clinical presentation of syphilis infection

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Syphilis is an infection caused by bacteria. Most often, it spreads through sexual contact. The disease starts as a sore that's often painless and typically appears on the genitals, rectum or mouth. Syphilis spreads from person to person through direct contact with these sores. It also can be passed to a baby during pregnancy and childbirth and sometimes through breastfeeding.

After the infection happens, syphilis bacteria can stay in the body for many years without causing symptoms. But the infection can become active again. Without treatment, syphilis can damage the heart, brain or other organs. It can become life-threatening.

Early syphilis can be cured, sometimes with a single shot of medicine called penicillin. That's why it's key to get a health care checkup as soon as you notice any symptoms of syphilis. All pregnant people should get tested for syphilis at their first prenatal checkup too.

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• Primary syphilis

Primary syphilis causes painless sores (chancres) on the genitals, rectum, tongue or lips. The disease can be present with the appearance of a single chancre (shown here on a penis) or many.

Syphilis develops in stages. The symptoms vary with each stage. But the stages may overlap. And the symptoms don't always happen in the same order. You may be infected with syphilis bacteria without noticing any symptoms for years.

The first symptom of syphilis is a small sore called a chancre (SHANG-kur). The sore is often painless. It appears at the spot where the bacteria entered your body. Most people with syphilis develop only one chancre. Some people get more than one.

The chancre often forms about three weeks after you come in contact with syphilis bacteria. Many people who have syphilis don't notice the chancre. That's because it's usually painless. It also may be hidden within the vagina or rectum. The chancre heals on its own within 3 to 6 weeks.

Secondary syphilis

You may get a rash while the first chancre heals or a few weeks after it heals.

A rash caused by syphilis:

• Often is not itchy.
• May look rough, red or reddish-brown.
• Might be so faint that it's hard to see.

The rash often starts on the trunk of the body. That includes the chest, stomach area, pelvis and back. In time, it also could appear on the limbs, the palms of the hands and the soles of the feet.

Along with the rash, you may have symptoms such as:

• Wartlike sores in the mouth or genital area.
• Muscle aches.
• Sore throat.
• Tiredness, also called fatigue.
• Weight loss.
• Swollen lymph nodes.

Symptoms of secondary syphilis may go away on their own. But without treatment, they could come and go for months or years.

Latent syphilis

If you aren't treated for syphilis, the disease moves from the secondary stage to the latent stage. This also is called the hidden stage because you have no symptoms. The latent stage can last for years. Your symptoms may never come back. But without treatment, the disease might lead to major health problems, also called complications.

Tertiary syphilis

After the latent stage, up to 30% to 40% of people with syphilis who don't get treatment have complications known as tertiary syphilis. Another name for it is late syphilis.

The disease may damage the:

• Blood vessels.
• Bones and joints.

These problems may happen many years after the original, untreated infection.

Syphilis that spreads

At any stage, untreated syphilis can affect the brain, spinal cord, eyes and other body parts. This can cause serious or life-threatening health problems.

Congenital syphilis

Pregnant people who have syphilis can pass the disease to their babies. Unborn babies can become infected through the organ that provides nutrients and oxygen in the womb, called the placenta. Infection also can happen during birth.

Newborns with congenital syphilis might have no symptoms. But without fast treatment, some babies might get:

• Sores and rashes on the skin.
• A type of discolored skin and eyes, called jaundice.
• Not enough red blood cells, called anemia.
• Swollen spleen and liver.
• Sneezing or stuffed, drippy nose, called rhinitis.
• Bone changes.

Later symptoms may include deafness, teeth problems and saddle nose, a condition in which the bridge of the nose collapses.

Babies with syphilis also can be born too early. They may die in the womb before birth. Or they could die after birth.

When to see a doctor

Call a member of your health care team if you or your child has any symptoms of syphilis. These could include any unusual discharge, a sore or a rash, especially in the groin area.

Also get tested for syphilis if you:

• Have had sexual contact with someone who might have the disease.
• Have another sexually transmitted disease such as HIV .
• Are pregnant.
• Regularly have sex with more than one partner.
• Have unprotected sex, meaning sex without a condom.
• Mayo Clinic Minute: Signs and symptoms of syphilis

Vivien Williams: Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum. Dr. Stacey Rizza, an infectious diseases specialist at Mayo Clinic, says syphilis affects men and women and can present in various stages.

Stacey Rizza, M.D.: Primary syphilis causes an ulcer, and this sometimes isn't noticed because it's painless and can be inside the vagina or on the cervix…after a few weeks, two months, they can get secondary syphilis, which is a rash.

