, 1 had a serological failure and 11 were missing). Five patients became HIV-positive and 4 new cases of HCV occurred during the first year after syphilis diagnosis. Furthermore, 14 new syphilis reinfection cases occurred, 5 of them in HIV-positive patients.

Molecular typing was performed in 78 anogenital ulcers samples (16 samples could be typed only partially): 55 were from genital ulcers and 23 from anal ulcers. A high variety of strains was found making clinical associations unreliable. The strain type distribution (compared by proportions and graphics) between genital and anal chancre was similar, with 14d/g isolated most often in both (12.7% in genital chancre; 30.4% in anal chancre), followed by 14f/g (9.0% in genital chancre; 17.3% in anal chancre). In multiple chancres, 14d/g was also most common (20.0%). One patient with concomitant genital and anal chancres had different types in anal chancre (14f/g) compared with genital chancre (−p/g partial result).

Comparative study by HIV status

All HIV-positive patients were MSM. Compared with HIV-negative patients, HIV-positive patients were older (39 [34–44] vs 34[29–43] years, p  = 0.01), and were more likely to have had previous episodes of NG, CT, and syphilis, as well as HCV coinfection (Table  4 ). They also had more anonymous contacts in the past 12 months (87.0% vs 91%) with a median of 10 [5.75–32.8],3 [1-7]of which were CAS. There was no difference between the group in insertive anal sex; however, HIV-positive patients had more receptive anal sex (82.8% vs. 67.3%; p  = 0.011) (Table 1 ). Concerning condom use for anal sex, HIV-positive patients were more likely to practice CAS (84.3%) than HIV-negative patients (65.5%; p  = 0.002). Remarkably, 43.1% of HIV-positive patients practiced serosorting and 25.4% practiced seropositioning, while HIV-negative patients more frequently had CAS after having been tested for HIV (Table 1 ). Other risk factors were also more common in HIV-positive patients, such as having sex in group (69.4%), use of toys (46.4%), and drugs for sex (71.0%), mainly involving cocaine, GHB, mephedrone, sildenafil, and crystal methamphetamine. Poly drug use was reported by 34 HIV-positive patients (35.7%) and chemsex by 40 (42.1%). Among HIV-negative patients, 27 (16.1%) reported poly drug use ( p  = 0.05), and 26 (15.5%) reported chemsex ( p  = 0.001). Four patients, all HIV-positive, reported IV drug use. The final regression model showed that HIV-positive patients with syphilis were more likely to have previous syphilis (adjusted-OR, (ad-OR) 4.81 [2.88–8.15)] and previous NG infection (ad-OR 3.8 [2.28–6.43)]. Although mainly related with people with HIV, serosorting (ad-OR 20.4 [7.99–60.96)] was strongly associated with syphilis in HIV-positive patients.

Clinically, in HIV-positive patients, secondary syphilis was the most common stage (61.9%). Primary syphilis was seen less often (15.2%), with a similar proportion to early latent syphilis (22.6%) compared with HIV-negative patients (early latent syphilis in 20.2%,secondary syphilis in 44.5%, primary in 35%; p  = 0.002). After stratifying for previous syphilis as a possible confounding factor, the difference was still significant, secondary syphilis occurred more often in HIV-positive patients without a previous history of syphilis. Anal chancres were more common in HIV-positive patients than in HIV-negative patients (41.2% vs. 17.0%; p  = 0.04). In secondary syphilis, there were no significant difference between these two groups (Table 2 ), even in terms of coexistent chancres. Median RPR titers were higher in HIV-positive patients at 1/64 [1/32–1/64] than in HIV-negative patients at 1/16 [1/4–1/64] p  < 0.001 (Table 3 ). RPR titres stratified by previous history of syphilis showed that this difference persisted among patients without a previous history of syphilis. When RPR titers were stratified by stage the difference disappeared in secondary syphilis, in contrast with primary and early latent syphilis where RPR titers were higher in HIV-positive patients. There were no differences between the two groups in treatment received, evolution of RPR or cure of syphilis after 1 year of treatment ( p  = 0.2).

In our study the dominant profile of the epidemic was MSM. Globally in high-income settings, MSM accounts for a disproportionate burden of syphilis infections [ 19 ]. This study shows that this cohort of patients with early syphilis, especially HIV-positive patients, engage in high-risk sexual behaviors. At our clinic we had previously found an HIV coinfection rate of 30% in a study conducted between 2003 and 2013 [ 20 ]. In this study, we show that this relationship has persisted over time, as we have now found that 36% of patients with syphilis were HIV-positive and 8.5% were newly diagnosed concomitantly with syphilis. HIV and syphilis are related to each other [ 21 , 22 ], and syphilis itself could increase the risk of HIV infection [ 23 ]. However, this increased risk could also be associated with sexual behavior, as HIV-positive patients engage in more high-risk behaviors than HIV-negative patients as we report here, similarly to others researches [ 24 , 25 , 26 , 27 ]. Factors such as sex in group, multiple sex partners, CAS and use of drugs for sex, could also each raise the risk of syphilis [ 3 , 7 ]. However, these factors are mutually linked, a fact that might increase the probability of infection. An example of this interrelationship is chemsex, a growing global phenomenon which has been associated with a higher number of partners and CAS, situations in which patients more likely to be diagnosed with acute rectal or bacterial STIs, and HCV [ 28 ].

From a clinical perspective, HIV may modify the clinical presentation [ 22 ] and course of syphilis. After adjusting for a previous history of syphilis, we found that there were still differences in the stage depending on HIV status, with secondary syphilis being more common among HIV-positive patients, similar to the findings of Hutchinson et al. [ 9 ] An atypical presentation of syphilis, such as multiple chancres and concurrent primary chancres in secondary syphilis, had been described more often in HIV-positive patients [ 8 , 22 ]. In our study we found no such differences with the exception that HIV-positive patients had more anal chancres. This could be explained by seropositioning, in addition to the fact that HIV-positive patients practiced receptive anal sex more often than HIV-negative patients. When taking into account T. pallidum typing, molecular studies have associated some strain types with clinical outcomes, such as neurosyphilis [ 10 ], ocular involvement [ 11 ], or serofast status [ 12 ]. Following this methodology, we explored whether or not multiple chancres and other clinical manifestations of early syphilis could be related to a specific strain. We found a high diversity of strains in a limited sample size, precluding any associations. More refined molecular methods such as multilocus sequence typing (MLST) or whole genome sequencing could perhaps be more conclusive [ 29 ]. We speculate that HIV could influence the clinical presentation of syphilis in a way similar to how immunological factors affect the manifestation of syphilis in patients with a history of syphilis [ 30 ].

Factors that influence the natural course of an infection include host susceptibility, bacterial characteristic and transmissibility, and host immunity [ 31 ]. Rekart et al. [ 32 ] suggested that ART could increase the susceptibility to syphilis due to changes in the innate and adaptive immune responses to T. pallidum by suppressing mitochondrial function, proinflammatory response, and macrophage activation. They concluded that the immunological effects of ART and ART-induced behavioral changes could act synergistically to increase susceptibility to syphilis. Could this be the reason why HIV-positive patients are more likely to have secondary syphilis than HIV-negative patients? In view of our findings on risk behaviors in HIV-positive patients compared with HIV-negative patients, we suggest that sexual behavior probably has a much greater effect than other factors, as Tuddenhem et al. [ 33 ] argued.

This study did have several limitations. First, it was carried out at a single center in Barcelona and, therefore, the findings could not be generalized. Nevertheless, the clinic is a known referral center attending a large number of patients with high-risk sexual behaviors and the main findings are in line with those reported by others elsewhere. Another limitation is the use of self-reporting, sometimes with partial information, an approach that could have influenced some of the results. Apart from the inherent constraints of this method, the limited number of samples for molecular typing made it impossible to gather relevant information on the clinical manifestations of syphilis. Further results on microbiological typing in syphilis obtained in this study will be published elsewhere (Fernandez-Naval C. et al, submitted). Last, the sample size is underpowered to make multiple comparisons between groups but the results are consistent with those of other studies.

In conclusion, HIV-positive MSM patients are more likely than HIV-negative patients to have risk factors for syphilis, such as anonymous contacts, CAS, and chemsex. These factors facilitate syphilis acquisition and and have been found to contribute to the syphilis epidemic in Western countries. HIV-positive patients practicing receptive anal sex and seropositioning may cause them to have anal chancres more often than HIV-negative patients. HIV could influence the natural course of syphilis as secondary syphilis has been found to be more common in HIV-positive patients. These findings are an updated report on syphilis in Barcelona and provide important information to be considered for public health interventions, including STI screening and, access to health services and risk-reduction programs targeting high-risk groups.

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due to the sensitivity of the topic and hence to ensure confidentiality of the information but are available from the corresponding author on reasonable request.

Abbreviations

Antiretroviral therapy

• Condomless anal sex

Confidence interval

Chlamydia trachomatis

Gammahydroxybutrate

Hepatitis C virus

Human immunodeficiency virus

Interquartile range

• Men who have sex with men

Neisseria gonorrhoeae

Polymerase chain reaction

Rapid plasma reagin

Standard deviation

Sexually transmitted infections

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MA and MV contributed to the study design and conduct and to manuscript preparation. MM contributed to the statistical analysis MA, CF, DM, PA, MJB, JE and MV contributed to the acquisition of clinical and microbiological data of patients. MM, CF, DM, PA, MJB and JE reviewed the article. All authors read and approved the final manuscript.

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Arando, M., Fernandez-Naval, C., Mota-Foix, M. et al. Early syphilis: risk factors and clinical manifestations focusing on HIV-positive patients. BMC Infect Dis 19 , 727 (2019). https://doi.org/10.1186/s12879-019-4269-8

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Global, regional, and national trends of syphilis from 1990 to 2019: the 2019 global burden of disease study

• Yu-Ting Tao 1 ,
• Teng-Yu Gao 1 ,
• Hao-Yang Li 1 ,
• Yu-Tong Ma 1 ,
• Hui-Jun Li 1 ,
• Chen-Yang Xian-Yu 1 ,
• Nian-Jia Deng 1 &
• Chao Zhang 1  

BMC Public Health volume  23 , Article number:  754 ( 2023 ) Cite this article

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Syphilis is a sexually transmitted disease caused by Treponema pallidum , and the infection source is syphilis patients. This study aimed to estimate the incidence, mortality rate, and disability-adjusted life years (DALYs) of syphilis to improve the understanding of the current global situation of syphilis.

This study collected data on syphilis incidence, mortality, and DALYs from the 2019 Global Burden of Disease database.

The global number of incident cases and age-standardized incidence rate (ASIR) increased from 8,845,220 (95% UI: 6,562,510–11,588,860) in 1990 to 14,114,110 (95% UI: 10,648,490–18,415,970) in 2019 and 160.03/100,000 persons (95% UI: 120.66–208.1) to 178.48/100,000 persons (95% UI: 134.94–232.34), respectively. The estimated annual percentage change (EAPC) in the ASIR was 0.16 (95% CI: 0.07–0.26). The EAPC in the ASIR associated with high and high-middle sociodemographic indices increased. The ASIR increased among males but decreased among females, and the incidence peaked among males and females between the ages of 20 and 30 years. The EAPCs in the age-standardized death rate and age-standardized DALY rate decreased.

Conclusions

The incidence and ASIR of syphilis increased worldwide from 1990 to 2019. Only the regions with high and high-middle sociodemographic indices showed an increase in the ASIR. Moreover, the ASIR increased among males but decreased among females. The age-standardized death rate and DALY rate both declined worldwide. The increase in the global ASIR of syphilis is a challenge.

Peer Review reports

Syphilis is a sexually transmitted disease caused by Treponema pallidum (TP) [ 1 ], and the infection source is syphilis patients. Syphilis is highly infectious, and its early symptoms are chancroid and syphilis rash [ 2 ]. After contracting syphilis, specific TP antibodies develop in the serum with indefinite positive reactions [ 3 ].

More than 5 million new cases [ 4 ] of syphilis are reported worldwide each year. Epidemiological studies have reported that the incidence of syphilis among males has more than tripled in the United States since 2000, leading to a sharp increase in early cases [ 5 ]. Early in 2012, the World Health Organization reported that the number of infected people aged 15–49 years had reached 17.7 million [ 6 ]. In regions with severe poverty and poor development, syphilis is inevitably widespread, given the prevalence of sexually transmitted diseases. Syphilis emerged as early as the sixteenth century [ 7 ] and has continued to plague humans. To control syphilis, the greatest challenge is preventing transmission. Currently, perceptions and behaviours are more open, and statistical data are needed to determine the current syphilis situation.

The syphilis population according to the Global Burden of Disease (GBD) reports for the last 30 years, from 1990 to 2019, was classified by region, sociodemographic index (SDI), age, and sex, and the incidence, mortality rate, disability-adjusted life years (DALYs), and changing trends of syphilis were statistically estimated. This study can provide national health organizations and syphilis researchers with a better understanding of the global situation of syphilis and effective data to guide the management and prevention of syphilis.

Data sources

The Global Health Data Exchange (GHDx) query tool ( http://ghdx.healthdata.org/gbd-results-tool ) [ 8 ] was used to obtain data including the annual incidence, mortality rate, and DALYs for syphilis from 1990 to 2019. The demographic data of the syphilis population obtained were nationality, sex, and age. Two hundred four countries and territories around the world were divided into 21 subregions [ 9 ] to facilitate in-depth estimations of the trends in different regions. In addition, this study retrieved the SDIs for 204 countries and regions for the last 30 years. The SDIs were categorized into low, low-middle, middle, high-middle, and high, and their association with morbidity, mortality, and DALYs was estimated. The SDI denotes the overall capacity of a country and incorporates income per capita, educational attainment, and total fertility rates, among other factors [ 10 ]. The global disease burden of syphilis was determined with comparison charts and maps.

