Syphilis is back

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The most comprehensive genomic study of syphilis to date has mapped the recent resurgence of the disease around the world.

There is widespread global transmission of syphilis, particularly within the last 20 years, according to research published in Nature Microbiology.

Researchers at the London School of Hygiene & Tropical Medicine (LSHTM), Wellcome Sanger Institute, the UK Health Security Agency, and their collaborators mapped the recent resurgence of the disease around the world. They found almost identical syphilis samples between 14 countries, with the global syphilis population made up of two lineages, SS14 and Nichols.

Detailed analysis of these lineages provides important insights into the genetic diversity of syphilis, with implications for vaccine design and antimicrobial resistance.

Syphilis is one of the most common sexually-transmitted infections (STI) globally, with approximately six million infections each year. Caused by the bacterium Treponema pallidum, it is easily treatable, although symptoms may fade before an individual realizes they are infected or may not appear at all. If left untreated syphilis can cause serious long-term health problems.

Syphilis infections occurring during pregnancy can be passed on to the child, causing congenital syphilis. This is the second leading cause of stillbirth globally and can have severe developmental outcomes for children carried to term. It can be prevented through early screening and treatment during pregnancy. Congenital syphilis is more common in countries without such screening programs.

For this study – funded by Wellcome – researchers at LSHTM and the Wellcome Sanger Institute coordinated the collection of 726 syphilis samples from 23 countries. This included well-sampled areas such as the United States and Western Europe, as well as poorly sampled regions such as Central Asia, Australia and Africa.

The Sanger Institute sequenced the genome of each sample and conducted phylogenetic and cluster analyses to map the global syphilis population.

Because DNA changes occur at a known and predictable rate over time, the ancestral relationships between different sequences can be established.

The team found that all the samples came from just two deeply branching lineages, Nichols and SS14. Both lineages are currently circulating in 12 of the 23 countries sampled, and almost identical samples were present in 14 of these countries.

Dr. Mathew Beale, first author of the study from the Wellcome Sanger Institute, said: “The dominant syphilis lineages infecting patients prior to 1983 were not the same as those infecting patients today.

Our analysis shows a population bottleneck occurred in the late 1990s that indicates a large decline in the population size of T. pallidum, most likely as a result of the HIV/AIDS crisis.

The concerning thing from a public health perspective is that the presence of almost identical samples in numerous countries suggests the disease is being transmitted internationally on a regular basis. Syphilis is back and it is global.”

Syphilis incidence declined during the 1980s and 1990s, in part due to safer sexual practices in the wake of the HIV/AIDS epidemic.

But in recent decades syphilis has increased again, rising by over 300% in some countries since 2010. Syphilis disproportionately affects men who have sex with men (MSM) in some countries – for example, 90% of UK syphilis cases in 2017 were among MSM.

Dr. Helen Fifer, a senior author of the paper from the UK Health Security Agency (UKHSA), said: “The explosion of syphilis cases in recent decades is hugely concerning. It is a sexually transmitted infection that can easily go undetected, with a large proportion of cases being diagnosed at the latent stage among men who have sex with men (MSM) in recent years.

An increase in syphilis among heterosexuals is also concerning due to the risk of congenital syphilis. Anyone having sex with new or casual partners should use a condom and get tested—STIs can pose serious consequences to the health of individuals and the health of their current or future sexual partners.”

The study is a valuable resource for understanding the genetic diversity of T. pallidum that will have implications for vaccine design and drug resistance. Many of the samples sequenced were resistant to macrolides, a class of antibiotics used to treat many STIs – though none showed resistance to the most common syphilis treatment, benzathine benzylpenicillin.

Any syphilis vaccine will need to be tailored to the most common lineages of T. pallidum currently in circulation.

Professor Nicholas Thomson, senior author of the study from LSHTM and the Wellcome Sanger Institute, said: “It’s been a huge logistical effort to bring this study together and we couldn’t have done it without our international collaborators. We wanted to build the field of syphilis genomics and these data provide a solid foundation for future research.

