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Try out PMC Labs and tell us what you think. Learn More. Treponema pallidum subspecies pallidum T. pallidum causes syphilis via sexual exposure or vertical transmission during pregnancy. 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. Get me laid johnson city.

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 85557 In the s, investigators screened E. coli recombinant libraries with syphilitic sera and murine monoclonal antibodies based upon the ugradjenje-opremanje.comoven and, as it turned out, immunologically incorrect assumption that immunoreactive proteins ought to be surface-exposed in T.

pallidum 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 6773 - However, convincing evidence now shows that the spirochete displays small amounts of lipoproteins on its surface that have the potential to enhance infectivity Fig.

For example, TP also known as pallilysin is a laminin-binding lipoprotein and zinc-dependent metalloproteinase capable of degrading clots and extracellular matrix 76 - Although expressed by T.

pallidum in minute quantities, surface exposure of TP has been demonstrated by knock-in experiments in Borrelia burgdorferi the spirochete that causes Lyme borreliosis 79and the cultivatable commensal treponeme T. phagedenis 80opsonophagocytosis assays in T.

pallidum 77 and, most recently, protection of immunized rabbits against dissemination of spirochetes following intradermal challenge The X-ray structure of TP, demonstrating an unusual lipocalin fold, should inform efforts to clarify its multi-functionality Additionally, the lipoprotein Tpp17 also known as TP has been shown to be at least partially surface-exposed and can function as a cytadhesin The structurally characterized lipoprotein TP attaches to the inner leaflet of the outer membrane via its N-terminal lipids and two amphipathic helices within its protein moiety Shown in the outer membrane are TP as known as pallilysin 7981 and Tpp17 also known as TP 82- two surface-exposed lipoproteins; TP, a lipoprotein attached to the inner leaflet of the outer membrane 83 ; BamA also known as TP 8494 ; a full-length T.

pallidum repeat Tpr attached by its N-terminal portion to the peptidoglycan 9394 ; and a generic ?-barrel that represents other non-Tpr outer-membrane proteins identified by computational mining of the T. pallidum genome 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 SBPusually 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 Symporter permeases for example, TP use the chemiosmotic or electrochemical gradient across the cytoplasmic membrane to drive substrate transport 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 TP likely associates with the SBP TatP also known as TP that binds ligands perhaps hydrophobic molecules, such as long chain fatty acidsuptake of which is probably is facilitated by the permease TatQ-M also known as TP Figure adapted from Ref.

With the publication of the T. pallidum genome in Ref. BamA has a dual domain architecture consisting of a stranded, outer membrane-inserted, C-terminal ?-barrel and five tandem polypeptide transport-associated POTRA repeats within the periplasm 84 pallidum strains BamA is the essential central component of the molecular machine that catalyses insertion of newly exported outer membrane proteins to the outer membrane pallidum repeat Tpr proteins, a 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 Of these, TprK TP has received the greatest attention because of its presumed role in immune evasion by the spirochete 8788 ; it has been shown to undergo antigenic variation in seven regions believed to be extracellular loops harbouring B-cell epitopes 89 - 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 Two other Tpr proteins, TprC and TprI, have met stringent experimental criteria for rare outer membrane proteins. They form trimeric ?-barrels when refolded in vitrocause large increases in permeability upon insertion into liposomes and are surface-exposed opsonic targets in T.

pallidum 93 Unlike classic porins, for which the entire polypeptide forms a ?-barrel, TprC and TprI are bipartite. As with BamA, the C-terminal domain forms the surface-exposed ?-barrel, whereas the N-terminal half anchors the barrel to the peptidoglycan sacculus. These proteins also furnish a topological template for efforts to understand how antibody responses to Tprs promote bacterial clearance.

pallidum has evolved to dispense with a vast amount of the biosynthetic machinery found in other bacterial pathogens 5563 - 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.

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.

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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 Transmission of venereal syphilis occurs during sexual contact with an actively infected partner; exudate containing as few as 10 organisms can transmit disease 8 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 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 7697 - Once below the epithelium, organisms multiply locally and begin to disseminate through the lymphatics and bloodstream. Ex vivo studies using cultured human umbilical vein endothelial cells Fig. The infection rapidly becomes systemic 916 Profuse spirochetes within the epidermis and superficial dermis in secondary syphilitic lesions Fig.