Statistical analysis

In this study, the incidence and mortality rates of syphilis were evaluated based on the annual age-standardized incidence rate (ASIR), age-standardized death rate (ASDR), and age-standardized DALY rate to prevent the influence of age on the data. The most obvious advantages of the ASIR are that it eliminates the effect of different ages and provides more impartial criteria to explain the epidemic characteristics of syphilis. DALYs are the sum of years lived with disability (YLD) and years of life lost (YLL) [ 11 ] due to premature mortality. The ASR (age-standardized incidence/death/DALY rate) (per 100,000 population) is the sum of the products of the specific age ratios ( \({a}_{i}\) ) of the age groups \((i)\) and the sizes (or weights) ( \({w}_{i}\) ) of the reference standard population groups \((i)\) divided by the sum of the sizes (or weight) of the reference populations; it is represented as \(\mathrm{ASR}=\frac{{\sum }_{i=1}^{A}{a}_{i}{w}_{i}}{{\sum }_{i=1}^{A}{w}_{i}}\times 100, 000\) [ 12 ]. The data for the cases and rates were limited by a 95% uncertainty interval (UI) [ 13 ]. With the known ASR in the database, the estimated annual percentage changes (EAPCs) and their 95% confidence intervals (CIs) can be obtained by the following two regression equations. The formula is y = α + βx + ɛ, \(EAPC=\left(\frac{{\widehat{ASR}}_{x+1}-{\widehat{ASR}}_{x}}{{\widehat{ASR}}_{x}}\right)\cdot 100=\left(\frac{{\widehat{ASR}}_{x+1}}{{\widehat{ASR}}_{x}}-1\right)\cdot 100=\left(\frac{{e}^{\widehat{y}+\widehat{\beta }}\left(x+1\right)}{{e}^{\widehat{y}+\widehat{\beta }}\cdot x}-1\right)\cdot 100=\left(exp\left(\beta \right)-1\right)\times 100\) [ 14 ], where y represents ln (ASR), and x is expressed as the calendar year. We obtained the ASR directly from the database, so plugging x into the first formula can calculate β. Then, the EAPC was calculated by substituting β into the second simplified formula. When the EAPC value and lower limit of the 95% CI are positive, the ASR tends to increase; higher values are associated with more rapid increments in the ASR. When the EAPC value and upper limit of the 95% CI are negative, the ASR tends to decrease; higher absolute values are associated with a more rapid decline in the ASR. When the EAPC value is close to 0 and the maximum and minimum 95% CIs are on either side of 0, the ASR tends to be stable. To more intuitively estimate the changing ASR trends, this study also evaluated the changing situations in different parts of the world through mapping. Scatter plots were used to determine the relationship between the ASR and SDI, with positive and negative ρ (Pearson’s coefficient) values representing positive and negative correlations, respectively. P values less than 0.05 denoted statistical significance. In this study, a visual flow chart (Fig.  1 ) was drawn to present the research process more clearly.

Visualized flow chart for describing methods

Global burden of syphilis

The global incidence of syphilis increased from 8,845,220 (95% UI: 6,562,510–11,588,860) in 1990 to 14,114,110 (95% UI: 10,648,490–18,415,970) in 2019 (Table 1 ) at an approximate rate of 60%. The ASIR increased from 160.03/100,000 persons (95% UI: 120.66–208.1) to 178.48/100,000 persons (95% UI: 134.94–232.34). The global ASIR continued to increase rapidly, especially from 2010 to 2019. In five SDI subregions, the ASIR was inversely correlated with the SDI from 1990 to 2019 and almost consistently five times higher in territories with low SDIs than in those with high SDIs (Fig.  2 A). The EAPCs for middle (-0.18, 95% CI: -0.30– -0.06), low-middle (-0.27, 95% CI: -0.39 – -0.15) and low (-0.74, 95% CI: -0.80– -0.67) SDI regions showed a decreasing ASIR from 1990 to 2019. In contrast, the EAPCs for high SDI regions were greater than 0, indicating that the ASIRs were increasing (Table 1 ). The comprehensive ASIR chart in Fig.  2 A shows that the ASIRs in low SDI regions increased annually from 2015 to 2019, and the ASIRs in other regions increased from 2010 to 2019.

The change trends of incident cases, ASIR and EAPC among different SDI quintiles. Note: A indicates the variation trend of ASIR in different SDI over time, B indicates the incident cases of different SDI, C indicates the correlation between SDI and ASR among 21 regions, D indicates the ASIR in map, E indicates EAPC of ASIR in map

The global ASDR decreased from 1.55/100,000 persons (95% UI: 0.54–3.24) in 1990 to 1.28/100,000 persons (95% UI: 0.45–2.62) in 2019 (Table 2 ), and the age-standardized DALY rate also decreased from 135.08/100,000 persons (95% UI: 45.61–284.1) in 1990 to 113.09/100,000 persons (95% UI: 39.49–231.38) in 2019 (Table 3 ). Their EAPCs were -1.06 (95% CI: -0.89– -1.23) and -1.01 (95% CI: -1.18– -0.84), respectively. However, from the perspective of trend changes, the global ASDR and age-standardized DALY rate decreased rapidly before 2010 before slowing down from 2010 to 2017; there were minimal increments after 2017. Compared to the ASIR, the ASDR and age-standardized DALY rate were also inversely correlated with the SDI, and the ASDR and age-standardized DALY rate for low SDI regions were almost 100 times higher than those for high SDI regions in 1990 and 2019 (Supplementary Figs.  1 A and 2 A).

With the increase in the SDI, the changes in the ASIR, ASDR, and age-standardized DALY rate in 2019 were similar ( P  < 0.05) (Supplementary Fig.  3 A, B, and C), and Pearson's coefficient was negative; however, the ASDR and age-standardized DALY rate peaked when the SDI approached 0.3. The EAPC was negatively correlated with the ASIR but positively correlated with the ASDR and age-standardized DALY rate in 1990 (Supplementary Fig.  3 D, E, and F).

Global burden of syphilis by region

In the 21 regions, South Asia recorded the highest number of incident cases at 2,332,440 (95% UI: 1,691,290–3,098,810) in 1990, and Australia recorded the lowest number of incident cases at 14,100 (95% UI: 10,460–18,960). Central Sub-Saharan Africa recorded the highest ASIR of 1,153.28/100,000 persons (95% UI: 880.53–1,482.29), while South Asia ranked seventh (Table 1 ). In 2019, Central Sub-Saharan Africa still recorded the highest ASIR among the 21 regions. In South Asia, the annual cases increased by 59.7% from 1990 to 2019, but the ASIR decreased to 190.99/100,000 persons (95% UI: 140.95–254.13), and the EAPC was -0.71 (95% CI: -0.95– -0.47) (Table 1 ). The situations in most regions were similar to those in South Asia, but European countries had fewer cases and lower ASIRs in 2019 than in 1990; given the negative EAPC, the number of incident cases and ASIR were much lower than for other territories.

From 1990 to 2019, Central Sub-Saharan Africa and many other African regions consistently had the highest ASIRs among the 21 regions (Figs.  2 C and 3 ). In Latin America, the ASIR for Andean Latin America was the highest, and that of South Asia was the highest in Asia. The ASIR was generally lower for Europe than for other regions. As shown in Fig.  3 , the ASIR has shown the most rapid increase since 2005 for Tropical Latin America and has increased rapidly since 2010 after a sharp decline for Southern Sub-Saharan Africa. Although the ASIR in Central Sub-Saharan Africa fluctuated, it tended to decline overall.

The trend of ASIR with the year among 21 regions

Central Sub-Saharan Africa consistently had a low SDI and a high ASIR between 1990 and 2019 (Fig.  2 C), while Western Sub-Saharan Africa and Eastern Sub-Saharan Africa had less than half of the ASIR of Central Sub-Saharan Africa with similar SDIs. Southern Sub-Saharan Africa had a moderate SDI, but its ASIR was markedly higher than those of other regions with similar SDIs.

The map in Fig.  2 D shows darker red areas corresponding to Central and Southern Sub-Saharan Africa, indicating higher ASIRs for these regions in 2019. The EAPC for the ASIR is represented by the deepest red on the map for Greece, followed by that for Mongolia, indicating that their ASIRs were increasing at almost the fastest rate worldwide (Fig.  2 E). In addition, from the base data, India and China had the highest numbers of incident cases, 2,729,026.77 (95% UI: 2,009,271.45–3,626,658.48) and 1,411,512.57 (95% UI: 1,055,475.01–1,896,966.91), respectively, among 204 countries and territories in 2019 (Supplementary Table 1 ).

In 1990, the three regions with the highest ASDRs were Central Sub-Saharan Africa, Eastern Sub-Saharan Africa, and Southern Sub-Saharan Africa (Table 2 ). The same pattern was observed for the age-standardized DALY rate (Table 3 ). In 2019, with the global decline in the ASDR and age-standardized DALY rate, the EAPC of the ASDR in Eastern Europe was -9.75 (95% CI: -8.09– -11.37), and the EAPC of the age-standardized DALY rate was -7.80 (95% CI: -9.32– -6.25), which was the maximum for the 21 regions. The ASDR and age-standardized DALY rate are still increasing in the Caribbean and Southeast Asia. Eastern Sub-Saharan Africa, Central Sub-Saharan Africa, and Oceania have low-level SDIs, and their ASDRs and age-standardized DALY rates are nearly the highest in the world (Supplementary Figs.  1 C and 2 C). Among the 204 countries and territories, the two countries with the greatest number of deaths in 2019 were Nigeria, located in Africa, and India, 8,785.56 (95% UI: 2,805.97–20,068.23) and 7,175.64 (95% UI: 2,417.34–15,408.55), respectively (Supplementary Table 2 ). Even though the number of incident cases in China ranked second among 204 countries and territories, after India, the number of deaths in China ranked fifteenth, substantially lower than those in India in 2019. Similarly, Nigeria and India also had the highest DALYs among these territories, 779,214.85 (95% UI: 248,649.87–1,780,486.93) and 621,529.6 (95% UI: 198,919.02–1,350,394.75), respectively (Supplementary Table 3 ). Additional visual conditions for the ASDR and age-standardized DALY rate are shown in Supplementary Figs.  1 and 2 .

Global burden of syphilis by age and sex

Intuitively, both globally and in the five SDI regions, the incident cases, deaths and DALYs among males were higher than those among females (Fig.  2 B, Supplementary Figs.  1 B and 2 B). Similarly, the ASIR, ASDR, and age-standardized DALY rate for males have always been markedly higher than those for females (Tables 1 , 2 and 3 and Fig.  4 A). The ASIR of syphilis has increased worldwide but has declined for females, with an EAPC of -0.30 (95% CI: -0.49– -0.11) (Table 1 and Fig.  4 D). Only Tropical Latin America and Southern Latin America showed ASIRs for females higher than those for males for the entire 30 years; in Tropical Latin America, the male ASIR has stabilized, but the female ASIR has surged rapidly in recent years. The ASIR for females declined rapidly to become lower than that for males in Southern Sub-Saharan Africa, while it increased slowly to become greater than that for males in the Caribbean (Figs.  3 and 4 C). There was an overall inverse relationship between the ratio of male to female incidence rate and SDI in 204 countries and territories, and the inverse relationship is more pronounced after SDI greater than 0.5 (Fig.  4 B).

The ASIR, SDI and EAPC of male and female. Note: A indicates ASIR in male and female from 1990 to 2019, B indicates the correlation between the ration of female to male incident cases and SDI, C indicates the ASIR of male and female in 21 regions, D indicates the EAPC of ASIR in male and female among 21 regions

The ASDR and age-standardized DALY rate for both males and females have declined globally, but they were always higher for males than for females (Tables 2 and 3 ). In 1990 and 2019, the incidence of syphilis showed a unimodal peak for all ages for both males and females, with a peak at 20–24 years for females and 24–29 years for males. There were more infected female than male patients younger than 19 years and older than 19 years (Fig.  5 A and B). Children under the age of five had a higher death rate and DALY rate than any other age group in both 1990 and 2019 (Fig.  5 C, D, E, F).

The incidence, death and DALYs rates of male and female at different ages in 1990 and 2019. Note: A indicates the incidence rate of male and female at different ages in 1990, B indicates the incidence rate of male and female at different ages in 2019, C indicates the death rate of male and female at different ages in 1990, D indicates the death rate of male and female at different ages in 2019, E indicates the DALYs rate of male and female at different ages in 1990, F indicates the DALYs rate of male and female at different ages in 2019

This study statistically estimated the global syphilis situation from 1990 to 2019 using data from the GBD 2019. Overall, there was a minimal increase in the morbidity rate, whereas the mortality rate and DALY rate decreased during the past 30 years. Although the overall situation of syphilis has improved slightly, there are still large differences in terms of the syphilis situation in different regions of the world, which is closely related to the economic, medical and educational levels of different regions and countries. For example, in areas with high SDIs, syphilis transmission is relatively less widespread, while in areas with low SDIs, syphilis is more widespread. Therefore, this study evaluated the situation of syphilis at the global level and regional level from various aspects.

