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Syphilis
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Syphilis
Rosanna W. Peeling1, David Mabey1, Mary L. Kamb2, Xiang-Sheng Chen3, Justin David
Radolf4, and Adele Schwartz Benzaken5
1London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK
2Divisionof STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD and TB
Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
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3NationalCenter for STD Control, Chinese Academy of Medical Sciences and Peking Union
Medical College Institute of Dermatology, Nanjing, China
4Department of Medicine, UConn Health, Farmington, Connecticut, USA
5Department of Surveillance, Prevention and Control of STI, HIV/AIDS and Viral Hepatitis,
Ministry of Health, Brasília, Brazil
Abstract
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
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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.
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Introduction
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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 debate1.
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 Africa2. These estimates argue against the so-called Columbian
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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
15th century3.
guidelines from the United States12 and Europe13 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 Mimicker14. 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,
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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
relapses15. 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 involvement9. 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 syphilis16. Importantly, neurosyphilis is
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Peeling et al. Page 3
typically described as a late manifestation but can occur in early syphilis. Indeed, T.
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pallidum can be frequently identified in the cerebral spinal fluid (CSF) of patients with early
disease9,15,17. 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 neurosyphilis12. 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 time18. The rate of fetal infection depends on
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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
delivery19–21. 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 hours22, 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
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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 HIV23,24, with perinatal deaths owing to untreated syphilis exceeding those of
HIV or malaria25. Syphilis is now the second leading cause of preventable stillbirths
worldwide, following malaria25.
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 cured9,16. Nevertheless,
syphilis remains a continuing public health challenge globally26. In this Primer, we describe
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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
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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 year27 (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 LMICs27. The greatest burden of maternal syphilis occurs in Africa,
representing >60% of the global estimate23,24.
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) infection28. 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
country29. A large study of >1,000 FSWs in Kampala, Uganda, showed 21% were
seropositive for syphilis and 10% had active infection30. 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 clients31,32. 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 FSWs33.
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partners; sexual activity connected with illicit drug use; seeking sex partners through the
internet and other high-risk sexual network dynamics37–41. Risk factors for syphilis are
frequently overlapping40. 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 syphilis42.
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MTCT
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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 pregnancy21.
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
problem43–45. 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 treatment23. 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 interventions46. Furthermore, studies
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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 women47–50. 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-effective51.
Since 2007, an increasing number of countries have implemented regional and national
initiatives to prevent MTCT of syphilis52, 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 programmes53. 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
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of maternal and congenital syphilis decreased by 38% and 39%, respectively23,24. In 2015,
Cuba became the first country to be validated for having achieved elimination of MTCT of
HIV and syphilis54. 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 unchanged23,24.
Mechanisms/pathophysiology
Although a local inflammatory response elicited by spirochetes is thought to be the root
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cause of all clinical manifestations of syphilis9, 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 progress55. Additionally, the fragility and low protein content of its outer
membrane have confounded efforts to characterize surface-exposed molecules56,57. Finally,
facile murine models to dissect the host response and the components of protective
immunity are also lacking58. Outbred rabbits are essential for isolating T. pallidum strains
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from clinical specimens59 and routine propagation in the laboratory60. Because rabbits are
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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
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(the spirochete that causes Lyme borreliosis79), and the cultivatable commensal treponeme
T. phagedenis80, opsonophagocytosis assays in T. pallidum77 and, most recently, protection
of immunized rabbits against dissemination of spirochetes following intradermal
challenge81. The X-ray structure of TP0751, demonstrating an unusual lipocalin fold, should
inform efforts to clarify its multi-functionality79. Additionally, the lipoprotein Tpp17 (also
known as TP0435) has been shown to be at least partially surface-exposed and can function
as a cytadhesin82. The structurally characterized lipoprotein TP0453 attaches to the inner
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Peeling et al. Page 7
leaflet of the outer membrane via its N-terminal lipids and two amphipathic helices within
its protein moiety83.
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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: 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
periplasm84,85. 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 strains85. BamA is the essential central component of the molecular machine
that catalyses insertion of newly exported outer membrane proteins to the outer membrane86.
Tpr proteins—The T. pallidum repeat (Tpr) proteins, a 12-member paralogous family with
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sequence homology to the major outer sheath protein of the oral commensal T. denticola,
were also identified by the T. pallidum genomic sequence65. Of these, TprK (TP0897) has
received the greatest attention because of its presumed role in immune evasion by the
spirochete87,88; it has been shown to undergo antigenic variation in seven regions believed to
be extracellular loops harbouring B-cell epitopes89–92. 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 conversion89. 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. pallidum93,94.