Vivien Williams: It may then progress to latent stage syphilis and, finally, the most serious stage: tertiary. Pregnant women are not immune to syphilis. Congenital syphilis can lead to miscarriage, stillbirth or infant deaths. That's why all pregnant women should be screened. Syphilis is preventable and treatable. As for prevention, Dr. Rizza recommends barrier protection during sex.

Dr. Rizza: And that's during oral sex, anal sex, vaginal sex — using condoms, dental dams and any other barrier protection.

Vivien Williams: For the Mayo Clinic News Network, I'm Vivien Williams.

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The cause of syphilis is a bacterium called Treponema pallidum. The most common way syphilis spreads is through contact with an infected person's sore during vaginal, oral or anal sex.

The bacteria enter the body through minor cuts or scrapes in the skin or in the moist inner lining of some body parts.

Syphilis is contagious during its primary and secondary stages. Sometimes it's also contagious in the early latent period, which happens within a year of getting infected.

Less often, syphilis can spread by kissing or touching an active sore on the lips, tongue, mouth, breasts or genitals. It also can be passed to babies during pregnancy and childbirth and sometimes through breastfeeding.

Syphilis can't be spread through casual contact with objects that an infected person has touched.

So you can't catch it by using the same toilet, bathtub, clothing, eating utensils, doorknobs, swimming pools or hot tubs.

Once cured, syphilis doesn't come back on its own. But you can become infected again if you have contact with someone's syphilis sore.

Risk factors

The risk of catching syphilis is higher if you:

• Have unprotected sex.
• Have sex with more than one partner.
• Live with HIV , the virus that causes AIDS if untreated.

The chances of getting syphilis also are higher for men who have sex with men. The higher risk may be linked, in part, with less access to health care and less use of condoms among this group. Another risk factor for some people in this group includes recent sex with partners found through social media apps.

Complications

Without treatment, syphilis can lead to damage throughout the body. Syphilis also raises the risk of HIV infection and can cause problems during pregnancy. Treatment can help prevent damage. But it can't repair or reverse damage that's already happened.

Small bumps or tumors

Rarely in the late stage of syphilis, bumps called gummas can form on the skin, bones, liver or any other organ. Most often, gummas go away after treatment with medicine called antibiotics.

Neurological problems

Syphilis can cause many problems with the brain, its covering or the spinal cord. These issues include:

• Meningitis, a disease that inflames the protective layers of tissue around the brain and spinal cord.
• Confusion, personality changes or trouble focusing.
• Symptoms that mimic dementia, such as loss of memory, judgment and decision-making skills.
• Not being able to move certain body parts, called paralysis.
• Trouble getting or keeping an erection, called erectile dysfunction.
• Bladder problems.

Eye problems

Disease that spreads to the eye is called ocular syphilis. It can cause:

• Eye pain or redness.
• Vision changes.

Ear problems

Disease that spreads to the ear is called otosyphilis. Symptoms can include:

• Hearing loss.
• Ringing in the ears, called tinnitus.
• Feeling like you or the world around you is spinning, called vertigo.

Heart and blood vessel problems

These may include bulging and swelling of the aorta — the body's major artery — and other blood vessels. Syphilis also may damage heart valves.

HIV infection

Syphilis sores on the genitals raise the risk of catching or spreading HIV through sex. A syphilis sore can bleed easily. This provides an easy way for HIV to enter the bloodstream during sex.

Pregnancy and childbirth complications

If you're pregnant, you could pass syphilis to your unborn baby. Congenital syphilis greatly raises the risk of miscarriage, stillbirth or your newborn's death within a few days after birth.

There is no vaccine for syphilis. To help prevent the spread of syphilis, follow these tips:

• Have safe sex or no sex. The only certain way to avoid contact with syphilis bacteria is not to have sex. This is called abstinence. If a person is sexually active, safer sex means a long-term relationship in which you and your partner have sex only with each other, and neither of you is infected. Before you have sex with someone new, you should both get tested for syphilis and other sexually transmitted infections (STIs).
• Use a latex condom. Condoms can lower your risk of getting or spreading syphilis. But condoms work only if they cover an infected person's syphilis sores. Other types of birth control do not lower your risk of syphilis.
• Be careful with alcohol and stay away from street drugs. Drinking too much alcohol or taking drugs can get in the way of your judgment. Either can lead to unsafe sex.
• Do not douche. It can remove some of the healthy bacteria that's usually in the vagina. And that might raise your risk of getting STIs .
• Breastfeed with caution. Syphilis can pass from a parent to a baby during breastfeeding if sores are on one or both breasts. This can happen when the baby or pumping equipment touches a sore. To keep that from happening, pump or hand-express breastmilk from the breast with sores. Do so until the sores heal. If your pump touches a sore, get rid of the milk you just pumped.