The GBD database divides the world into 21 unique regions. Sub-Saharan Africa has always had a higher burden of syphilis [ 15 ]; its ASIR was generally high, and the ASIRs for Central and Southern Sub-Saharan Africa were the highest. Africa has had a long history of slow and inefficient development, which has markedly been less rapid than that of other regions; this is partially attributed to the subpar medical system. The lack of a comprehensive system of prevention, screening, and treatment [ 16 ], coupled with the tropical climate in Africa, facilitates the spread of several diseases. The lack of medical treatment facilities and disease prevention strategies and the weak economy in areas in Africa facilitate the wanton spread of diseases without any obstacles. The Central African Republic, which had the highest incidence among the 204 countries and regions, unsurprisingly had a low SDI. In contrast, the ASIR for Europe was generally low. Regions such as Europe are generally considered to be well developed, and they have medium or higher SDIs, most of which are high-middle or high. However, the prevalence of syphilis has continued to increase in these high-income countries in recent years [ 6 ]. As seen in the results, the ASIR of syphilis increased worldwide, especially in two countries, Greece and Mongolia, where small populations play an important role. China and India have large populations; large numbers of incident cases were hidden in large populations. The result, therefore, was a large number of incident cases with an inconspicuous upward trend.

The GBD data showed that the ASDR and age-standardized DALY rate overlapped both globally and for the 21 individual regions. Their change patterns were similar to those of the ASIR. The ASDR and age-standardized DALY rate were higher in low-SDI areas but lower in high-SDI areas. The inadequacy of medical care leaves syphilis sufferers with little hope and a lifetime of caution. Especially in the late stages of syphilis, the consequences can be lifelong disability and even loss of life expectancy when the disease affects the cardiovascular and nervous systems. For example, TP invades arteries and causes arteritis, which may develop into more serious pathological phenomena, such as aneurysms [ 17 ]. Other complications include blindness and permanent hearing loss [ 18 ] caused by syphilis. The above adverse effects of syphilis could directly lead to an increase in YLL and YLD without prevention and control, which is ultimately reflected in the DALY burden. However, countries and regions with high ASDRs and age-standardized DALY rates are still concentrated in sub-Saharan Africa.

Before 2015, the ASIR, ASDR, and age-standardized DALY rate of syphilis had all substantially decreased, especially in areas with low and low-middle SDIs. This implies that with the development of comprehensive capabilities worldwide, there have been improvements in each region. However, the ASIR began increasing again after 2015 [ 19 ], which means that there are unpredictable difficulties in preventing or treating syphilis, leading to a resurgence in syphilis incidence, mortality and DALYs. These are global changes in the ASIR. However, the ASIR declined in most regions between 1990 and 2019.

Although treatment and prevention strategies are available, syphilis has not yet been completely eliminated. Therefore, there is still a long way to go in the fight against syphilis. With the advent of penicillin, the first kind of antibiotic, within the last century [ 20 ], syphilis is no longer incurable. Early syphilis can be cured with long-term penicillin treatment [ 21 ], but it is often difficult for patients to receive continuous penicillin treatment and titre testing. Patients often return to normal life without complete recovery or regular testing because syphilis is difficult to control. Moreover, the adverse consequence of the long-term use of antibiotics is resistance to antibiotics, such as penicillin and macrolides, which are the first- and second-line drugs for the treatment of syphilis, respectively [ 22 ]. However, antibiotic resistance due to misuse is now a global problem, not just a problem of syphilis treatment. On the other hand, screening is a pivotal step in syphilis prevention [ 23 ], and all countries and territories cannot perfectly prevent syphilis. All these factors may lead to the spread of syphilis and make it more difficult to control, so this is not a good trend for global public health prevention and control. To solve the problem of syphilis completely, it is necessary to find a new method for antibiotic treatment and prevention screening.

The high incidence rates in both males and females were concentrated in the adolescent stage. However, the peak age of incidence rate in females is 20 to 24 years, whereas in males it is 25 to 29 years. This is associated with slightly earlier exposure to sex, including precocious puberty and forced sexual assault, in females than in males [ 24 ]. The increase in the number of men who have sex with men can not only lead to wide spread of syphilis in males but also in heterosexual relationship [ 25 ]. From this perspective, reasonable and safe sexuality erotism can be helpful in the control of syphilis.

Strikingly, the ASDR and age-standardized DALY rate of syphilis among children under 5 years of age were much higher than those of any other age groups, and even played a decisive role in death and DALY burden globally. Pregnant women infected with syphilis who are not cured will transmit syphilis to the foetus, which can lead to stillbirth or neonatal death [ 26 ], or even if born alive, the children can be crippled for life by syphilis, leading to severe mortality and DALYs among children under 5 years of age. According to the World Health Organization [ 27 ], more than 500,000 cases of congenital syphilis were recorded in 2016, including more than 200,000 stillbirths and deaths. Such a high mortality rate makes congenital syphilis the second leading cause of stillbirth after malaria globally. Congenital syphilis demonstrated an increasing prevalence in several parts of developed European countries in 2011 [ 28 ]. Pregnant women who are infected with syphilis after the prenatal exam can go unnoticed and are more difficult to treat [ 29 ]. Therefore, maternal health care after pregnancy is essential for managing syphilis [ 30 ], and regular prenatal care is the best way to monitor the foetal condition.

This study had the following highlights. First, the GBD 2019 is one of the most complete databases on the global burden of disease and contains data on 354 diseases in 204 countries and territories from 1990 to 2019. Second, this study estimated the global burden of syphilis from 1990 to 2019 by SDI, sex and age in 21 regions. This will help researchers to more clearly understand the characteristics of the syphilis epidemic over the last 30 years, and at the same time, allow people to pay more attention to the target population of syphilis. Third, age-standardized rates can eliminate the influence of age and better compare the trend of syphilis between different countries and territories, supplemented by the EAPC to obtain trends over the 30-year period. Finally, in addition to the tables, this study adopted figures to visually present the research results and make more targeted statistical analyses of SDIs, sex and age in 21 regions.

However, this study has the following limitations. First, the GBD database does not have accurate records of all syphilis cases, leading to an underestimation. The database includes low-quality evidence from underdeveloped regions and outdated data. In addition, some individuals may avoid screening or hide their pathogenetic condition because of sexual shame, and some individuals cannot be detected from serological tests [ 31 ] in the early incubation period due to the absence of obvious symptoms, both resulting in the omission of the fact that syphilis is present. These above factors may have led to an underestimation of the data. Second, this study could not estimate trends in syphilis from a racial perspective because specific categories of race were not included in the GBD database. Finally, the smallest estimated units in the GBD database are countries and territories, and the data could not be further compared by province, urban or rural categories.

In general, the incidence of syphilis is increasing worldwide, but the mortality rate and DALYs have improved. Although the incidence of sexually transmitted diseases has decreased in Sub-Saharan Africa, it is still markedly higher than in other regions. In South Asia, the incidence is not significant; however, the number of cases is high, which places a considerable burden on public health prevention and control. The incidence of syphilis is highest among adolescents, and adolescent sex education should be given urgent attention. If appropriate steps are not taken, an increase in the incidence of syphilis will place substantial stress on humans.

Availability of data and materials

To download the data used in these analyses, please visit the Global Health Data Exchange GBD 2019 data-input sources tool at http://ghdx.healthdata.org/gbd-2019/data-input-sources . No permission is required for anyone to access this data.

Abbreviations

Age-standardized death rate

Age-standardized incidence rate

Confidence interval

• Disability-adjusted life year

Estimated annual percentage change

Global Burden of Disease

Global Health Data Exchange

Socio-demographic index

Treponema pallidum

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Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, No.32, Renmin South Road, Shiyan, 442000, Hubei, China

Yu-Ting Tao, Teng-Yu Gao, Hao-Yang Li, Yu-Tong Ma, Hui-Jun Li, Chen-Yang Xian-Yu, Nian-Jia Deng & Chao Zhang

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CZ designed the research; YTT, TYG and HYL collected the data and verified the accuracy of the data. YTM, NJD and CY XY verified the accuracy of the data; YTT, HJL and TYG contributed to data interpretation; TYG, YTT and HYL performed the statistical analysis and visualization; YTT wrote the manuscript. All authors read, critically reviewed, and approved the final manuscript.

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Supplementary Information

Additional file 1:.

Supplementary Table 1. The incident cases and ASIR of syphilis in 1990 and 2019, and its temporal trends from 1990 to 2019. Supplementary Table 2. The death cases and ASDR of syphilis in 1990 and 2019, and its temporal trends from 1990 to 2019. Supplementary Table 3. The DALYs and Age-standardized DALY rate of syphilis in 1990 and 2019, and its temporal trends from 1990 to 2019.  Supplementary Figure 1. The change trends ofdeath cases, ASDR and EAPC among different SDI quintiles. SupplementaryFigure 2. The change trendsof DALYs, age−standardized DALY rate and EAPC among different SDI quintiles. SupplementaryFigure 3. The correlationbetween ASIR, ASDR, age−standardized DALY in 2019 and SDI, and the correlationbetween EAPCs and ASIR, ASDR, DALY in 1990.

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Tao, YT., Gao, TY., Li, HY. et al. Global, regional, and national trends of syphilis from 1990 to 2019: the 2019 global burden of disease study. BMC Public Health 23 , 754 (2023). https://doi.org/10.1186/s12889-023-15510-4

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• Published: 12 October 2017
• Rosanna W. Peeling 1 ,
• David Mabey 1 ,
• Mary L. Kamb 2 ,
• Xiang-Sheng Chen 3 ,
• Justin D. Radolf 4 &
• Adele S. Benzaken 5  

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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.

Introduction

Syphilis is a sexually transmitted infection (STI) that can also be transmitted vertically. It is caused by the spirochaete Treponema pallidum subspecies pallidum (order Spirochaetales) ( Fig. 1 ). Three other organisms within this genus are causes of nonvenereal or endemic treponematoses. T. pallidum subspecies pertenue is the causative agent of yaws, T. pallidum subspecies endemicum causes endemic (nonvenereal) syphilis and T. carateum causes pinta. These pathogens are morphologically and antigenically indistinguishable. However, they can be differentiated by their age at acquisition, principal mode of transmission, clinical manifestations, capacity for invasion of the central nervous system (CNS) and placenta, and genomic sequences, although the accuracy of these differences remains a subject of debate 1 . Analyses based on the mutation rates of genomic sequences suggest that the causative agents of yaws and venereal syphilis diverged several thousand years ago from a common progenitor originating in Africa 2 . These estimates argue against the so-called Columbian hypothesis — the notion that shipmates of Christopher Columbus imported a newly evolved spirochaete causing venereal syphilis from the New World into western Europe in the late 15th century 3 .

a | Like all spirochaetes, Treponema pallidum consists of a protoplasmic cylinder and cytoplasmic membrane bounded by a thin peptidoglycan sacculus and outer membrane 239 , 240 . Usually described as spiral-shaped, T. pallidum is actually a thin planar wave similar to Borrelia burgdorferi , the agent that causes Lyme borreliosis 239 . The bacterium replicates slowly and poorly tolerates desiccation, elevated temperatures and high oxygen tensions 55 . b | Periplasmic flagellar filaments, a defining morphological feature of spirochaetes, originate from nanomotors situated at each pole and wind around the cylinder atop the peptidoglycan, overlapping at the middle of the cell. Force exerted by the rigid filaments against the elastic peptidoglycans deforms the sacculus to create the flat-wave morphology of the spirochaete 100 . Panel b is reproduced with permission from American Society for Microbiology (Ref. 239 ): Journal of Bacteriology, volume 191, 7566–7580, doi: 10.1128/JB.01031-09. c | Ultrathin section of T. pallidum showing the outer and cytoplasmic membranes and flagellar filaments (endoflagella) within the periplasmic space 9 . d | Surface rendering of a flagellar motor based on cryo-electron tomograms. Panel d is reproduced with permission from Ref. 240 , Elsevier. e | Darkfield micrograph showing the flat-wave morphology of T. pallidum . The arrow and arrowhead indicate segments that are oriented 90° from each other. The different appearances of the helical wave at 90° to the viewer can be explained only by a flat-wave morphology; a corkscrew shape would appear the same from any angle. Panel e is reproduced with permission from American Society for Microbiology (Ref. 239 ): Journal of Bacteriology, volume 191, 7566–7580, doi: 10.1128/JB.01031-09.

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T. pallidum is an obligate human pathogen renowned for its invasiveness and immune-evasiveness 4 – 7 ; clinical manifestations result from the local inflammatory response elicited by spirochaetes replicating within tissues 8 – 10 . Infected individuals typically follow a disease course divided into primary, secondary, latent and tertiary stages over a period of ≥10 years. Different guidelines define early latency as starting 1–2 years after exposure. Typically, ‘early syphilis’ refers to infections that can be transmitted sexually (including primary, secondary and early latent infections) and is synonymous with active (infectious) syphilis; the WHO defines ‘early syphilis’ as an infection of <2 years duration 11 , whereas the guidelines from the United States 12 and Europe 13 define it as an infection <1 year in duration. These differences in definition can affect the interpretation of results and the prescription of therapeutic regimens used in some circumstances.