A Transmission electron micrograph of T. pallidum arrowheads penetrating the junctions between cultured umbilical vein endothelial cells.

pallidum access to tissue parenchyma during haematogenous dissemination. Reprinted with permission from Reference 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.

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Reprinted with permission from 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. 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 cellswhich 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.

Activated lesional T cells secrete IFN-?, promoting clearance by macrophages, but also bolstering the production of tissue-damaging cytokines, such as tumor necrosis factor TNF and IL-6 10, 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 pallidum is widely regarded as an extracellular bacterium 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- Accordingly, one can envision a scenario whereby nonbinders replenish the spirochetes that bind and are cleared Understanding the basis for the heterogeneity of T. 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 9although a hyper-intense cellular response to the spirochete is generally believed to be the cause of the highly destructive lesions of tertiary syphilis 9.

Cardiovascular syphilis, typically involving the aortic arch and leading to aneurysmal dilatation, usually occurs years after the initial infection 9. 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 weeks of gestation 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 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.

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 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 2145 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. A syphilis diagnosis is often based on a suggestive clinical history and supportive laboratory 916 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 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 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 - 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. The choice of method for diagnosing syphilis depends on the stage of disease and the clinical presentation 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.

Diagnosis can be made during the clinical visit by visualization of characteristic motile organisms. Useful for unusual forms of syphilis if tissue biopsies are obtained when syphilis is not initially suspected. Microscopy had been used for direct detection and diagnosis sincebut is now used infrequently.

A 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 The most recent European guidelines recommended against DFA-TP testing in clinical settings, and the reagents are no longer available PCR techniques are increasingly used; however, there is as yet no commercially available or internationally approved test for T.

Species-specific and subspecies-specific T. pallidum PCR testing is a developing technology that is still primarily available in research laboratories, 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 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 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. 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 phosphatidylethanolaminecholesterol and cardiolipin.

NTTs are useful in detecting active syphilis. 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 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 TPHAT. pallidum Particle Assay TPPAFluorescent Treponemal Antibody Absorption assay FTA-ABSenzyme 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 RPRVenereal Disease Research Laboratory VDRL or toluidine red unheated serum TRUST tests and usually appear week after treponemal antibodies.

With effective treatment which is arbitrarily shown here at 6 monthsthe non-treponemal antibody levels decline whereas the treponemal antibodies remain high for many years. 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. Antigen suspension can be purchased commercially and is stable does not require daily preparation. False positives can occur in dusty settings e. rural clinics and due to cross-reactivity with acute and chronic conditions.

Time consuming, expensive and difficult to read, requires specialized reagents, and microscope. Occasional biological false positives in pregnancy or patients with autoimmune disease. Can be automated, especially suitable for high-throughput screening of asymptomatic populations and blood or plasma donors.

IgM EIA has low sensitivity in active syphilis, not helpful in staging or evaluating treatment efficacy. Overall performance for diagnosis of active infection of Can detect treponemal and HIV antibodies in the same test using a single finger prick specimen. 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 Without treatment, titres peak at 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. These patients are labelled as having a serofast status and are observed more commonly with treatment for late latent than early syphilis 37 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 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 days after the primary chancre appears 5 weeks after infection and, therefore, may be useful to detect early syphilis missed by NTT testing.

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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-TPthe 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.

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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- 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 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 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. 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, 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 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. POC rapid TTs are a recent technology that enable onsite screening and treatment, and are particularly useful in settings with limited laboratory capacity. Various rapid tests have been evaluated in a range of clinical and community settings and shown to fulfil the ASSURED criteria- 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.

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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 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 At least one test has been developed that enables simultaneous detection of non-treponemal and treponemal antibodies in a single POC device - These are an increasingly important tool in the global elimination of MTCT of HIV and syphilis in settings in which laboratory capacity is limited 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 Other CSF tests, including serological assays - such as the Rapid Plasma Reagin RPRFTA-ABS and TPHA - and molecular assays including PCR have all been assessed for CSF and have variable specificity and sensitivity for the diagnosis of neurosyphilis.

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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; thus, discerning the cause of pleocytosis in co-infected individuals is not always possible.