Combined with the recent ability to culture T. pallidum in the lab, there is now a wealth of activity in this field, which is important because syphilis is fast becoming an urgent public health issue.”


Syphilis is a bacterial STI caused by Treponema pallidum that results in substantial morbidity and mortality. Syphilis is transmitted through sexual contact with infectious lesions of the mucous membranes or abraded skin, via blood transfusion, or transplacentally from a pregnant woman to her fetus. Untreated, the disease lasts many years and is divided into stages.

Early syphilis consists of primary syphilis, secondary syphilis and early latent syphilis, while late syphilis consists of late latent syphilis and tertiary syphilis (neurosyphilis, cardiosyphilis and gumma).

Primary syphilis classically presents as a solitary, painless chancre at the site of inoculation.

However, the primary chancre may go unnoticed by patients. If untreated, the disease progresses to the secondary stage, characterized by generalized mucocutaneous lesions affecting both skin, mucous membranes and lymphnodes. The rash of secondary syphilis can vary widely and mimic other infectious and non-infectious conditions, but characteristically affects the palms and soles. The  symptoms  and  signs of secondary syphilis spontaneously resolve, even without treatment, and if left untreated, the patient enters the latent stage.

Latent syphilis is asymptomatic, characterized by positive syphilis serology with no clinical manifestations. Latent syphilis is often divided into two phases: early latent syphilis is defined as infection for less than two years while late latent syphilis is the presence of the disease for two years or more. Sexual transmission typically occurs during primary, secondary or early latent stage infections; however, mother-to-child transmission has been documented to occur in untreated cases several years after initial maternal infection.

Mother-to-child transmission of syphilis (congenital syphilis) is usually devastating to the fetus if maternal infection is not detected and treated sufficiently early in pregnancy. The burden of morbidity and mortality due to congenital syphilis is high. In 2012, an estimated 350 000 adverse pregnancy outcomes worldwide were attributed to syphilis, including 143 000 early fetal deaths/stillbirths, 62 000 neonatal deaths, 44 000 preterm/low-birth-weight babies and 102 000 infected infants. Most untreated primary and secondary syphilis infections in pregnancy result in severe adverse pregnancy outcomes. Latent (asymptomatic) syphilis infections in pregnancy also cause serious adverse pregnancy outcomes in more than half of cases.

Mother-to-child transmission of syphilis is declining globally due to increased efforts to screen and treat pregnant women for syphilis.

Syphilis diagnosis is usually based on clinical history, physical examination, laboratory testing and sometimes radiology. In most laboratory settings, the diagnosis is based upon serologic tests. These include treponemal tests that measure antibodies to infection (including Treponema pallidum haemagglutination assay [TPHA], Treponema pallidum particle agglutination assay [TPPA], fluorescent treponemal antibody absorbed [FTA-ABS]) and non-treponemal tests that are indirect markers measuring host immune response to infections (including rapid plasma reagin [RPR], Venereal Diseases Research Laboratory [VDRL], Toluidine Red Unheated Serum Test [TRUST]). Rapid treponemal tests for syphilis and dual HIV and syphilis tests are now available. These tests will increase coverage for diagnosing syphilis.

EPIDEMIOLOGY, BURDEN AND CLINICAL CONSIDERATIONS

Syphilis is a bacterial sexually transmitted infection (STI) caused by Treponema pallidum. It results in substantial morbidity and mortality. WHO estimates that 5.6 million new cases of syphilis occurred among adolescents and adults aged 15–49 years worldwide in 2012 with a global incidence rate of 1.5 cases per 1000 females and 1.5 per 1000 males.

The estimated 18 million prevalent cases of syphilis in 2012 translates to a global prevalence of 0.5% among females and 0.5% among males aged 15–49 years, with the highest prevalence in the WHO African Region (1).

Mother-to-child transmission may occur if the expectant mother has syphilis. Mother-to-child transmission of syphilis (congenital syphilis) is usually devastating to the fetus in cases where maternal infection is not detected and treated sufficiently early in pregnancy.