Partner notification and preventive treatment

If tests show that you have syphilis, your sex partners need to know so that they can get tested. This includes your current partners and any others you've had over the last three months to 1 year. If they're infected, they can then get treatment.

After you learn you have syphilis, your local health department may contact you. A department employee talks with you about private ways to let your partners know that they've been exposed to syphilis. You can ask the department to do this for you without revealing your identity to your partners.

Or you can contact your partners along with a department employee or simply tell your partners yourself. This free service is called partner notification. It can help limit the spread of syphilis. The practice also steers those at risk toward counseling and the right treatment.

And since you can get syphilis more than once, partner notification lowers your risk of getting infected again.

Screening tests for pregnant people

You can be infected with syphilis and not know it. And the disease can have deadly effects on unborn babies. For this reason, health officials recommend that all pregnant people be tested for the disease.

• Syphilis — CDC detailed fact sheet. Centers for Disease Control and Prevention. https://www.cdc.gov/std/syphilis/stdfact-syphilis-detailed.htm. Accessed April 27, 2023.
• Sexually transmitted infections treatment guidelines, 2021: Syphilis. Centers for Disease Control and Prevention. https://www.cdc.gov/std/treatment-guidelines/syphilis.htm. Accessed April 27, 2023.
• Hicks CB, et al. Syphilis: epidemiology, pathophysiology, and clinical manifestations in patients without HIV. https://www.uptodate.com/contents/search. Accessed April 27, 2023.
• Syphilis. Merck Manual Professional Version. https://www.merckmanuals.com/professional/infectious-diseases/sexually-transmitted-diseases-stds/syphilis. Accessed April 27, 2023.
• Hicks CB, et al. Syphilis: Treatment and monitoring. https://www.uptodate.com/contents/search. Accessed April 27, 2023.
• Hicks CB, et al. Syphilis: Screening and diagnostic testing. https://www.uptodate.com/contents/search. Accessed April 27, 2023.
• Syphilis — CDC basic fact sheet. Centers for Disease Control and Prevention. https://www.cdc.gov/std/syphilis/stdfact-syphilis.htm. Accessed April 27, 2023.
• Loscalzo J, et al., eds. Syphilis. In: Harrison's Principles of Internal Medicine. 21st ed. McGraw Hill; 2022. https://accessmedicine.mhmedical.com. Accessed July 14, 2019.
• AskMayoExpert. Syphilis (adult). Mayo Clinic; 2021.
• Sexually transmitted infections. Office on Women's Health. http://womenshealth.gov/publications/our-publications/fact-sheet/sexually-transmitted-infections.html. Accessed April 27, 2023.
• Tosh PK (expert opinion). Mayo Clinic. May 1, 2023.
• Cáceres CF, et al. Syphilis in men who have sex with men: advancing research and human rights. The Lancet Global Health. 2021; doi:10.1016/S2214-109X(21)00269-2.
• How can partner services programs help me and my patients? Centers for Disease Control and Prevention. https://www.cdc.gov/hiv/clinicians/screening/partner-notification.html. Accessed April 28, 2023.
• Penicillin allergy FAQ. American Academy of Allergy, Asthma & Immunology. https://www.aaaai.org/tools-for-the-public/conditions-library/allergies/penicillin-allergy-faq. Accessed April 28, 2023.
• Just diagnosed? Next steps after testing positive for gonorrhea or chlamydia. Centers for Disease Control and Prevention. https://www.cdc.gov/std/prevention/NextSteps-GonorrheaOrChlamydia.htm. Accessed May 1, 2023.

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

Nature Reviews Disease Primers volume  3 , Article number:  17073 ( 2017 ) Cite this article

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Treponema pallidum subspecies pallidum ( T. pallidum ) causes syphilis via sexual exposure or via vertical transmission during pregnancy. T. pallidum is renowned for its invasiveness and immune-evasiveness; its clinical manifestations result from local inflammatory responses to replicating spirochaetes and often imitate those of other diseases. The spirochaete has a long latent period during which individuals have no signs or symptoms but can remain infectious. Despite the availability of simple diagnostic tests and the effectiveness of treatment with a single dose of long-acting penicillin, syphilis is re-emerging as a global public health problem, particularly among men who have sex with men (MSM) in high-income and middle-income countries. Syphilis also causes several hundred thousand stillbirths and neonatal deaths every year in developing nations. Although several low-income countries have achieved WHO targets for the elimination of congenital syphilis, an alarming increase in the prevalence of syphilis in HIV-infected MSM serves as a strong reminder of the tenacity of T. pallidum as a pathogen. Strong advocacy and community involvement are needed to ensure that syphilis is given a high priority on the global health agenda. More investment is needed in research on the interaction between HIV and syphilis in MSM as well as into improved diagnostics, a better test of cure, intensified public health measures and, ultimately, a vaccine.