Unlike classic porins, for which the entire polypeptide forms a β-barrel, TprC and TprI are
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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 fluids95,96. 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 pathogens55,63–65. To compensate for its loss
of biosynthetic capacity, the spirochete maintains a complex assortment of ABC transporters
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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
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to the cytosol (Fig. 3). Whereas many pathogens have highly redundant systems for uptake
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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 flux63.
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
interaction76,97–99. 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 penetration7,101. The infection rapidly becomes systemic9,16,100. Profuse
spirochetes within the epidermis and superficial dermis in secondary syphilitic lesions (Fig.
4B) enable tiny abrasions created during sexual activity to transmit infection10,102.
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arteries and severe clinical manifestations, such as the stroke syndromes of meningovascular
syphilis)9,110.
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Antibody avoidance
T. pallidum is widely regarded as an extracellular bacterium61. 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 response8,68,69. 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 kinetics10,111–114. Accordingly, one
can envision a scenario whereby nonbinders replenish the spirochetes that bind and are
cleared63.
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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
lipoproteins67,77,82,84,93; in the case of bipartite outer membrane proteins, limited production
of antibodies against surface-exposed epitopes along with skewed production of antibodies
against periplasmic domain84,93; organism-to-organism variation in the levels of expression
of outer membrane proteins and outer surface lipoproteins through a variety of mechanisms,
including phase variation82,92,115,116; and, in the case of TprK, antigenic variation as a result
of intra-genomic recombination89,92,117. Additionally, the ability of motile spirochetes to
‘outrun’ infiltrating phagocytes and reach sequestered locations, including the epidermis,
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typically involving the aortic arch and leading to aneurysmal dilatation, usually occurs 10–
30 years after the initial infection9.
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
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early as 9–10 weeks of gestation118. Although fetal syphilis infection was not thought to
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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 declines18,45.
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
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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.
that can be performed at the POC has greatly increased access to prenatal screening and
diagnosis, even in low-resourced and remote settings.
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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 available13. PCR
techniques are increasingly used; however, there is as yet no commercially available or
internationally approved test for T. pallidum13. Species-specific and subspecies-specific T.
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pallidum PCR testing is a developing technology that is still primarily available in research
laboratories127,128, 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 lesions129. 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 individuals130,131.
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.
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
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syphilis-infected individuals have a persistently reactive (albeit low-titre) NTT even after
treatment, possibly related to a less robust pro-inflammatory immune response135. These
patients are labelled as having a serofast status and are observed more commonly with
treatment for late latent than early syphilis37,136. 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 studied137.
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–
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TTs—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
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(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.
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 approach144. As this pattern of serological reactivity occurs in very early
primary syphilis, in previously treated disease and late infection, considerable attention
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should be given to a thorough physical examination of the patient, previous history and
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recent sexual risk before initiating any treatment and partner notification activities.
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 minutes145 (Table 2). Various rapid
tests have been evaluated in a range of clinical and community settings and shown to fulfil
the ASSURED criteria134,146–154. 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
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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 mother45,155. 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 NTT11.
At least one test has been developed that enables simultaneous detection of non-treponemal
and treponemal antibodies in a single POC device156–158. 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
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limited159.
relationship between the two diseases. CSF pleocytosis occurs in individuals with either
infection alone37,165; thus, discerning the cause of pleocytosis in co-infected individuals is
not always possible.
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difficult to interpret and is not recommended37. An infant with a reactive RPR or VDRL
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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 guidelines11,13 but not others37. Maternal syphilis infection is highly
correlated with fetal loss, therefore, evaluation of a stillborn infant should include evaluation
of maternal tests for syphilis11.
Screening
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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 women13,166, adults and adolescents at increased risk for infection13,40
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 neurosyphilis13,37.
recommend syphilis screening at the first prenatal visit, ideally during the first
trimester11,37,41,170. Some countries recommend that women at high risk have repeat
screening in the third trimester and again at delivery to identify new infections37. 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 pregnancy148.
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 delivery11,37.
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
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congenital syphilis43,44 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
lacking23,43,44,46,145. 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
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Peeling et al. Page 15
testing with other prenatal interventions, including HIV testing, has been shown to be cost-
effective across settings, even when syphilis prevalence is low48–51. Strategies that enhance
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screening coverage, such as increased use of POC rapid testing and integrating syphilis and
HIV screening, will further support global elimination of congenital syphilis145,172–174.