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 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 1113 but not others Maternal syphilis infection is highly correlated with fetal loss, therefore, evaluation of a stillborn infant should include evaluation of maternal tests for syphilis 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, adults and adolescents at increased risk for infection 1340 and individuals donating blood, blood products or solid organs 13- 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 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 113741 Global normative authorities and most national guidelines recommend syphilis screening at the first prenatal visit, ideally during the first trimester 113741 Some countries recommend that women at high risk have repeat screening in the third trimester and again at delivery to identify new infections Women should be tested in each pregnancy, even if they have tested negatively in a previous pregnancy.

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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 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 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 4344 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 23434446 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 - 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- 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 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 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 3740, At-risk communities are often marginalized from care and experience discrimination and stigma when using traditional STI services 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 Evaluation studies of other interventions, such as pre-exposure prophylaxis PrEP for syphilis, are also underway One option in the future might be to simultaneously administer PrEP for syphilis and HIV Although syphilis was among the first identified infectious risks for blood donation and s transmission through blood has been documented -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 Survival of T.

Syphilis screening of blood, blood components or solid organs remains a recommendation in many countries 13 Occasional cases of transfusion-transmitted syphilis are still reported in settings with high syphilis prevalence, particularly with transfusion of fresh blood 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 Treatment of exposed sex partners is important to avoid reinfection 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.

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The CDC guidelines do not offer procaine penicillin as a treatment, but are otherwise identical 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.

From Ref. Penicillin has been the mainstay of treatment for syphilis since it first became widely available in the late s. 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. 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 1213 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 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 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 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 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 - A study in HIV-positive patients with syphilis showed that azithromycin to prevent opportunistic infections led to better serological outcomes 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. 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 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 Notably, the 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.

However, using a last-observed-carried-forward analysis to account for missing data, the authors concluded that Given the inconclusive results of these studies, many clinicians continue to offer enhanced therapy to HIV co-infected patients with early syphilis. Adverse pregnancy outcomes are common in women with syphilis 45 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 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 TTs are not useful in infants due to persistent maternal antibody. 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 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 days 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 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 Reductions in syphilis prevalence were documented after the introduction of penicillin 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 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 communitieswith delayed treatment associated with permanently diminished visual acuity 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. 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 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 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 Untreated maternal syphilis results in severe adverse perinatal outcomes, most prominently stillbirth, in at least half of affected pregnancies 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 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 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.

Economic research suggests a stillbirth results in substantial direct and indirect costs and can sometimes require more resources than a livebirth 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. 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.

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 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.

This low coverage has resulted in a high burden of entirely preventable stillbirths and neonatal deaths 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 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 Perhaps with this awareness and political will, syphilis MTCT elimination programmes - which have failed to progress in the past 10 years - 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 settingsand the WHO campaign for the elimination of MTCT of HIV and syphilis has increased the visibility of syphilis on the global health agenda.

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 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.

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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 and microfluidic assays powered by smart phones for real-time monitoring of progressand routine provision of proficiency testing panels 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 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 However, the alarming increase in incidence of syphilis, compared to other STIs, in HIV-infected MSM cannot be explained by behavioural factors alone.

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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 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.

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 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 ; 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 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 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 syphilislending 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. Human challenge studies have shown that people with late latent syphilis are resistant to symptomatic reinfection with heterologous strains of T.

pallidumand protective immunity has been induced in rabbits by repeated inoculation with ?-irradiated T. pallidum Accordingly, it should be possible to develop protective vaccines.

Get the latest science news and technology news, read tech reviews and more at ABC News 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 (Ref. 34).Location: Rockville Pike, Bethesda, MD Today, best-in-class apps provide comprehensive nutrition databases that tell a user the nutritional content after scanning the barcode, allow them to search for restaurant menu items or popular meals by their names, or recognize food items on a plate. 44 Smartphone sensors using machine learning and symbolic reasoning can recognize and quantify high-level lifestyle activities of patients with

However, research on virulence determinants of T. pallidumand 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 92This 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 A recent study showed that immunization of rabbits with the lipoprotein TP prevented dissemination of T.

pallidum and, hence, has become a promising vaccine candidate 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.

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

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. National Center for Biotechnology InformationU.

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Journal List HHS Author Manuscripts PMC Nat Rev Dis Primers. Author manuscript; available in PMC Oct PMCID: PMC NIHMSID: NIHMS Rosanna W. Peeling1 David Mabey1 Mary L. Kamb2 Xiang-Sheng Chen3 Justin David Radolf4 and Adele Schwartz Benzaken 5. Mary L. Xiang-Sheng Chen 3 National Center for STD Control, Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Dermatology, Nanjing, China Find articles by Xiang-Sheng Chen. Justin David Radolf 4 Department of Medicine, UConn Health, Farmington, Connecticut, USA Find articles by Justin David Radolf.