The burden of morbidity and mortality due to congenital syphilis is high. In 2012, an estimated 350 000 adverse pregnancy outcomes worldwide were attributed to syphilis, including 143 000 early fetal deaths/stillbirths, 62 000 neonatal deaths, 44 000 preterm/low-birth-weight babies and 102 000 infected infants. There is also an increase in mother-to-child transmission of HIV among pregnant women co-infected with syphilis and HIV.

Untreated primary and secondary syphilis infections in pregnancy typically result in severely adverse pregnancy outcomes, including fetal deaths in a substantial proportion of cases. Latent syphilis infections in pregnancy result in serious adverse pregnancy outcomes in more than half of cases. The burden of disease is highest in low- and middle-income countries, particularly in the WHO African Region (2).

Congenital syphilis is preventable, however, and elimination of mother-to-child transmission of syphilis can be achieved through implementation of effective early screening and treatment strategies for syphilis in pregnant women (3). The fetus can be easily cured with treatment, and the risk of adverse outcomes to the fetus is minimal if the mother receives adequate treatment during early pregnancy – ideally before the second trimester. There are indications that mother-to-child transmission of syphilis is beginning to decline globally due to increased efforts to screen and treat pregnant women for syphilis.

CLINICAL PRESENTATION

Syphilis is transmitted through sexual contact with infectious lesions of the mucous membranes or abraded skin, via blood transfusion, or transplacentally from a pregnant woman to her fetus. Untreated, the disease lasts many years and is divided into stages. Early syphilis consists of primary syphilis, secondary syphilis and early latent syphilis, while late syphilis consists of late latent syphilis and tertiary syphilis.

Primary syphilis classically presents as a solitary, painless chancre at the site of inoculation, usually in the vagina, penis or anus (but it may be extra-genital), after a mean incubation period of 21 days (range: 9–90 days). The primary lesion begins as a raised papule and ulcerates before healing within 3 to 10 weeks, with or without treatment. The primary chancre may go unnoticed by patients.

If untreated, the disease progresses to the secondary stage, four to eight weeks after the appearance of the primary lesion.

Secondary syphilis is characterized by generalized mucocutaneous lesions affecting both skin and mucous membranes. The rash of secondary syphilis can vary widely and mimic other infectious or non-infectious conditions, but characteristically affects the palms and soles.

The rash is often symmetrical and non-itchy, but may have several manifestations and can be minimal enough to be overlooked. In warm and moist areas of the body, such as the anus and labia, large white or grey raised lesions develop as a result of the spread of the treponemes from the primary lesion.

These are known as condylomata lata. The lesions of the skin and mucous membranes may be associated with non-specific constitutional symptoms of malaise, fever and lymphadenopathy. The symptoms and signs of secondary syphilis spontaneously resolve, even without treatment, and if left untreated, the patient enters the latent stage.

Latent syphilis is characterized by positive syphilis serology with no clinical symptoms or signs. Latent syphilis is often categorized in two phases: early latent syphilis is defined as infection for less than  two  years and late latent syphilis is the presence of the disease for two years or more. The treatment of latent syphilis is different for the early and late phases.

Patients with unknown duration of infection should be treated for late latent syphilis. Sexual transmission typically occurs only during primary, secondary and early latent infection. Mother-to-child transmission, however, has been documented to occur up to several years after initial infection.

If left untreated, most patients will remain in the latent stage. Approximately 25% will develop the late clinical sequelae of tertiary syphilis (4), which can affect any organ system up to 30 years or more after infection. The main manifestations of tertiary syphilis are neurological disease (neurosyphilis), cardiovascular disease (cardiosyphilis) and gummatous lesions (gumma).

Neurosyphilis can occur at any stage of syphilis infection, even in the first few months. Early neurological manifestations include acute changes in mental status, meningitis, stroke, cranial nerve dysfunction and auditory or ophthalmic and ocular abnormalities.

Late neurosyphilis occurs 10–30 years or more after infection and is characterized by tabes dorsalis and general paresis.