Owing to its varied and often subtle manifestations, which can mimic other infections, syphilis has earned the names the Great Imitator and Great Mimicker 14 . Patients with primary syphilis present with a single ulcer (chancre) or multiple lesions on the genitals or other body sites involved in sexual contact and present regional lymphadenopathy ∼ 3 weeks after infection; these are typically painless and resolve spontaneously. Resolution of primary lesions is followed 6–8 weeks later by secondary manifestations, which can include fever, headache and a maculopapular rash on the flank, shoulders, arm, chest or back and that often involves the palms of the hands and soles of the feet. As signs and symptoms subside, patients enter a latent phase, which can last many years. A patient in the first 1–2 years of latency is still considered infectious owing to a 25% risk of secondary syphilis-like relapses 15 . Historical literature suggests that 15–40% of untreated individuals will develop tertiary syphilis, which can manifest as destructive cardiac or neurological conditions, severe skin or visceral lesions (gummas) or bony involvement 9 . Recent data suggest that tertiary syphilis is less common today, perhaps owing to the wide use of antibiotics. Numerous case reports and small series suggest that HIV infection increases the risk of neuro-ophthalmological complications in those with syphilis 16 . Importantly, neurosyphilis is typically described as a late manifestation but can occur in early syphilis. Indeed, T. pallidum can be frequently identified in the cerebral spinal fluid (CSF) of patients with early disease 9 , 15 , 17 . However, the majority of patients with early syphilis who have CSF abnormalities do not demonstrate CNS symptoms and do not require therapy for neurosyphilis 12 . Symptomatic manifestations of neurosyphilis include chronic meningitis, meningovascular stroke-like syndromes and manifestations common in the neurological forms of tertiary syphilis (namely, tabes dorsalis and general paresis, a progressive dementia mimicking a variety of psychotic syndromes) 9 . Numerous case reports and small series suggest that HIV infection predisposes individuals with syphilis to neuro-ophthalmological complications 16 . Cardiovascular syphilis, typically involving the aortic arch and leading to aneurysmal dilatation, usually occurs 10–30 years after the initial infection 9 .

Sexual transmission of syphilis occurs during the first 1–2 years after infection (that is, during primary, secondary and early latent stages of infection) 9 . The risk of mother-to-child transmission (MTCT) is highest in primary and secondary stages, followed by the early latent stage. However, transmission risk continues during the first 4 years after exposure, after which the risk of vertical transmission declines over time 18 . The rate of fetal infection depends on the stage of maternal infection, with ∼ 30% of pregnancies resulting in fetal death in utero , stillbirth (late second and third trimester fetal death) or death shortly after delivery 19 – 21 . Infants born to infected mothers are often preterm, of low birthweight or have clinical signs that mimic neonatal sepsis (that is, poor feeding, lethargy, rash, jaundice, hepatosplenomegaly and anaemia).

Given that T. pallidum has a long generation time of 30–33 hours 22 , long-acting penicillin preparations (such as benzathine penicillin G) are the preferred therapies for most patients with syphilis. Since the 1940s (when penicillin became widely available), syphilis prevalence has continued to decline in regions able to appropriately test for and treat the infection. However, syphilis outbreaks continue to occur throughout the world. In particular, with declining AIDS-related mortality related to effective HIV treatment over the past two decades, syphilis has re-emerged in urban settings among men who have sex with men (MSM). High-income and middle-income countries have observed rises in syphilis case rates as well as increased neurosyphilis case rates (such as ocular syphilis) and, in some countries, congenital syphilis. In low-income countries where syphilis prevalence has remained high, MTCT of syphilis continues to be the most common cause of STI-related mortality outside HIV 23 , 24 , with perinatal deaths owing to untreated syphilis exceeding those due to HIV or malaria 25 . Following malaria, syphilis is now the second-leading cause of preventable stillbirths worldwide 25 .

Syphilis should be an ideal disease for elimination as it has no known animal reservoir, can usually be diagnosed with simple and inexpensive tests and can be cured 9 , 16 . Nevertheless, syphilis remains a continuing public health challenge globally 26 . In this Primer, we describe recent discoveries that have improved our understanding of the biological and genetic structure of the pathogen, novel diagnostic tests and testing approaches that can improve disease detection and current, evidence-based management recommendations. We also draw attention to the call for the global elimination of MTCT of syphilis and HIV, as well as recent successes in eliminating syphilis in low-income and middle-income countries (LMICs), particularly through fundamental public health strategies such as ensuring quality antenatal care that includes testing for syphilis early in pregnancy and providing prompt treatment of women and their partners. We also report on the rising numbers of syphilis cases in MSM and ongoing work supporting improved interventions against syphilis in marginalized populations and, ultimately, the development of an effective vaccine.

Epidemiology

According to the most recent estimation of the WHO, ∼ 17.7 million individuals globally 15–49 years of age had syphilis in 2012, with an estimated 5.6 million new cases every year 27 ( Fig. 2 ). The estimated prevalence and incidence of syphilis varies substantially by region or country, with the highest prevalence in Africa and >60% of new cases occurring in LMICs 27 . The greatest burden of maternal syphilis occurs in Africa, representing >60% of the global estimate 23 , 24 .

The WHO estimates of incident cases of syphilis by region in 2012 are shown for the different geographical regions. Data from Ref. 27 .

Prevalence and incidence

In LMICs, the heterosexual spread of syphilis has declined in the general population but remains problematic in some high-risk subpopulations, such as female sex workers (FSWs) and their male clients. A recent study of FSWs in Johannesburg, South Africa, showed that 21% of participating women had antibodies suggestive of past or current infection, and 3% had an active (infectious) infection 28 . Another study of FSWs in 14 zones in Sudan showed a high seroprevalence (median 4.1%), with the highest value (8.9%) in the eastern zone of the country 29 . A large study of >1,000 FSWs in Kampala, Uganda, showed that 21% were seropositive for syphilis and 10% had an active infection 30 . Studies in emerging economies, such as China, indicate that syphilis is increasing among ‘mobile men with money’ (Ref. 31 ). Although syphilis case rates are low in the general population in China, syphilis prevalence is ∼ 5% among FSWs and ∼ 3% among their male clients 31 , 32 . The risk of infection varies among FSWs working in different venues, with the highest prevalence ( ∼ 10%) among street-based FSWs and the lowest prevalence ( ∼ 2%) among venue-based FSWs 33 .

By contrast, higher-income countries have had declining syphilis prevalence among heterosexual men and women. However, a resurgence of syphilis that disproportionately affects MSM has been noted. Syphilis is associated with high-risk sexual behaviours and infection substantially increases in association with HIV transmission and acquisition. Indeed, the numbers and rates of reported cases of syphilis among MSM in the United States and western Europe have been increasing since 1998 (Ref. 34 ). In 2015, the case rate for primary and secondary syphilis among MSM (309 per 100,000) in the United States was 221-fold the rate for women (1.4 per 100,000) and 106-fold the rate for heterosexual men (2.9 per 100,000) 35 . In Canada, the incidence of syphilis was 300-fold greater among MSM positive for HIV than the reported case rate in the general male population 36 . Syphilis infection has been associated with certain behavioural and other factors, including incarceration, multiple or anonymous sex partners, sexual activity connected with illicit drug use, seeking sex partners on the Internet and other high-risk sexual network dynamics 37 – 41 . Risk factors for syphilis are frequently overlapping 40 . Reports of unusual presentations and rapid progression of syphilis in patients with concurrent HIV infection have led to the hypothesis that infection with or treatment for HIV alters the natural history of syphilis 42 .

Adverse birth outcomes caused by fetal exposure to syphilis are preventable if women are screened for syphilis and treated before the end of the second trimester of pregnancy 21 . However, MTCT of syphilis caused such a high rate of perinatal and infant mortality that, in 2007, the WHO and partners launched a global initiative to eliminate it as a public health problem 43 – 45 . At the time of the campaign launch, ∼ 1.4 million pregnant women had active syphilis infections, of whom 80% had attended at least one antenatal visit, suggesting missed opportunities for testing and treatment 23 . At that time, untreated maternal syphilis infections were estimated to have resulted in >500,000 adverse pregnancy outcomes, including >300,000 perinatal deaths (stillbirths and early neonatal deaths).

Syphilis testing and treatment during pregnancy are highly effective and were included in the Lives Saved Tool for effective maternal–child health interventions 46 . Furthermore, studies have shown that prenatal syphilis screening, testing to support treatment and treatment during pregnancy are highly cost-effective in most countries regardless of disease prevalence or the availability of resources and can even be cost-saving in LMICs with a syphilis prevalence ≥3% in pregnant women 47 – 50 . In China, where syphilis and HIV prevalence in pregnant women are low but increasing, the integration of prenatal syphilis and HIV screening was shown to be highly cost-effective 51 .

Since 2007, an increasing number of countries have implemented regional and national initiatives to prevent MTCT of syphilis 52 , improving guidance documents, using point-of-care (POC) tests as a means of improving access to testing and treatment and integrating behavioural and medical interventions into HIV prevention and control programmes 53 . By 2012, these efforts had contributed to a reduction in the global number of adverse pregnancy outcomes due to MTCT of syphilis to 350,000, including 210,000 perinatal deaths, and had decreased the rates of maternal and congenital syphilis by 38% and 39%, respectively 23 , 24 . In 2015, Cuba became the first country to be validated for having achieved the elimination of MTCT of HIV and syphilis 54 . Subsequently, Thailand, Belarus and four United Kingdom Overseas Territories (Bermuda, the Cayman Islands, Montserrat and Antigua) were validated for the elimination of MTCT of HIV and syphilis, Moldova was validated for the elimination of MTCT of syphilis and Armenia was validated for the elimination of MTCT of HIV. However, these gains were mostly in Asia and the Americas — the maternal prevalence in Africa has remained largely unchanged 23 , 24 .

Mechanisms/pathophysiology

Although a local inflammatory response elicited by spirochaetes is thought to be the root cause of all clinical manifestations of syphilis 9 , the mechanisms that cause tissue damage, as well as the host defences that eventually gain a measure of control over the bacterium, are ill-defined. The recalcitrance of T. pallidum to in vitro culture and the consequent inability to harness genetic techniques to delineate its virulence determinants remain the primary obstacles to progress 55 . Additionally, the fragility and low protein content of its outer membrane have confounded efforts to characterize surface-exposed molecules 56 , 57 . Finally, facile murine models to dissect the host response and the components of protective immunity are also lacking 58 . Outbred rabbits are essential for isolating T. pallidum strains from clinical specimens 59 and for routine propagation in the laboratory 60 . Because rabbits are highly susceptible to T. pallidum infection, develop lesions grossly and histopathologically resembling chancres following intradermal inoculation and generate antibody responses similar to those in humans, the rabbit is the model organism of choice for studying endogenous and exogenous protective immunity 61 , 62 . However, the rabbit model poorly recapitulates some clinical and immunological facets of the human disease 63 . Not surprisingly, even in the post-genomics era, our understanding of the pathogenic mechanisms in syphilis lags well behind that of other common bacterial diseases 63 .

Molecular features

The morphological features of T. pallidum are described in Fig. 1 . Because of its double-membrane structure, the spirochaete is often described as a Gram-negative bacterium. However, this analogy is phylogenetically, biochemically and ultrastructurally inaccurate 63 , 64 . The T. pallidum outer membrane lacks lipopolysaccharides 65 and has a markedly different phospholipid composition than the outer membranes of typical Gram-negative bacteria 66 . Although T. pallidum expresses abundant lipoproteins, these molecules reside predominantly below the surface 5 , 63 , 67 . Accordingly, this paucity of surface-exposed pathogen-associated molecular patterns (PAMPs) enables the spirochaete to avoid triggering host innate surveillance mechanisms, facilitating local replication and early dissemination. Its limited surface antigenicity promotes the evasion of adaptive immune responses (that is, antibody recognition), facilitating persistence 5 , 56 , 68 , 69 . Collectively, these attributes have earned T. pallidum its designation as ‘the stealth pathogen’ (Refs 63 , 69 ). Understanding events unfolding at the host–pathogen interface requires a detailed knowledge of the T. pallidum repertoire of surface-exposed proteins. However, characterization of the protein constituents of the outer membrane has been, and continues to be, daunting 8 , 55 , 57 , 63 .

Lipoproteins . In the 1980s, investigators screened E. coli recombinant libraries with syphilitic sera and murine monoclonal antibodies based upon the unproven (and, as it turned out, immunologically incorrect) assumption that immunoreactive proteins ought to be surface-exposed in T. pallidum 57 . Biochemical and genetic analyses subsequently revealed that most of the antigens identified by these screens are lipoproteins 70 – 72 tethered by their N-terminal lipids to the cytoplasmic membrane (hence, the protein moieties are in the periplasmic space) 67 , 73 – 75 . However, convincing evidence now shows that the spirochaete displays small amounts of lipoproteins on its surface that have the potential to enhance infectivity ( Fig. 3 ). For example, TP0751 (also known as pallilysin) is a laminin-binding lipoprotein and zinc-dependent metalloproteinase capable of degrading clots and the extracellular matrix 76 – 78 . Although expressed by T. pallidum in minute quantities, surface exposure of TP0751 has been demonstrated by knock-in experiments in Borrelia burgdorferi (the spirochaete that causes Lyme borreliosis 79 ) and the cultivatable commensal treponeme Treponema phagedenis 80 , in opsonophagocytosis assays in T. pallidum 77 and, most recently, in the protection of immunized rabbits against the dissemination of spirochaetes following intradermal challenge 81 . The X-ray structure of TP0751, which demonstrates an unusual lipocalin fold, should inform efforts to clarify its multifunctionality 79 . Additionally, the lipoprotein Tpp17 (also known as TP0435) has been shown to be at least partially surface-exposed and can function as a cytadhesin 82 . The structurally characterized lipoprotein TP0453 attaches to the inner leaflet of the outer membrane via its N-terminal lipids and two amphipathic helices within its protein moiety 83 .