Author information Copyright and License information Disclaimer. Correspondence to: R. mthsl gnileep. Copyright notice. The publisher's final edited version of this article is available at Nat Rev Dis Primers.

See other articles in PMC that cite the published article. Abstract Treponema pallidum subspecies pallidum T. Introduction Syphilis is a sexually and vertically transmitted infection STI caused by the spirochaete Treponema pallidum subspecies pallidum order Spirochaetales Fig.

Open in a separate window. Figure 1. Treponema pallidum A Like all spirochetes, T. Epidemiology According to the most recent estimation of the WHO, approximately Figure 2. Incidence of syphilis worldwide The WHO estimates of incident cases of syphilis by region in are shown for the different geographical regions.

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. MTCT 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 Molecular Features The morphological features of T.

Lipoproteins In the s, investigators screened E. Figure 3. Molecular architecture of the cell envelope of Treponema pallidum Shown in the outer membrane are TP as known as pallilysin 7981 and Tpp17 also known as TP 82- two surface-exposed lipoproteins; TP, a lipoprotein attached to the inner leaflet of the outer membrane 83 ; BamA also known as TP 8494 ; a full-length T.

BamA With the publication of the T. Tpr proteins The T. Biosynthetic machinery T. 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 Figure 4.

Treponema pallidum invasion A Transmission electron micrograph of T. Adaptive immune response and inflammation Although the paucity of PAMPs in the T. Antibody avoidance T.

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. Diagnosis, screening and prevention Syphilis has varied and often subtle manifestations that make clinical diagnosis difficult and lead to many infections being unrecognized. Figure 5. Clinical presentation of primary, secondary and congenital syphilis A Primary chancre.

Definitive diagnosis by direct detection The choice of method for diagnosing syphilis depends on the stage of disease and the clinical presentation Table 1 Direct detection methods for Treponema pallidum. pallidum Sample from chancres or erosive cutaneous lesions of primary, secondary or congenital syphilis Can be used for oral lesions Specific detection of T. 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.

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Figure 6. Table 2 Serological tests for Treponema pallidum. TTs In contrast to NTTs, TTs detect antibodies directed against T. Figure 7. Screening algorithms for syphilis A The traditional algorithm begins with a qualitative non-treponemal test NTT that is confirmed with a treponemal test TT.

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. Tests useful in special situations Neurosyphilis The diagnosis of neurosyphilis is challenging. Congenital syphilis Diagnosis of congenital syphilis in exposed, asymptomatic infants is another area in testing can be improved.

Screening 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.

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 113741 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 Blood bank screening Although syphilis was among the first identified infectious risks for blood donation and s transmission through blood has been documented -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 Prevention 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.

Management 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.

Box 1 WHO guidelines for the treatment of syphilis. Penicillin Penicillin has been the mainstay of treatment for syphilis since it first became widely available in the late s. 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.

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 Treatment in pregnancy Adverse pregnancy outcomes are common in women with syphilis 45 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 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.

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. 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.

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.

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. Vaccine development Human challenge studies have shown that people with late latent syphilis are resistant to symptomatic reinfection with heterologous strains of T.

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. Footnotes Author contributions Introduction R. and D. and X. and A. References 1.

Giacani L, Lukehart SA. The Endemic Treponematoses. Clin Microbiol Rev. Smajs D, Norris SJ, Weinstock GM. Genetic diversity in Treponema pallidum: implications for pathogenesis, evolution and molecular diagnostics of syphilis and yaws.

Infect Genet Evol. de Melo FL, de Mello JCM, Fraga AM, Nunes K, Eggers S. Syphilis at the crossroad of phylogenetics and paleopathology. PLoS Negl Trop Dis. PENN CW. Avoidance of Host Defences by Treponema pallidum in Situ and on Extraction from Infected Rabbit Testes. Stamm LV, Hodinka RL, Wyrick PB, Bassford PJ. regulators for younger children, and millions of teens have already safely received the shot. Brazil scientists test frozen jaguar semen to help species Brazilian and American scientists have performed artificial insemination using frozen sperm for the first time on a wild-born female jaguar.

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