At-risk communities are often marginalized from care and experience discrimination and
stigma when using traditional STI services177. 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 delivery178,179. Evaluation studies of other interventions, such as pre-exposure
prophylaxis (PrEP) for syphilis, are also underway180. One option in the future might be to
simultaneously administer PrEP for syphilis and HIV181.
Blood bank screening—Although syphilis was among the first identified infectious risks
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for blood donation and s transmission through blood has been documented182–184, 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 components183,185.
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 periods183. Syphilis screening of blood, blood components or
solid organs remains a recommendation in many countries13,169. Occasional cases of
transfusion-transmitted syphilis are still reported in settings with high syphilis prevalence,
particularly with transfusion of fresh blood167.
Prevention
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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 partners37. Treatment of exposed sex partners is important to
avoid reinfection37.
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Management
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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 guidelines11 (Box 1) and
European guidelines13 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 identical12.
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.
Box 1
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Late syphilis
Congenital syphilis
Penicillin
Penicillin has been the mainstay of treatment for syphilis since it first became widely
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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
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syphilis recommended by the CDC and European (authored by the International Union
Against Sexually Transmitted Infections) guidelines are very similar12,13 as are
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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
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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 state186. 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 treatment187. 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 ensured12.
Second-line treatments
Patients who are allergic to penicillin should be treated with doxycycline or ceftriaxone
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(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 G188,189. 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 Australia190–194. A study in HIV-positive patients
with syphilis showed that azithromycin to prevent opportunistic infections led to better
serological outcomes195. 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
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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
patients196,197. 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
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receiving standard or enhanced treatment15. Notably, the 101 HIV-infected patients enrolled
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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 analysis199. 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.
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Treatment in pregnancy
Adverse pregnancy outcomes are common in women with syphilis45,119. 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 infant21. 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’ gestation201 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 saved202.
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
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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
penicillin12.
Congenital syphilis
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 months12. TTs are not useful in infants due to persistent maternal antibody.
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recommends that adults with neurosyphilis or ocular syphilis should be treated with high-
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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 and anxiety around its highly toxic ‘cures’ (heavy metal therapy with
mercury, arsenicals 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; non-healing
ulcerations; painful bony lesions that often involved destruction of the nose and palate;
visceral involvement; dementia and other incapacitating neurological complications; and
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early death208. 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 disease209. Reductions in syphilis prevalence were documented after the
introduction of penicillin210 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 disease211.
Nevertheless, continuing reports emphasize that complications of late syphilis, particularly
those involving the eyes, CNS and cardiovascular system, can cause lifelong disability and
even death9. For example, case numbers of ocular syphilis have increased with rising
syphilis incidence rates in many communities212, with delayed treatment associated with
permanently diminished visual acuity213. It is essential, therefore, that caregivers be
cognizant of the need to screen at-risk patients for latent infection and administer therapy if
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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 treatment214. 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
relationship177. 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
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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 conditions216.
Untreated maternal syphilis results in severe adverse perinatal outcomes, most prominently
stillbirth, in at least half of affected pregnancies45. While MTCT of syphilis is clearly linked
to lack of prenatal care, WHO data indicate that globally, whether in wealthy or poor
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nations, most adverse pregnancy outcomes caused by maternal syphilis are in women who
attended prenatal care but were not adequately tested or treated24. This suggests other
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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 play217. 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
dissolution218–220. 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 suffering221. Economic
research suggests a stillbirth results in substantial direct and indirect costs and can
sometimes require more resources than a livebirth219.
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Outlook
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).
Box 2
Develop new oral drugs to prevent transmission to fetus and to sexual partners
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Develop vaccines
• Requires research to better understand pathogenesis
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-emerged222. 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 syphilis24. This low
coverage has resulted in a high burden of entirely preventable stillbirths and neonatal
deaths23. Exacerbating this situation, the WHO has received reports of stock outs and
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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
available51,202. Perhaps with this awareness and political will, syphilis MTCT elimination
programmes — which have failed to progress in the past 10 years224 — will witness the
success of the MTCT HIV programmes in Africa. Other developments are occurring that are
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forging change. For example, the availability of POC tests has led to increased coverage of
antenatal screening and treatment for syphilis in many settings148, 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
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woment225. Additionally, the WHO has conducted a systematic review of the performance
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of dual HIV-syphilis rapid tests and issued an information note on testing algorithms for dual
HIV-syphilis tests226.