Shown in the outer membrane are TP0751 (as known as pallilysin) 79 , 81 and Tpp17 (also known as TP0435) 82 , 241 , two surface-exposed lipoproteins; TP0453, a lipoprotein attached to the inner leaflet of the outer membrane 83 ; β-barrel assembly machinery A (BamA, also known as TP0326) 84 , 94 ; a full-length T. pallidum repeat (Tpr) attached by its N-terminal portion to the peptidoglycan 93 , 94 ; and a generic β-barrel that represents other non-Tpr outer membrane proteins (OMPs) identified by computational mining of the T. pallidum genome 112 . Substrates and nutrients present in high concentration in the extracellular milieu (such as glucose) traverse the outer membrane through porins, such as TprC. At the cytoplasmic membrane, prototypic ABC-like transporters (such as RfuABCD, a riboflavin transporter) use a periplasmic substrate-binding protein (SBP), usually lipoproteins, and components with transmembrane and ATP-binding domains to bind nutrients that have traversed the outer membrane for transport across the cytoplasmic membrane. The energy coupling factor (ECF)-type ABC transporters use a transmembrane ligand-binding protein in place of a separate periplasmic SBP for binding of ligands (BioMNY is thought to transport biotin) 242 . Symporter permeases (for example, TP0265) use the chemiosmotic or electrochemical gradient across the cytoplasmic membrane to drive substrate transport 243 . The tripartite ATP-independent periplasmic (TRAP)-type transporters also use transmembrane electrochemical gradients to drive substrate transport; the periplasmic component protein TatT (also known as TP0956) likely associates with the SBP TatP (also known as TP0957), which binds ligands (perhaps hydrophobic molecules, such as long chain fatty acids), the uptake of which is probably facilitated by the permease TatQ-M (also known as TP0958) 244 , 245 . Figure adapted from Ref. 63 , Macmillan Publishers Limited.

BamA . With the publication of the T. pallidum genome in 1998 (Ref. 65 ), only one protein with sequence relatedness to an outer membrane protein of Gram-negative bacteria was identified: β-barrel assembly machinery A (BamA, also known as TP0326) 84 , 85 . BamA has a dual domain architecture consisting of a 16-stranded, outer membrane-inserted, C-terminal β-barrel and five tandem polypeptide transport-associated repeats within the periplasm 84 , 85 . The opening of the channel is covered by a ‘dome’ comprising three extracellular loops, one of which contains an opsonic target that is sequence-variable among T. pallidum strains 85 . BamA is the essential central component of the molecular machine that catalyses the insertion of newly exported outer membrane proteins to the outer membrane 86 .

Tpr proteins . The T. pallidum repeat (Tpr) proteins, a 12-member paralogous family with sequence homology to the major outer sheath protein of the oral commensal Treponema denticola , were also identified in the T. pallidum genomic sequence 65 . Of these, TprK (TP0897) has received the most attention because of its presumed role in immune evasion by the spirochaete 87 , 88 ; it has been shown to undergo antigenic variation in seven regions believed to be extracellular loops harbouring B cell epitopes 89 – 92 . DNA sequence cassettes that correspond to V-region sequences in an area of the T. pallidum chromosome located away from the tprK gene have been proposed to serve as unidirectional donor sites for the generation of variable regions by nonreciprocal gene conversion 89 . Two other Tpr proteins, TprC and TprI, have met stringent experimental criteria for being classified as rare outer membrane proteins. They form trimeric β-barrels when refolded in vitro , cause large increases in permeability upon insertion into liposomes and are surface-exposed opsonic targets in T. pallidum 93 , 94 . Unlike classic porins, for which the entire polypeptide forms a β-barrel, TprC and TprI are bipartite. As with BamA, the C-terminal domain forms the surface-exposed β-barrel, whereas the N-terminal half anchors the barrel to the peptidoglycan sacculus. These results collectively imply that Tprs serve as functional orthologues of Gram-negative porins, using variations in the substrate specificities of their channel-forming β-barrels, probably along with differential expression, to import the nutritional requirements of the spirochaete into the periplasmic space from blood and body fluids 95 , 96 . These proteins also furnish a topological template for efforts to understand how antibody responses to Tprs promote bacterial clearance.

Biosynthetic machinery . T. pallidum has evolved to dispense with a vast amount of the biosynthetic machinery found in other bacterial pathogens 55 , 63 – 65 . T. pallidum relies on an optimized conventional glycolytic pathway as its primary means for generating ATP. By dispensing with oxidative phosphorylation, the spirochaete has no need for cytochromes and the iron required to synthesize them. Accordingly, the spirochaete maintains a complex, yet parsimonious, assortment of ABC transporters and symporters (totalling ∼ 5% of its 1.14 Mb circular genome) to transfer essential molecules from the periplasmic space to the cytosol ( Fig. 3 ). Whereas many pathogens have highly redundant systems for the uptake of transition metals across the cytoplasmic membrane, T. pallidum accomplishes this task with just two ABC transporters (Tro, which imports zinc, manganese and iron, and Znu, which is zinc-specific). A small but powerful arsenal of enzymes neutralizes superoxides and peroxides to fend off host responses to infection. Lastly, the spirochaete possesses novel and surprisingly intricate mechanisms ostensibly to redirect transcription and fine-tune metabolism in response to environmental cues and nutrient flux 63 .

Transmission and dissemination

Transmission of venereal syphilis occurs during sexual contact with an actively infectious partner; exudate containing as few as ten organisms can transmit the disease 8 , 68 . Spirochaetes directly penetrate mucous membranes or enter through abrasions in skin, which is less heavily keratinized in perigenital and perianal areas than skin elsewhere 8 , 68 . To establish infection, T. pallidum must adhere to epithelial cells and the extracellular matrix components; in vitro binding studies suggest that fibronectin and laminin are key substrates for these interactions 76 , 97 – 99 . Once below the epithelium, organisms multiply locally and begin to disseminate through the lymphatic system and bloodstream. Spirochaetes penetrate the extracellular matrix and intercellular junctions via ‘stop and go’ movements that coordinate adherence with motility and are powered by front-to-back undulating waves generated by flagellar rotation and presumably assisted by the proteolytic activity of TP0751 (Refs 77 , 100 ). Ex vivo studies using cultured human umbilical vein endothelial cells ( Fig. 4a ) suggest that spirochaetes invade tissues using motility to negotiate their way through intercellular junctions: so-called ‘interjunctional’ penetration 7 , 101 . The infection rapidly becomes systemic 9 , 16 , 100 . Profuse spirochaetes within the epidermis and superficial dermis in secondary syphilitic lesions ( Fig. 4b ) enable tiny abrasions created during sexual activity to transmit infection 10 , 102 . Penetration of the blood–brain barrier, occurring in as many as 40% of individuals with untreated early syphilis, can cause devastating neurological complications 9 , 16 .

a | Transmission electron micrograph of Treponema pallidum (arrowheads) penetrating the junctions between cultured umbilical vein endothelial cells. ‘Interjunctional invasion’ following attachment to the vascular endothelium is thought to provide T. pallidum access to tissue parenchyma during haematogenous dissemination. Part a is reproduced by permission of Oxford University Press (Ref. 101 ): Riley, B.S. et al ., Virulent Treponema pallidum activates human vascular endothelial cells, The Journal of infectious diseases, 1992, 165, 3, 484–493. b | Immunohistochemical staining (using commercial anti- T. pallidum antibodies) of a secondary syphilitic skin lesion reveals abundant spirochaetes embedded within a mixed cellular inflammatory infiltrate in the papillary dermis. The inflammatory response elicited by spirochaetes replicating in tissues is widely thought to be the cause of clinical manifestations at all stages of syphilis. Reproduced from Ref. 10 . c | Fluorescence microscopy images showing that human syphilitic serum (HSS) dramatically enhances opsonophagocytosis of T. pallidum by purified human peripheral blood monocytes compared with part d , which shows normal human serum (NHS). Arrowheads indicate treponemes being degraded within phagolysosomes.

Adaptive immune response and inflammation

Although the paucity of PAMPs in the T. pallidum outer membrane enables the bacterium to replicate locally and undergo repeated bouts of dissemination, pathogen sensing in the host is eventually triggered. The organisms are taken up by dendritic cells 103 , which then traffic to draining lymph nodes to present cognate treponemal antigens to naive B cells and T cells. The production of opsonic antibodies markedly enhances the uptake and degradation of spirochaetes by phagocytes ( Fig. 4c,d ), liberating lipopeptides and other PAMPs for binding to Toll-like receptors lining the interior of the phagosome and antigenic peptides for presentation to locally recruited T cells 62 , 104 , 105 . Activated lesional T cells secrete IFNγ, promoting clearance by macrophages but also bolstering the production of tissue-damaging cytokines, such as tumour necrosis factor and IL-6 (Refs 10 , 106 , 107 ). Immunohistochemical analysis has identified CD4 + and CD8 + T cells 10 , 106 , 108 , 109 , natural killer cells 10 and activated macrophages in early syphilitic lesions 10 , 109 . Perivascular infiltration of lymphocytes, histiocytes (phagocytic cells in connective tissues) and plasma cells with endothelial cell swelling and proliferation are characteristic histopathological findings in all stages of syphilis and can progress to frank endarteritis obliterans (leading to the occlusion of arteries and severe clinical manifestations, such as the stroke syndromes of meningovascular syphilis) 9 , 110 .

Antibody avoidance

T. pallidum is widely regarded as an extracellular bacterium 61 . Thus, a question of paramount importance is why, unlike ‘classic’ extracellular pathogens, syphilis-causing spirochaetes not only fail to be cleared rapidly but can also replicate and circulate in the midst of a prolific antibody response 8 , 68 , 69 . Immunolabelling, opsonophagocytosis and complement-dependent neutralization assays have shown that T. pallidum populations consist of antibody-binding and nonbinding subpopulations; the minority of organisms that bind antibodies do so in minute amounts and with delayed kinetics 10 , 111 – 114 . Accordingly, one can envision a scenario whereby nonbinders replenish the spirochaetes that bind and are cleared 63 .

Understanding the basis for the heterogeneity of T. pallidum 's surface antigenicity is critical to unravelling its strategy for antibody avoidance. The picture emerging from our evolving understanding of the molecular architecture of the spirochaete is multifactorial and probably involves the copious production of antibodies against subsurface lipoprotein ‘decoys’ (Refs 57 , 110 ); poor target availability due to low copy numbers of outer membrane proteins and surface-exposed lipoproteins 67 , 77 , 82 , 84 , 93 ; in the case of bipartite outer membrane proteins, limited production of antibodies against surface-exposed epitopes along with the skewed production of antibodies against periplasmic domains 84 , 93 ; organism-to-organism variation in the levels of expression of outer membrane proteins and outer surface lipoproteins through a variety of mechanisms, including phase variation 82 , 92 , 115 , 116 ; and, in the case of TprK, antigenic variation as a result of intra-genomic recombination 89 , 92 , 117 . Additionally, the ability of motile spirochaetes to ‘outrun’ infiltrating phagocytes and reach sequestered locations, including the epidermis, could be an under-appreciated aspect of immune evasion 10 , 102 . As infection proceeds, the antibody repertoire possibly broadens and intensifies to the point where the antigen-poor surface of the spirochaete is overwhelmed and its capacity for antigenic variation is exhausted, ushering in the asymptomatic period called latency. Once in the latent state, the organism can survive for years in untreated individuals, establishing niduses of inflammation in skin, bones, the thoracic aorta, the posterior uveal tract and the CNS that set the stage for recrudescent disease — collectively referred to as tertiary syphilis. How immune containment mechanisms decline and enable the balance to shift back in favour of the pathogen in tertiary syphilis is unclear 9 , although a hyper-intense cellular response to the spirochaete is generally believed to be the cause of the highly destructive lesions of tertiary syphilis 9 .

Congenital infection

Although MTCT of syphilis can occur at the time of delivery, the overwhelming majority of cases are caused by in utero transmission. Studies have shown spirochaetes in placental and umbilical cord samples, supporting the transplacental passage of the organism to the fetus, as early as 9–10 weeks of gestation 118 . Although fetal syphilis infections were thought to not occur before the second trimester, the fetus can indeed be infected very early in pregnancy but may be unable to mount a characteristic immune response until the development of the embryonic immune system at 18–20 weeks of gestation.

Transmission risk is directly related to the stage of syphilis in the pregnant woman (that is, the extent and duration of fetal exposure to spirochetes). Small case series have found the highest MTCT risk in primary and secondary stages, during which transmission probability may be ≥80%. Systematic reviews assessing women with predominantly asymptomatic infections are consistent in showing that delayed or inadequate treatment results in stillbirth, early neonatal death, prematurity, low birthweight or congenital infection in infants (more than half of syphilis-exposed fetuses); syphilitic stillbirth was the most commonly observed adverse outcome 21 , 45 , 119 .

Diagnosis, screening and prevention

Syphilis has varied and often subtle manifestations that make clinical diagnosis difficult and can lead to many infections being unrecognized. The classically painless lesions of primary syphilis can be missed, especially in hidden sites of exposure such as the cervix or rectum. The rash ( Fig. 5 ) and other symptoms of secondary syphilis can be faint or mistaken for other conditions. A syphilis diagnosis is often based on a suggestive clinical history and supportive laboratory 9 , 16 (that is, serodiagnostic) test results. Serological testing has become the most common means to diagnose syphilis, whether in people with symptoms of syphilis or in those who have no symptoms but are identified through screening. A limitation of all syphilis serological tests is their inability to distinguish between infection with T. pallidum subspecies pallidum and the T. pallidum subspecies that cause (nonvenereal) yaws, pinta or bejel.

a | Primary chancre. b | Primary chancre with rash in secondary syphilis. c | Secondary syphilis in a pregnant woman who has a palmar rash. d | Palmar rash in secondary syphilis. e | 3-month-old baby with congenital syphilis showing hepatosplenomegaly and a desquamating rash. The child also presented with nasal discharge. f | Typical palmar desquamating rash in a baby with congenital syphilis.