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Introduction

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

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

PowerPoint slide

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

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

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

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

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

Epidemiology

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

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

Prevalence and incidence

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

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

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

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

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

Mechanisms/pathophysiology

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

Molecular features

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

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

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

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

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

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

Transmission and dissemination

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

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

Adaptive immune response and inflammation

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

Antibody avoidance

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

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

Congenital infection

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

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

Diagnosis, screening and prevention

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

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

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

Definitive diagnosis by direct detection

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

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

Diagnosis using serology

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

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

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

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

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

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

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

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

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

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

Tests useful in special situations

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

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

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

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

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

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

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

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

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

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

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

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

Second-line treatments

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

HIV co-infection

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

Treatment during pregnancy

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

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

Congenital syphilis

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

Neurosyphilis and ocular syphilis

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

Box 1: WHO guidelines for the treatment of syphilis

Early syphilis

Intramuscular benzathine penicillin G (single dose)

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

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

Late syphilis

Intramuscular benzathine penicillin G (weekly doses for 3 weeks)

Or intramuscular procaine penicillin (daily doses for 20 days)

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

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

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

*Contraindicated during pregnancy. From Ref. 11

Quality of life

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

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

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

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

Elimination of MTCT of syphilis

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

Strong advocacy will be needed to ensure that the control and elimination of syphilis is given a high priority on the global health agenda. Policy makers and funders need to be made aware that syphilis is a leading cause of preventable stillbirths and neonatal death, that these deaths can be prevented with a single dose of penicillin given to the mother before 28 weeks of gestation and that this is one of the most cost-effective health interventions available 51 , 202 . Perhaps with this awareness and political will, syphilis MTCT elimination programmes, which have failed to progress in the past 10 years 224 , will witness the same success achieved in the MTCT of HIV programmes in Africa. Other developments are occurring that are forging change. For example, the availability of POC tests has led to increased coverage of antenatal screening and treatment for syphilis in many settings 148 , and the WHO campaign for the elimination of MTCT of HIV and syphilis has increased the visibility of syphilis on the global health agenda. In 2014, the WHO target for the elimination of MTCT of syphilis was ≤50 cases of congenital syphilis per 100,000 live births. The targeted processes are antenatal care coverage (at least one visit) of ≥95% of pregnant women, syphilis testing coverage for ≥95% of pregnant women and treatment of ≥95% of pregnant women seropositive for syphilis WHO http://apps.who.int/iris/bitstream/10665/112858/1/9789241505888_eng.pdf (2014)." href="/articles/nrdp201773#ref-CR225" id="ref-link-section-d176205621e3628">225 . Additionally, the WHO has conducted a systematic review of the performance of rapid, dual HIV and syphilis tests and issued an information note on testing algorithms for dual HIV and syphilis tests 226 .

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

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

HIV and syphilis co-infection in MSM

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

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

Better diagnostic tests

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

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

Better use of existing drugs

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

Vaccine development

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

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

Eliminate mother-to-child transmission of syphilis

Requires political commitment

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

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

Address HIV and syphilis co-infection in MSM

Requires research into potential synergies between the two infections

Implement scientific and community involvement to reach at-risk populations

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

Develop tests for active infection, neurosyphilis and congenital syphilis

Identify and validate biomarkers for test development

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

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

Provide incentives for drug discovery programmes

Provide incentives to evaluate drug combinations

Develop vaccines

Requires research to better understand syphilis pathogenesis

Requires research to identify vaccine targets and methods for validation

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Acknowledgements

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Contributions

Introduction (R.W.P. and D.M.); Epidemiology (D.M. and X.-S.C.); Mechanisms/pathophysiology (J.D.R.); Diagnosis, screening and prevention (R.W.P., M.L.K., X.-S.C. and A.S.B.); Management (D.M.); Quality of life (M.K. and A.S.B.); Outlook (all authors); overview of the Primer (R.W.P.).

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

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Syphilis infection

Highlights & basics, diagnostic approach, risk factors, history & exam, differential diagnosis.