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
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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 readers227 and microfluidic assays powered by smart phones228 for
real-time monitoring of progress229, and routine provision of proficiency testing
panels121,122. 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
settings123.
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 HIV42,230. 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 behaviours231. 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
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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
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and treatment strategies and partner notification systems for MSM in different cultural,
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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.
pallidum236,237.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
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Peeling et al. Page 24
overcome this limitation, genome sequencing of T. pallidum directly from clinical samples is
now possible92,238 This advance should enable understanding of strain variation on a global
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scale, and help to identify outer membrane proteins and other surface antigens as possible
vaccine candidates81. A recent study showed that immunization of rabbits with the
lipoprotein TP071 prevented dissemination of T. pallidum and, hence, has become a
promising vaccine candidate81. 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.
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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.
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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 transport243. 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.
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purified human peripheral blood monocytes compared with D | normal human serum (NHS).
Arrowheads indicate treponemes being degraded within phagolysosomes.
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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 serofast187. 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
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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 results143,247,248. 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,
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in most developing countries, and in particular given the serious consequences of syphilis in
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Table 1
Darkfield microscopy Fresh (<20 minutes) • Diagnosis can be made • Insensitive: false negatives in
sample from chancres during the clinical visit ≤30% of samples
or erosive cutaneous by visualization of
lesions of primary, characteristic motile • Should not be used in oral or
secondary or organisms rectal specimens due to
congenital syphilis commensal treponemes
• Requires specialist equipment
• Labour-intensive expertise is
needed
• Subjective
• Rarely used anymore
Direct fluorescent Sample from chancres • Can be used for oral • Insensitive: negative test does
antibody staining for T. or erosive cutaneous lesions not rule out syphilis
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Immunohistochemistry Skin, mucosal or • Samples can be saved or • Insensitive: negative test does
tissue lesions shipped for verification not rule out syphilis
performed on fixed
paraffin embedded • Can use tissue samples • Requires specialized
tissues using from placenta and equipment and stains
commercially umbilical cord
• Labour-intensive expertise is
available treponemal
• Useful for unusual forms needed
antibody reagents
of syphilis if tissue
biopsies are obtained • Subjective
when syphilis is not
initially suspected
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Table 2
Venereal Disease Research Laboratory Serum, plasma or • Can be used to • False positives due
(VDRL) slide test CSF monitor treatment to cross-reactivity
efficacy with acute and
chronic conditions
• Only test suitable for
diagnosis of • Must be done
neurosyphilis using manually
cerebral spinal fluid
• Subjective
• Inexpensive and
relatively simple • Requires a
microscope
• Results can be
available in <15 • Antigen
minutes suspension must be
freshly prepared
• Sensitivity of 71– daily (not
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Rapid Plasma Reagin (RPR) or Toluidine Serum or plasma • Can be used to • False positives can
Unheated Serum Test (TRUST) monitor treatment occur in dusty
efficacy settings (e.g. rural
clinics) and due to
• Inexpensive and cross-reactivity
relatively simple with acute and
compared to VDRL chronic conditions
• Does not require a • False negatives can
microscope since occur in early
results can be read by primary syphilis or
eye due to prozone
effect
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• Antigen suspension
can be purchased • Must be done
commercially and is manually
stable (does not
require daily • Subjective
preparation)
• Cards cannot be
• Results can be reused
available in <15
minutes • Cannot be used on
whole blood;
• Sensitivity of 73– requires a
100% depending on centrifuge
the disease stage
• Specificity of 98%
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specialized
reagents, and
microscope
• Manual operation
• Occasional
biological false
positives in
pregnancy or
patients with
autoimmune
disease
T. pallidum Particle Agglutination (TPPA) Serum or plasma • Inexpensive and • Manual and
widely available subjective to
individual
• Sensitivity of 82– interpretation
100% depending on
disease stage
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• Specificity of 99%
Rapid tests
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• Median sensitivity of
86%250; pooled
sensitivity of 84%
(serum test) and 80%
(whole blood)251
Treponemal/nontreponemal test Whole blood, • Rapid, easy to use • Can be more costly
plasma or serum and enables testing than traditional
and treatment at the TTs on a per test
clinical visit basis
• Can distinguish
between new and
previously treated
infections
• Overall performance
for diagnosis of active
infection of 88.3%
(range 87.1–89.4%)
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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.
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