Ensuring the accuracy and reliability of syphilis testing is important, especially in nonspecialized laboratories, where most patient samples are tested 120 . Syphilis-specific quality assurance strategies include the training of technologists on specific techniques as well as implementation of internal quality control systems, test evaluation and interassay standardization of commercially available test kits on a regular basis 37 , 120 . It is especially important to provide adequate training and regular external quality assessment or proficiency testing with corrective action to ensure the quality of tests and testing for health care providers who perform rapid tests in clinic-based or outreach settings 121 – 124 . Because many parts of the world lack laboratory capacity for making an accurate diagnosis, the requirement for laboratory testing has greatly constrained the control of syphilis and the elimination of congenital syphilis. However, the development of inexpensive, rapid tests that can be performed at the POC has greatly increased access to prenatal screening and diagnosis, even in under-resourced and remote settings.

Definitive diagnosis by direct detection

The choice of method for diagnosing syphilis depends on the stage of disease and the clinical presentation 125 . In patients presenting with primary syphilitic ulcers, condyloma lata (genital lesions of secondary syphilis) or lesions of congenital syphilis, direct detection methods — which include darkfield microscopy, fluorescent antibody staining, immunohistochemistry and PCR — can be used to make a microbiological diagnosis. However, with the exception of PCR, these methods are insensitive and require fresh lesions from which swab or biopsy material can be collected, as well as experienced technologists ( Table 1 ).

Microscopy had been used for direct detection and diagnosis since 1920 but is now used infrequently. A 2014 survey of national reference and large clinical laboratories in Latin America and the Caribbean showed that only two of 69 participating facilities, of which half were reference laboratories, still performed darkfield or direct fluorescent antibody staining for T. pallidum (DFA-TP) 126 . The most recent European guidelines recommended against DFA-TP testing in clinical settings, and the reagents are no longer available 13 . PCR techniques are increasingly used; however, there is as yet no commercially available or internationally approved PCR test for T. pallidum 13 . Species-specific and subspecies-specific T. pallidum PCR testing is a developing technology that is still primarily available only in research laboratories 127 , 128 , although these tests are anticipated to be more widely available in the near future. A systematic review and meta-analysis concluded that T. pallidum PCR testing was more efficient for confirming a diagnosis of syphilis than for excluding a diagnosis in samples from lesions 129 . Recent research indicates that this technology might be helpful for the diagnosis of neurosyphilis via the detection of T. pallidum DNA in the CSF of patients with syphilis, particularly among individuals infected with HIV 130 , 131 .

Diagnosis using serology

Serodiagnostic tests are the only means for screening asymptomatic individuals and are the most commonly used methods to diagnose patients presenting with signs and symptoms suggestive of syphilis. Serodiagnostic tests for syphilis can be broadly categorized into nontreponemal tests (NTTs) and treponemal tests (TTs).

NTTs . NTTs measure immunoglobulins (IgM and IgG) produced in response to lipoidal material released from the bacterium and/or dying host cells. The most commonly used NTTs — the rapid plasma reagin (RPR) test, the toluidine red unheated serum test (TRUST) and the Venereal Disease Research Laboratory (VDRL) test — are flocculation (precipitation) tests that detect antibodies to a suspension of lecithin (including phosphatidylcholine and phosphatidylethanolamine), cholesterol and cardiolipin. NTTs are useful in detecting active syphilis. However, because individuals with an infection do not become positive until 10–15 days after the onset of the primary lesion, 25–30% of primary syphilis cases may be missed 132 , 133 ( Fig. 6 ). Although simple and inexpensive, NTTs must be performed manually on serum, and they rely on a subjective interpretation ( Table 2 ). These tests also require trained laboratory personnel and specialized reagents and equipment and, therefore, do not fulfil the ASSURED (affordable, sensitive, specific, user-friendly, rapid and robust, equipment-free and deliverable to those who need them) criteria for tests that can be used at the POC 134 .

Diagnosis of syphilis can be made by measuring a patient's serological response to infection. IgM antibodies against Treponema pallidum proteins are the first to appear, followed a few weeks later by IgG antibodies. Both IgM and IgG antibodies can be measured using treponemal tests such as the T. pallidum haemagglutination assay (TPHA), T. pallidum particle assay (TPPA), fluorescent treponemal antibody absorption assay (FTA-ABS), enzyme immunoassays (EIAs) and chemiluminescence immunoassays (CIAs). IgM and IgG antibodies against proteins that are not specific to T. pallidum (nontreponemal antibodies) can be detected using the rapid plasma reagin (RPR) Venereal Disease Research Laboratory (VDRL) or toluidine red unheated serum (TRUST) tests and usually appear 2–3 weeks after treponemal antibodies are detected. With effective treatment (which is arbitrarily shown here as occurring at 6 months), the nontreponemal antibody levels decline, whereas the treponemal antibodies remain high for many years. In ∼ 20% of patients, nontreponemal antibodies persist 6 months after treatment; these individuals are labelled as having a serofast status. Despite repeated treatment, ∼ 11% of patients remain serofast 187 . Here, we show early syphilis (including primary, secondary and early latent infections; infectious syphilis) and late syphilis (including late latent and tertiary infections) as being ≤1 year in duration and >1 year in duration, respectively, in line with US and European guidelines. However, the WHO guidelines place this demarcation at 2 years. Beyond primary and secondary syphilis, the pattern of serological response over time is less well defined and is accordingly not shown.

Without treatment, titres peak at 1–2 years after infection and remain positive even in late disease (usually at a low titre). After treatment, titres generally decline and in most immunocompetent individuals become nonreactive within 6 months. However, up to 20% of individuals infected with syphilis show persistently reactive (albeit low-titre) NTT results even after treatment, possibly related to a less-robust pro-inflammatory immune response 135 . These patients are labelled as having a serofast status, which is observed more commonly with treatment for late latent than for early syphilis 37 , 136 . Biological false-positive results can occur in ∼ 2–5% of the population, regardless of the NTT test used, although the proportion is difficult to estimate with certainty because it is influenced by the population studied 137 . These low-titre reactions might be of limited duration if related to acute factors (such as febrile illness, immunization or pregnancy) or longer duration if related to chronic conditions (such as autoimmune diseases, hepatitis C infection or leprosy) 136 , 138 . By contrast, false-negative results can occur in sera with very high titres (such as sera from patients with secondary syphilis) that are not diluted before testing, a phenomenon known as a prozone effect. Pre-dilution of sera re-establishes the concentration needed for optimal antibody–antigen interaction and avoids this problem.

TTs . In contrast to NTTs, TTs detect antibodies directed against T. pallidum proteins and are theoretically highly specific. However, as most individuals infected with syphilis develop treponemal antibodies that persist throughout life, TTs cannot be used to distinguish an active from a past or previously treated infection and are not useful in evaluating treatment effectiveness. TTs are used as confirmatory assays following a positive NTT result.

TT results become positive 6–14 days after the primary chancre appears ( ∼ 5 weeks after infection) and, therefore, may be useful to detect early syphilis missed by NTT testing. These tests are usually laboratory-based and include the fluorescent treponemal antibody absorbed (FTA-ABS) test, the microhaemagglutination assay for antibodies to T. pallidum (MHA-TP), the T. pallidum passive particle agglutination (TPPA) and T. pallidum haemagglutination (TPHA) assays ( Table 2 ). These tests also require trained personnel in a laboratory setting, are more expensive and technically complex than NTTs and involve specialized reagents and equipment. For these reasons, in the developing world, laboratory-based TTs are not widely available in primary care settings, hence limiting their utility as assays for confirming NTT results.

In recent years, TTs using recombinant T. pallidum antigens in enzyme and chemiluminescence immunoassays (EIA and CIA, respectively) have been commercialized. These assays are useful for large-scale screening as they are automated or semi-automated and, because they are read spectrophotometrically, are not subjective 13 , 139 – 142 . In higher-income countries, many health care institutions depend on high-throughput screening and have adopted ‘reverse’ algorithms that screen with an automated treponemal EIA or CIA and confirm results with an NTT rather than the opposite, traditional approach ( Fig. 7 ). Few studies as yet have addressed the accuracy of these ‘reverse testing’ algorithms 40 , 143 . The traditional and reverse approaches should theoretically produce the same result. However, the reverse algorithm results in the detection of patients with early syphilis (TT-positive, NTT-negative) who would not be detected by the conventional approach 144 . As this pattern of serological reactivity occurs in very early primary syphilis, in previously treated disease and late infection, considerable attention should be given to a thorough physical examination of the patient and assessment of previous history and recent sexual risk factors before initiating any treatment and partner notification activities.

a | The traditional algorithm begins with a qualitative nontreponemal test (NTT) that is confirmed with a treponemal test (TT). This algorithm has a high positive predictive value when both tests are reactive, although early primary and previously treated infections can be missed owing to the lower sensitivity of NTTs 136 . Importantly, this algorithm is less costly than reverse screening algorithms and does not require highly specialized laboratory equipment, but it is limited by the subjective interpretation of the technologist. Additionally, false-negative NTT results can arise from the prozone effect (when there is an excess of antibody). Finally, because the traditional algorithm is not always followed by a confirmatory TT, previously treated, early untreated and late latent patients can be missed, and biologically false-positive patients can be overtreated. b | The reverse screening algorithm uses a TT with recombinant T. pallidum antigens in enzyme immunoassay (EIA) or chemiluminescence immunoassay (CIA) formats that, when reactive, is followed by an NTT. This approach is associated with higher initial setup costs and ongoing operational costs than the traditional algorithm, but the algorithm permits treatment of 99% of patients with syphilis, which is higher than the percentage treated on the basis of the traditional algorithm in a low-prevalence setting 246 . However, this approach is at the expense of serodiagnosis in patients without risk factors and, therefore, who are unlikely to have syphilis, leading to potential overtreatment and any psychosocial consequences associated with a false positive result. Additionally, because TTs are not flocculation assays, false-negative test results due to the prozone effect do not occur. However, in high-risk populations, screening with a TT can result in a high rate of positive results due to previously treated infections, leading to an increase in the clinician workload needed to review cases and determine appropriate management. Some guidelines recommend further evaluation of reactive TT results with a quantitative NTT and, if results of the latter are nonreactive, a second (different) TT to help resolve the discordant results 143 , 247 , 248 . The European Centre for Disease Prevention and Control uses a variation of this approach: a reactive TT immunoassay is followed by a second (different) TT of any kind (that is, not followed by an NTT) 249 . Ideally, a positive TT result should be supplemented by another TT or an NTT. However, in most developing countries, particularly given the serious consequences of syphilis during pregnancy, treatment is recommended for a patient with a positive TT result. RPR, rapid plasma reagin test; TPHA, T. pallidum haemagglutination assay; TPPA, T. pallidum particle assay; VDRL, Venereal Disease Research Laboratory test.

Rapid tests . Rapid POC TTs are a recent technology that enable onsite screening and treatment and are particularly useful in settings with limited laboratory capacity. Rapid syphilis tests use a finger-prick whole blood sample and are typically immuno-chromatographic strip-based TT assays using components that can be stored at room temperature, require no equipment and minimal training and give a result in <20 minutes 145 ( Table 2 ). Various rapid tests have been evaluated in a range of clinical and community settings and shown to fulfil the ASSURED criteria 134 , 146 – 154 . Like other TTs, most POC diagnostics have the limitation of being unable to distinguish between recent and previously treated syphilis infections and, therefore, could lead to overtreatment. Ideally, patients who test positive to a POC TT would be further evaluated with an NTT to support management decisions; however, this is often not possible in settings with limited laboratory capacity as is the case in many antenatal care clinics and outreach programmes for high-risk populations. Rapid POC tests play an important part when delayed diagnosis is problematic, such as in pregnant women in whom delayed or no treatment poses substantial risks to the fetus that far outweigh the risks of overtreatment for the mother 45 , 155 . In nonpregnant individuals who test positive, the recommendations are treatment for those who have no prior history of treatment and referral to have an NTT for those with a prior history 11 .

At least one test has been developed that enables the simultaneous detection of nontreponemal and treponemal antibodies in a single POC device 156 – 158 . Additionally, rapid, dual syphilis and HIV tests are available to screen for HIV and treponemal antibodies using a single lateral-flow immuno-chromatographic strip. These tests are increasingly important tools for the global elimination of MTCT of HIV and syphilis in settings in which laboratory capacity is limited 159 .

Tests useful in special situations

Neurosyphilis . The diagnosis of neurosyphilis is challenging. The CSF is frequently abnormal in patients with neurosyphilis, with both pleocytosis (lymphocyte accumulation) and an increased protein concentration. The VDRL assay performed on CSF is considered the gold standard for specificity but is recognized to have limited sensitivity 160 , 161 . Other CSF tests, including serological assays, such as the RPR 162 , FTA-ABS 163 and TPHA tests 164 , and molecular assays, such as PCR 165 , have all been assessed and show differences in their specificity and sensitivity for the diagnosis of neurosyphilis. Difficulties in the interpretation of CSF pleocytosis in individuals co-infected with HIV and syphilis make it challenging to evaluate the relationship between the two diseases. CSF pleocytosis occurs in individuals with either infection alone 37 , 165 ; thus, discerning the cause of pleocytosis in individuals with co-infections is not always possible.

Congenital syphilis . Diagnosing congenital syphilis in exposed, asymptomatic infants is another area of testing that can be improved. Because maternal nontreponemal and treponemal IgG antibodies can be transferred from mother to child, treponemal testing of infant serum is difficult to interpret and is not recommended 37 . An infant with a reactive RPR or VDRL serum titre that is at least fourfold that of the mother is highly suggestive of congenital syphilis, but its absence does not exclude a diagnosis. A clinical examination, reactive infant CSF VDRL assay results, abnormal complete blood count or liver function test results or suggestive long-bone radiographs (that, for example, show retarded ossification or dislocation of epiphyses and radiolucencies (low-density areas)) can support a diagnosis of congenital syphilis. Use of IgM immunoblots is controversial due to the limited availability of tests and inconclusive data thus far on their sensitivity; their use in diagnosing congenital syphilis is recommended in some guidelines 11 , 13 but not others 37 . Maternal syphilis infection is highly correlated with fetal loss; thus, the evaluation of a stillborn infant should include an evaluation of maternal test results for syphilis 11 .