The most common manifestation of congenital syphilis is second or third trimester fetal loss or premature labour. Thus, serologic testing for syphilis should be performed for all mothers with stillborn infants, to document evidence of syphilis. In most countries, it is estimated that the majority of congenital syphilis cases result in syphilitic stillbirths, and these cases are often not recognized as having been caused by syphilis.

Infants born to mothers with positive syphilis serology should be examined for signs and symptoms of early congenital syphilis, including bullous rash, rhinitis, laryngitis, lymphadenopathy, hepatosplenomegaly, osteochrondritis, periostitis, meningitis and chorioretinitis. The signs of late congenital syphilis infection in children over the age of 2 years include inflammatory manifestations affecting the eyes, ears and joints, as well as skeletal malformations and stigmata resulting from developmental damage during the early stages of syphilis. However, it is important to keep in mind that many infants with syphilis infection will not have obvious clinical signs or symptoms.

LABORATORY DIAGNOSIS

Syphilis diagnosis is based on the patient’s history, physical examination, laboratory testing and sometimes radiology. The available laboratory tests for diagnosis of syphilis include direct detection methods (i.e. dark- field microscopy, direct fluorescent antibody test and nucleic acid amplification test), serology (treponemal and non-treponemal tests), and examination of cerebrospinal fluids (6).

DIRECT DETECTION METHODS

Direct detection methods require exudates from lesions of primary, secondary or early congenital syphilis, and need careful collection of samples.

Dark-field microscopy demonstrating treponemes with characteristic morphology and motility in lesion exudate or tissue is the most specific method  for  diagnosis  of the early stages of syphilis. The dark-field examination must be performed immediately after specimen collection from primary chancres, moist secondary lesions or lymph nodes or from mucocutaneous lesions in newborns. Dark-field microscopy requires specialized equipment and a trained, experienced microscopist, and is therefore usually limited to specialized laboratories.

Dark-field microscopy is highly specific, therefore the presence of characteristic spirochetes is diagnostic of an active infection. Its sensitivity, however, is less than 50%, so a negative result does not exclude syphilis.

Although dark-field microscopy is one of the simplest and most reliable methods for the direct detection of T. pallidum, its availability is increasingly limited.

The direct fluorescent antibody (DFA) test uses a fluorescence microscope to detect spirochetes that have been stained with fluorescein-labelled anti-

T. pallidum globulin. Specimens are obtained in the same way as for dark-field microscopy, but the fluorescein-stained organisms are  easier  to  detect and are not likely to be confused with other organisms, leading to a higher sensitivity and specificity for the DFA test. However, specialized equipment is required and the specific fluorescein conjugate is not commercially available in most countries.

Nucleic acid amplification tests (NAATs) directly detect T. pallidum DNA by polymerase chain reaction (PCR) from specimens of any lesion exudate, tissue or body fluid.

The sensitivity varies according to  the  specific PCR assay; most assays can detect approximately 10 organism equivalents, although some can detect one organism per PCR reaction. Commercial PCR tests for T. pallidum are not yet commercially available and therefore are relatively costly compared with other

tests used to diagnose syphilis. For studies with testing done in well-equipped laboratories, multiplex PCR assays have been developed for detection of the most common causes of genital ulcers, including syphilis, herpes simplex virus and H. ducreyi (chancroid).

SYPHILIS SEROLOGY

There are two types of serological tests for syphilis: non-treponemal and treponemal. A presumptive diagnosis of syphilis requires a positive result from at least one of these types of tests. A confirmed diagnosis requires positive results from both types of serologic tests.

Serum is the specimen of choice for serological testing, although plasma can be used in some non-treponemal serological tests. Cerebrospinal fluid is used to diagnose congenital and tertiary syphilis and when neurological symptoms are present.

The most widely available non-treponemal tests are the microscopic Venereal Diseases Research Laboratory (VDRL) and the macroscopic rapid plasma reagin (RPR) tests. These tests detect anti-lipid immunoglobin M or G (IgM or IgG) antibodies. Since these antibodies can also be produced in other diseases, non-treponemal tests are not highly specific for syphilis and can give false-positive results in conditions such as acute febrile viral infections and some chronic autoimmune diseases. Most false-positive results have low titres of less then 1 : 4.