The wide availability of effective treatments and resulting decline in syphilis prevalence has led to a low yield of screening in low-prevalence settings; thus, screening in low-risk adults (for example, premarital adults or those admitted to hospital) has been abandoned in most places. However, systematic reviews provide convincing evidence in favour of syphilis screening for pregnant women 13 , 166 , adults and adolescents at increased risk of infection 13 , 40 and individuals donating blood, blood products or solid organs 13 , 167 – 169 . Several countries also recommend syphilis testing in people with unexplained sudden visual loss, deafness or meningitis as these may be manifestations of early neurosyphilis 13 , 37 .

Prenatal screening . Syphilis screening is universally recommended for pregnant women, regardless of previous exposure, because of the high risk of MTCT during pregnancy and the availability of a highly effective preventive intervention against adverse pregnancy outcomes 11 , 37 , 41 , 46 . Global normative authorities and most national guidelines recommend syphilis screening at the first prenatal visit, ideally during the first trimester 11 , 37 , 41 , 170 . Some countries recommend that women at high risk have repeat screening in the third trimester and again at delivery to identify new infections 37 . Women should be tested during each pregnancy, even if they tested negative in a previous pregnancy. When access to prenatal care is not optimal or laboratory capacity is limited, rapid tests have been shown to be beneficial in detecting and treating syphilis in pregnant women 148 . Guidelines recommend that after delivery, neonates should not be discharged from the health facility unless the serological status of the mother had been determined at least once during pregnancy and preferably again at delivery 11 , 37 .

The importance of universal syphilis screening in pregnancy to prevent perinatal and infant morbidity and mortality is highlighted in the current WHO global initiative to eliminate congenital syphilis 43 , 44 and is justified by the continuing high global burden of congenital syphilis, availability of an effective and affordable preventive intervention and wider availability of low cost rapid POC tests that can be used when laboratory capacity is lacking 23 , 43 , 44 , 46 , 145 . A systematic review of studies (most of which were conducted in low-income countries) reporting on antenatal programmes initiating or expanding syphilis screening, compared with various local control conditions, found that enhanced screening reduced syphilis-associated adverse birth outcomes by >50% 171 . Integration of syphilis testing with other prenatal interventions, including HIV testing, has been shown to be cost-effective across settings, even when syphilis prevalence is low 48 – 51 . Strategies that enhance screening coverage, such as increased use of rapid POC testing and integrating syphilis and HIV screening, will further support the global elimination of congenital syphilis 145 , 172 – 174 .

Screening at-risk populations . Increased risks of infection can be related to personal or partner behaviours leading to syphilis infection or living in a community with a high syphilis prevalence 37 , 40 . In many countries, syphilis testing is recommended for all attendees at STI or sexual health centres and as part of integrated services targeted to high-risk groups (such as HIV testing centres or drug treatment centres) 13 , 37 . The optimal screening interval for individuals at an increased risk of infection is not well established; however, some guidelines suggest that MSM or people with HIV show a greater benefit from more frequent screening than others at risk of syphilis infection (for example, testing every 3 months rather than a single annual screening) 37 , 40 , 175 , 176 .

At-risk communities are often marginalized from care and experience discrimination and stigma when using traditional STI services 177 . Innovations in promoting the uptake of testing and developing user-friendly services are important in the control of syphilis in these communities to reduce transmission. Social entrepreneurship and crowdsourcing approaches have been shown as innovative approaches to improve HIV and syphilis testing coverage rates and accelerate linkage to care, two fundamental elements within the cascade of STI service delivery 178 , 179 . Studies evaluating other interventions, such as pre-exposure prophylaxis for syphilis, are also underway 180 . One future option might be to administer pre-exposure prophylaxis simultaneously for syphilis and HIV 181 .

Blood-bank screening . Although syphilis was among the first identified infectious risks for blood donation and syphilis transmission through blood has been documented 182 – 184 , reports of transfusion-transmitted syphilis have become exceedingly rare over the past 60 years as more countries adopt donor selection processes, universal serological screening of donors and the use of refrigerated products rather than fresh blood components 183 , 185 . The survival of T. pallidum in different blood components has been shown to vary according to storage conditions, with fresh blood or blood components stored for <5 days being more infectious than blood stored for longer periods 183 . Screening of blood, blood components and solid organs for syphilis remains a recommendation in many countries 13 , 169 . Occasional cases of transfusion-transmitted syphilis are still reported in settings with high syphilis prevalence, particularly with the transfusion of fresh blood 167 .

There is as yet no vaccine against syphilis; the most effective mode of prevention is prompt treatment to avoid continued sexual transmission or MTCT, and the treatment of all sex partners to avoid reinfection. Other prevention modalities against the sexual transmission of syphilis are latex condom use, male circumcision and avoiding sex with infected partners 37 . Treating exposed sex partners is important to avoid reinfection 37 .

Important factors in managing syphilis are early detection, prompt treatment with an effective antibiotic regimen and treating sex partners of a person with infectious syphilis (primary, secondary or early latent infections). The WHO guidelines 11 ( Box 1 ) and European guidelines 13 for the management of early syphilis in adults are the same. The US Centers for Disease Control and Prevention (CDC) guidelines do not suggest procaine penicillin as a treatment but are otherwise identical 12 . Patients with late syphilis are no longer infectious. Thus, the objective of treatment is to prevent complications in persons who are asymptomatic (that is, those who have late latent syphilis) or arrest disease development if the patient has manifestations of tertiary disease. Treating late syphilis requires longer courses of antimicrobial therapy than treating early syphilis.

Penicillin has been the mainstay of treatment for syphilis since it first became widely available in the late 1940s. Although its efficacy was never demonstrated in a randomized controlled trial, it was clearly far superior to all previous treatments, and T. pallidum resistance to penicillin has never been reported. As T. pallidum divides slower than most bacteria, it is necessary to maintain penicillin levels in the blood above the minimum inhibitory concentration for ≥10 days; this can be achieved by giving a single intramuscular injection of long-acting benzathine penicillin G (which benefits from not requiring patient adherence to a long-term drug regimen). The first-line treatments for early syphilis recommended by the CDC and European (authored by the International Union Against Sexually Transmitted Infections) guidelines are very similar 12 , 13 , as are recommendations for treating exposed sex partners. Patients with late syphilis, or with syphilis of unknown duration, should receive longer courses of treatment ( Box 1 ). Those with symptoms suggestive of neurosyphilis or ocular involvement should undergo lumbar puncture to confirm or rule out the presence of neurosyphilis, which requires more-intensive treatment. However, CDC and European guidelines define latent syphilis as occurring beginning at 1 year after infection, whereas the WHO defines latent syphilis to occur beginning at 2 years, resulting in some differences in management; that is, a longer treatment duration is recommended for some patients in the United States and Europe.

Given that confirmation or exclusion of the presence of viable T. pallidum after treatment is not possible, treatment efficacy is measured indirectly using serology. Being cured is usually defined as reversion to a negative serostatus or a fourfold reduction in the titre from an NTT. However, as noted earlier, a minority of patients remain seropositive, with a less than fourfold reduction in their NTT titre, in spite of almost certainly having been cured and with no evidence of progressive disease — the so-called serofast state 186 . The management of these patients depends on taking a careful sexual history to exclude the possibility of reinfection, which can be challenging as patients may not recognize new infections. The serofast state more commonly occurs in patients with late syphilis and low NTT titres and in patients positive for HIV who are not on antiretroviral treatment 187 . Because few data are available on long-term clinical outcomes in serofast patients, CDC guidelines recommend continuing clinical follow-up and retreatment if follow-up cannot be ensured 12 .

Second-line treatments

Patients who are allergic to penicillin should be treated with doxycycline or ceftriaxone (although an allergy to cephalosporins is more common in those who are allergic to penicillin) with repeat NTT serology as a follow-up. Doxycycline is contraindicated during pregnancy. Two treatment trials of early syphilis in Africa showed that a single oral dose of azithromycin was equivalent to treatment with benzathine penicillin G (Refs 188 , 189 ). Unfortunately, strains of T. pallidum with a mutation that confers resistance to azithromycin and other macrolide antibiotics are common in the United States, Europe, China and Australia 190 – 194 . A study of HIV-positive patients with syphilis showed that administering azithromycin to prevent opportunistic infections led to better serological outcomes 195 . The WHO recommends the use of azithromycin for the treatment of syphilis only in settings where the prevalence of macrolide-resistant T. pallidum is known to be very low.

HIV co-infection

In patients with early syphilis, an increased cell count and protein concentration are found more frequently in the CSF of patients with an HIV infection than in patients without an HIV infection, and there is some evidence that early symptomatic neurosyphilis is more common in patients positive for HIV 196 , 197 . As single-dose benzathine penicillin G treatment does not reliably lead to treponemicidal levels in the CSF, some experts have suggested that HIV co-infected patients with early syphilis should receive enhanced treatment 198 . However, a randomized controlled trial ( n = 541) showed no significant difference in clinical outcomes between patients receiving a standard or enhanced treatment 15 . Notably, the 101 patients infected with HIV enrolled in the trial responded less well serologically, but due to loss at follow-up, the study was underpowered to detect a twofold difference in the standard versus enhanced treatment in patients co-infected with HIV. Furthermore, a large ( n = 573) prospective observational study in Taiwan found no difference between single-dose benzathine penicillin G and enhanced treatments in a per-protocol analysis 199 . However, using a last-observed-carried-forward analysis to account for missing data, the authors concluded that 67.1% of those who received one dose responded serologically compared with the 74.8% response rate in those who received the enhanced treatment, a statistically significant difference ( P = 0.044) 199 . Finally, a retrospective study ( n = 478) showed no difference in serological response rates at 13 months between those receiving a single-dose of benzathine penicillin G or enhanced treatment 200 . Given the inconclusive results of these studies, many clinicians continue to offer enhanced therapy to patients with early syphilis and HIV co-infection.

Treatment during pregnancy

Adverse pregnancy outcomes are common in women with syphilis 45 , 119 . A study in Tanzania found that of women with latent syphilis who had RPR titres ≥1:8, 25% delivered a stillborn infant, and 33% delivered a live but preterm infant 21 . A second study showed that adverse pregnancy outcomes due to syphilis can be prevented with a single dose of benzathine penicillin G given before 28 weeks of gestation 201 and that, in this setting in which 5–6% of pregnant women had syphilis, this was one of the most cost-effective interventions available in terms of cost per disability-adjusted life years saved 202 .

Penicillin is the only antibiotic known to be effective in treating syphilis during pregnancy and preventing adverse birth outcomes. Given that doxycycline is contraindicated during pregnancy, and macrolides such as azithromycin and erythromycin do not cross the placenta effectively, there are few alternatives to penicillin for the treatment of pregnant women with syphilis who are allergic to penicillin. The CDC recommends desensitization for those who are allergic to penicillin 12 .

Congenital syphilis

The WHO recommends that infants with suspected congenital syphilis, including infants who are born to mothers who are seropositive for syphilis and not treated with penicillin >30 days before delivery, should be treated with aqueous benzyl penicillin or procaine penicillin ( Box 1 ). All infants exposed to syphilis, including infants without signs or symptoms at birth, should be followed closely, ideally with NTT titres. Titres should decline by 3 months of age and be nonreactive by 6 months 12 . TTs are not useful in infants due to persistent maternal antibodies.

Neurosyphilis and ocular syphilis

Involvement of the CNS can occur during any stage of syphilis, but there is no evidence supporting a need to deviate from recommended syphilis regimens without the presence of clinical neurological findings (such as ophthalmic or auditory symptoms, cranial nerve palsies, cognitive dysfunction, motor or sensory deficits or signs of meningitis or stroke) 203 . With symptoms and tests indicating neurosyphilis, or any suggestion of ocular syphilis regardless of CSF testing, more-intensive treatment is recommended. For example, the CDC recommends that adults with neurosyphilis or ocular syphilis should be treated with high-dose intravenous aqueous crystalline penicillin, or intramuscular procaine penicillin plus probenecid, for 10–14 days 204 .

Box 1: WHO guidelines for the treatment of syphilis

Early syphilis

Intramuscular benzathine penicillin G (single dose)

Or intramuscular procaine penicillin (daily doses for 10–14 days)

If penicillin-based treatment cannot be used, oral doxycycline (two doses daily for 10–14 days)* or intramuscular ceftriaxone (daily doses for 10–14 days)

Late syphilis

Intramuscular benzathine penicillin G (weekly doses for 3 weeks)

Or intramuscular procaine penicillin (daily doses for 20 days)

If penicillin-based treatment cannot be used, oral doxycycline (daily doses for 30 days)*

Intravenous aqueous benzyl penicillin (daily doses for 10–15 days)

Or intramuscular procaine penicillin (daily doses for 10–15 days)

*Contraindicated during pregnancy. From Ref. 11

Quality of life

Historical reports dating from the 15th century indicate that syphilis was perceived as a dangerous infection and a source of public alarm via fear of contagion and dread of its manifestations, as well as anxiety around its highly toxic ‘cures’ (heavy metal therapy with mercury, arsenic or bismuth) 205 – 207 . Case reports through the 19th century, as well as modern re-evaluations of skeletal remains, support the fact that the disease could cause severe physical stigmata, with individuals having disfiguring rashes, nonhealing ulcerations, painful bony lesions that often involved destruction of the nose and palate, visceral involvement, dementia and other incapacitating neurological complications and early death 208 . Stigmatization associated with syphilis was also evident, with symptomatic patients quarantined to specialized hospitals, and affected people hiding their symptoms, perhaps fearing societal shunning or the dubiously effective treatment regimens even more than they feared the disease 209 . Reductions in syphilis prevalence were documented after the introduction of penicillin 210 , and since that time, the most virulent manifestations of the disease have almost vanished; today it is rare to find a patient with tertiary disease 211 . Nevertheless, continuing reports emphasize that complications of late syphilis, particularly those involving the eyes, CNS and cardiovascular system, can cause lifelong disability and even death 9 . For example, the number of cases of ocular syphilis has increased with rising syphilis incidence in many communities 212 , with delayed treatment associated with permanently diminished visual acuity 213 . Thus, caregivers must be cognizant of the need to screen at-risk patients for latent infection and administer therapy if previous treatment has not been documented.

Few modern studies have addressed quality of life in men and women with syphilis, whether in social, psychological or economic contexts. One study ( n = 250) showed only a minor effect on patient-reported quality of life at time of treatment and essentially no effect 1 month after treatment 214 . The currently high case rates of syphilis infection and reinfection among MSM in urban centres throughout the world might lend support to the notion that syphilis in the modern era poses a limited impact on quality of life as long as it is detected and treated. However, partner notification studies suggest that STI diagnoses can lead to substantial social stigma, intense embarrassment and fear of retaliation, domestic violence or loss of relationships 177 . Public health experts have posited that syphilis is the source of more stigma than other STI diagnoses, although this is difficult to measure with certainty because STI programmes tend to focus contact tracing efforts more strongly on syphilis than on other curable STIs owing to its serious consequences 215 . In one study measuring the level of shame associated with several stigmatizing skin diseases, patients assigned the greatest shame to syphilis — more than to HIV/AIDS, other STIs or several disfiguring skin conditions 216 .

Untreated maternal syphilis results in severe adverse perinatal outcomes, most prominently stillbirth, in at least half of affected pregnant women 45 . Although MTCT of syphilis is clearly linked to a lack of prenatal care, WHO data indicate that globally, whether in wealthy or poor nations, most adverse pregnancy outcomes caused by maternal syphilis are in women who attended prenatal care but were not adequately tested or treated 24 . This suggests that other factors, such as ineffective health systems, gender inequality, lack of political will to support quality STI and reproductive health services or other structural influences associated with a lack of screening might be at play 217 . Increasing research supports the conclusion that, as for infant loss, a stillbirth can lead to poor mental and other health outcomes for both parents and the wider family, even extending to health care providers. For example, experiencing a stillbirth has been linked to ‘unspoken grief’ and a variety of psychosocial consequences such as depression, blame, shame, social isolation, problems in future pregnancies and relationship dissolution 218 – 220 . In Haiti, pregnancy loss associated with syphilis is so common (maternal prevalence of 6%) that a myth about a werewolf sucking the blood out of the unborn fetus has developed to help women with their loss and suffering 221 . Economic research suggests that a stillbirth results in substantial direct and indirect costs and can sometimes require more resources than a livebirth 219 .

With syphilis continuing to be the leading cause of preventable stillbirths in the developing world and re-emerging as a public health threat in developed nations, particularly in MSM co-infected with HIV, the demand for improved diagnostics, prevention strategies and treatments is growing. Here, we describe the most pressing issues and propose a call to action ( Box 2 ).

Elimination of MTCT of syphilis

The WHO campaign to eradicate yaws, which treated >50 million people with penicillin and reduced the number of cases by ≥95% worldwide between 1952 and 1964, was ultimately unsuccessful. What can we learn from this heroic failure? The yaws eradication campaign was based on clinical examination and serological testing to determine prevalence by community and on mass treatment or selective mass treatment (patients and contacts) of communities with penicillin depending on prevalence. Unfortunately, as the prevalence of yaws fell, it was no longer perceived as an important public health problem worthy of an expensive vertical programme; resources were diverted to other programmes, yaws was forgotten, and it re-emerged 222 . To some extent the same is true of syphilis; once penicillin became available, its incidence and prevalence declined in many parts of the world, and it was no longer seen as a public health priority. Although screening of all pregnant women for syphilis has continued to be recommended in most countries, coverage has been low in many regions; for example, WHO estimates that approximately 50% of antenatal clinic attendees in Africa are not currently screened for syphilis 24 . This low coverage has resulted in a high burden of entirely preventable stillbirths and neonatal deaths 23 . Exacerbating this situation, the WHO has received reports of depleted stocks and shortages of injectable benzathine penicillin G in multiple countries, many with a high burden of maternal and congenital syphilis. In collaboration with international partners, the WHO has spearheaded an initiative to assess the global supply, current and projected demand and production capacity for benzathine penicillin G (Ref. 223 ).

Strong advocacy will be needed to ensure that the control and elimination of syphilis is given a high priority on the global health agenda. Policy makers and funders need to be made aware that syphilis is a leading cause of preventable stillbirths and neonatal death, that these deaths can be prevented with a single dose of penicillin given to the mother before 28 weeks of gestation and that this is one of the most cost-effective health interventions available 51 , 202 . Perhaps with this awareness and political will, syphilis MTCT elimination programmes, which have failed to progress in the past 10 years 224 , will witness the same success achieved in the MTCT of HIV programmes in Africa. Other developments are occurring that are forging change. For example, the availability of POC tests has led to increased coverage of antenatal screening and treatment for syphilis in many settings 148 , and the WHO campaign for the elimination of MTCT of HIV and syphilis has increased the visibility of syphilis on the global health agenda. In 2014, the WHO target for the elimination of MTCT of syphilis was ≤50 cases of congenital syphilis per 100,000 live births. The targeted processes are antenatal care coverage (at least one visit) of ≥95% of pregnant women, syphilis testing coverage for ≥95% of pregnant women and treatment of ≥95% of pregnant women seropositive for syphilis WHO http://apps.who.int/iris/bitstream/10665/112858/1/9789241505888_eng.pdf (2014)." href="/articles/nrdp201773#ref-CR225" id="ref-link-section-d175137372e3628">225 . Additionally, the WHO has conducted a systematic review of the performance of rapid, dual HIV and syphilis tests and issued an information note on testing algorithms for dual HIV and syphilis tests 226 .

The huge reduction in the number of infants positive for HIV in Africa in recent years, a more difficult undertaking than reducing MTCT of syphilis, is proof of concept that congenital syphilis elimination is achievable. Given that Cuba, Thailand, Belarus, Moldova and Armenia have eliminated MTCT of HIV, syphilis or both, elimination can be achieved with political will and a well-organized health care system. Indeed, inclusion of syphilis and HIV screening with tests for anaemia, diabetes and pre-eclampsia as a package of essential diagnostics for prenatal care should be implemented as a minimum standard to ensure safe and healthy pregnancies worldwide.

The use of POC testing has greatly increased access to screening for pregnant women and has the potential to increase access to screening for high-risk groups such as MSM and FSWs through outreach programmes. However, the quality of testing must be assured given that these tests are conducted outside the laboratory. Strategies to ensure the reliability of POC tests include the use of electronic readers 227 and microfluidic assays powered by smart phones 228 for real-time monitoring of progress 229 and the routine provision of proficiency testing panels 121 , 122 . For example, one study in the Amazon region of Brazil showed that proficiency panels consisting of dried serum tubes that were assessed by each health care worker could be used to monitor the performance of health care workers in remote settings 123 .

HIV and syphilis co-infection in MSM

In developed countries, the incidence of syphilis in MSM is several hundred times higher than in the general population. Furthermore, the incidence continues to increase as condom use has fallen with increasing use of pre-exposure prophylactic antiretroviral medications for HIV 42 , 230 . Indeed, with wider HIV treatment coverage in recent years and HIV no longer considered a ‘death sentence’, safe sex practices have declined and risk-taking behaviours have increased 231 . However, the alarming increase in the incidence of syphilis, compared with that of other STIs, in HIV-infected MSM cannot be explained by behavioural factors alone. The frequent co-infection of HIV and syphilis in MSM in many countries has led researchers and policy makers to consider the hypothesis that treatment for HIV may be a double-edged sword that contributes to increased susceptibility to syphilis through impairment of the innate or acquired immunity to T. pallidum 42 , 232 .

Accordingly, research is urgently needed to understand the underlying causes of this twin epidemic. The involvement of the MSM community is critical in the design and implementation of innovative approaches to promote the uptake of testing and linkage to care, particularly as this community is still stigmatized and marginalized from care in many societies. Although self-testing for HIV and hepatitis C virus infection is now possible using highly sensitive and specific oral tests that are commercially available, syphilis does not elicit sufficient antibody levels for an oral test. Thus, implementation science is needed to integrate and optimize the delivery of a package of HIV, syphilis, hepatitis and other STI screening and treatment strategies and partner notification systems for MSM in different cultural, socioeconomic and political settings.

Better diagnostic tests

Research is needed to identify biomarkers that can more accurately distinguish between past, treated syphilis infections and active infections requiring treatment, can identify patients who have become reinfected and can provide a test of cure. Using current serological tools, a high proportion of patients have been shown to remain serofast after treatment in some settings, and the optimal management of these individuals is uncertain. Additionally, more-accurate diagnostic tests are needed to confirm the diagnosis of congenital syphilis, as serological tests based on IgG antibodies cannot distinguish between infected infants and those with passively acquired maternal antibodies. IgM tests can be highly sensitive in symptomatic infants but have suboptimal sensitivity in infants who are infected but not symptomatic at birth 12 .

The diagnosis of neurosyphilis also remains a challenge, particularly in patients co-infected with HIV, in whom an increased CSF protein concentration or cell count does not necessarily indicate that the patient has neurosyphilis. Promisingly, a rapid POC test has been adapted for the diagnosis of neurosyphilis using CSF 233 ; the performance of this test is better in cell-free specimens, requiring the use of a centrifuge. Another promising assay might be the measurement of macrophage migration factor (MIF); measurement of CSF levels of MIF alone was shown to have a sensitivity of 74.42% and a specificity of 67.74% for the diagnosis of neurosyphilis in one study ( n = 43) 234 . By integrating all CSF parameters (pleocytosis, increased protein concentrations and MIF), the sensitivity and specificity would be improved. Additionally, assays of B cell attractant chemokine CXCL13 in the CSF could be used to distinguish the pleocytosis caused by HIV from that caused by neurosyphilis in patients infected with HIV 235 .

Better use of existing drugs

With the use of penicillin, many countries still struggle with the fear of injections on the part of patients and the management of anaphylactic shock on the part of the health care providers. Oral regimens that are safe for use during pregnancy and effective in preventing the transmission of syphilis to the fetus are urgently needed. Furthermore, macrolide resistance is correlated with treatment failure in patients with primary syphilis 191 , lending further urgency to the need to find alternative oral therapies. Incentives for a drug discovery programme for syphilis need to be established and, in the meantime, evaluation of existing drug combinations might be useful as alternatives to reduce the threat of developing resistance.

Vaccine development

Human-challenge studies have shown that people with late latent syphilis are resistant to symptomatic reinfection with heterologous strains of T. pallidum , and protective immunity has been induced in rabbits by repeated inoculation with γ-irradiated T. pallidum 236 , 237 . Accordingly, it should be possible to develop protective vaccines. However, research on virulence determinants of T. pallidum and our understanding of protective immunity against T. pallidum have been hindered by our inability to culture the bacteria in vitro . Genome sequencing of T. pallidum directly from clinical samples is now possible, which can overcome this limitation 92 , 238 . This advance should enable the understanding of strain variation on a global scale and help to identify outer membrane proteins and other surface antigens as possible vaccine candidates 81 . A recent study showed that the immunization of rabbits with the lipoprotein TP0751 prevented the dissemination of T. pallidum and, hence, has become a promising vaccine candidate 81 . Integrating potential vaccine targets with diagnostic targets in discovery programmes also holds promise in accelerating progress towards the development of improved tools for the control, prevention and, ultimately, elimination of this disease.

Box 2: Major challenges and a call to action wish list

Eliminate mother-to-child transmission of syphilis

Requires political commitment

Prenatal syphilis screening to be integrated into mother-to-child transmission elimination programmes for HIV or as a component of an essential diagnostic package for prenatal care

Develop point-of-care tests with data connectivity or data transmission capability to facilitate automated surveillance and to improve the efficiency of health systems

Address HIV and syphilis co-infection in MSM

Requires research into potential synergies between the two infections

Implement scientific and community involvement to reach at-risk populations

Integrate programmes for HIV, syphilis, hepatitis and other sexually transmitted infections

Develop tests for active infection, neurosyphilis and congenital syphilis

Identify and validate biomarkers for test development

Develop a network of clinical sites for rapid validation of new tests

Develop new oral drugs to prevent transmission to fetus and to sex partners

Provide incentives for drug discovery programmes

Provide incentives to evaluate drug combinations

Develop vaccines

Requires research to better understand syphilis pathogenesis

Requires research to identify vaccine targets and methods for validation

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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.

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Rosanna W. Peeling & David Mabey

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Mary L. Kamb

National Center for STD Control, Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Dermatology, Nanjing, China

Xiang-Sheng Chen

Department of Medicine, UConn Health, Farmington, Connecticut, USA

Justin D. Radolf

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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.).

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Correspondence to Rosanna W. Peeling .

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

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Peeling, R., Mabey, D., Kamb, M. et al. Syphilis. Nat Rev Dis Primers 3 , 17073 (2017). https://doi.org/10.1038/nrdp.2017.73

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

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