Non-treponemal tests may be negative for up to four weeks after the lesion of primary syphilis first appears and can be negative in ate latent syphilis; additionally in primary and secondary syphilis, these tests may be false negative due to a prozone reaction (i.e. interference by high concentrations of antibodies in a specimen, which can be uncovered with dilution and retesting). In primary syphilis, repeated testing at two and four weeks may be required to exclude syphilis when suspect lesions are present. A negative non-treponemal test at three months after onset of the primary chancre virtually excludes the diagnosis of syphilis.

Non-treponemal tests may be qualitative or quantitative. Quantitative non-treponemal test titres can be used to monitor response to treatment.

Titres are expected to decrease following effective treatment and increase in untreated active infection. A four-fold change or higher in titre, equivalent to a change of at least two dilutions (e.g. from 1 : 16 to 1 : 4 for effective positive response to treatment, or from : 8 to 1 : 32 for continued active infection) is considered a significant difference between two sequential tests using the same method (e.g. VDRL or RPR) and preferably by the same laboratory. Titres that differ  by only one dilution (e.g. 1 : 8 versus 1 : 4 or 1 : 2 versus 1 : 1) are not considered significant and may only represent differences in laboratory interpretation).

Treponemal tests include the Treponema pallidum haemagglutination assay (TPHA), the Treponema pallidum particle agglutination assay (TPPA) and the fluorescent treponemal antibody absorbed (FTA-ABS) tests. These tests are highly specific because they detect antibodies against treponemal-specific antigens; however, they do not differentiate venereal syphilis from endemic syphilis (the latter includes yaws and pinta).

Classically, one of these tests is used as a confirmatory test following a positive non-treponemal test. Treponemal tests usually remain positive (85%) for the patient’s lifetime, regardless of treatment. Thus, a positive treponemal test does not distinguish between active infection and infection that has been previously treated.

All live or stillborn infants of seropositive mothers should be examined for evidence of congenital syphilis. Live-born infants should be examined and tested at birth and at monthly intervals for three months until it is confirmed that serological tests in the infant are, and remain, negative. Antibodies can be passively transmitted from the mother, complicating the interpretation of laboratory results in neonates, but usually disappear within three to four months after birth. However, maternal antibodies can sometimes persist for up to 18 months. In such cases, repeat testing with titration should be carried out and if a four-fold or greater increase in titre of a non-treponemal or treponemal test is detected, the baby should be treated for congenital syphilis.

RAPID DIAGNOSTIC TESTS

In the past decade, a number of point-of-care rapid diagnostic tests (RDTs) for treponemal antibodies in syphilis infection have been developed. RDTs provide treponemal antibody results in 10–15 minutes and can be performed in any setting since they do not require refrigerated storage or laboratory equipment. The sensitivity of the RDTs ranges from 85% to 98% and the specificity from 93% to 98%, compared to the TPHA or TPPA as reference standards.

In general, RDTs with higher sensitivities tend to have lower specificities and vice versa.

Most of the initial range of RDTs use T. pallidum antigens to detect treponema-specific antibodies. Many of the tests use immunochromatographic strips, which work by having a test strip impregnated with treponemal antigens that react with antibodies to syphilis in whole blood or serum.

The tests work on the same principle as the specific treponemal tests described above, thus a positive result does not distinguish between active and previously treated infections.

More recently, tests that can detect antibodies against cardiolipin-like materials have been developed that work on the same principle as other non-treponemal tests.

They are available in combination with the treponemal RDTs, providing both a screening (RPR/VDRL equivalent) and confirmatory (TPHA/TPPA equivalent) component. However, these dual RDTs have not yet been sufficiently evaluated or field-tested to be recommended.

reference : WHO – https://www.researchgate.net/publication/319321749


More information: Mathew A. Beale et al, Global phylogeny of Treponema pallidum lineages reveals recent expansion and spread of contemporary syphilis, Nature Microbiology (2021). DOI: 10.1038/s41564-021-01000-z

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