• Tx Approach

Emerging Tx

Complications.

PATIENT RESOURCES

Patient Instructions

Syphilis is a common sexually transmitted infection. An estimated 6 million new infections occurred worldwide in 2016. Incidence of congenital, primary, and secondary syphilis is increasing.

Caused by the spirochetal bacterium Treponema pallidum , subspecies pallidum .

Clinical presentation is often asymptomatic, but can manifest in a number of ways.

A painless ulcer (chancre) in the anogenital region is a hallmark of primary infection.

Diagnosis is usually straightforward after clinical exam and serologic tests.

Syphilis infection is treated with penicillin.

Untreated syphilis facilitates HIV transmission and causes considerable morbidity, such as cardiovascular and neurologic disease, as well as a congenital syndrome in the newborn.

Syphilis in pregnancy is a major cause of miscarriage, stillbirth, and perinatal morbidity and mortality in some parts of the world.

Quick Reference

Key Factors

anogenital ulcer

Lymphadenopathy, diffuse rash, constitutional symptoms, rhinitis (congenital syphilis), hepatosplenomegaly (congenital syphilis), patchy alopecia, condylomata lata, memory impairment, altered mood, confusion, or dementia, visual changes, argyll-robertson pupils, loss of sense of vibration, proprioception, and position sense, loss of anal and bladder sphincter control, positive romberg sign, diastolic murmur, rubbery lesions/nodules with a necrotic center, miscarriage, stillbirth, or neonatal death (congenital syphilis), premature labor and intrauterine growth retardation (congenital syphilis), neonatal skin rash (congenital syphilis), tibial bowing (congenital syphilis), craniofacial malformation (congenital syphilis), tooth abnormalities (congenital syphilis), necrotizing funisitis (congenital syphilis).

Other Factors

mouth ulcer

Asymptomatic with positive serology (latent syphilis), meningismus, hearing loss, peripheral edema, peripheral neuropathy, organomegaly, skin or visceral organ perforation or collapse of structure, neonatal neurologic abnormalities (congenital syphilis).

Diagnostics Tests

1st Tests to Order

dark-field microscopy of swab from lesion

Serum treponemal enzyme immunoassay (eia), serum treponema pallidum particle agglutination (tppa), serum treponema pallidum hemagglutination (tpha), serum fluorescent treponemal antibody absorption (fta-abs) test, immunocapture assay, line immunoassay (lia) serologic test, serum rapid plasma reagin (rpr) test, serum venereal disease research laboratory (vdrl) test.

Other Tests to consider

lumbar puncture, cerebrospinal fluid (CSF) analysis

Chest x-ray, echocardiogram, computed tomography brain, magnetic resonance imaging brain, fetal ultrasound scan, complete blood count, long-bone x-rays, liver enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) and bilirubin, auditory brainstem response, fetal skeletal survey.

Emerging Tests

Treponema pallidum polymerase chain reaction (PCR) (sample taken directly from ulcerative lesions)

Point of care (poc) testing with either treponemal or combination treponemal/nontreponemal antibody, treatment options.

presumptive

adults with suspected early infection or sexual contacts of patients with confirmed infection

consideration of empiric antibiotics

adults without neurosyphilis

without penicillin allergy

with penicillin allergy: nonpregnant

with penicillin allergy: pregnant

Classifications

Classification according to transmission

Transmission through direct person-to-person sexual contact with an individual who has early (primary or secondary) syphilis.

Transmission from mother to fetus during pregnancy

May result in miscarriage, stillbirth, or neonatal death [ 3 ]

Early (clinical manifestations occur from birth to 2 years of age)

Late (clinical manifestations occur >2 years of age).

Acquired syphilis, classified according to stage of infection

Initial inoculation of Treponema pallidum into tiny abrasions caused by sexual trauma results in local infection [ 5 ]

A single macule develops, which changes into a papule and then ulcerates, forming a chancre 9-90 days after exposure (usually 14-21 days after exposure). [ 5 ]

Clinical features develop 4 to 8 weeks after primary syphilis infection

Later presentation can occur up to 6 months after primary infection [ 6 ]

Characterized by spirochetemia and widespread dissemination of T pallidum to the skin and other tissues.

Asymptomatic infection diagnosed on the basis of positive serology alone, acquired <1 year previously (according to Centers for Disease Control and Prevention [CDC] criteria) or <2 years previously (according to World Health Organization [WHO] criteria). [ 7 ] [ 8 ]

Relapse to secondary syphilis may occur during the early latent stage.

Asymptomatic infection acquired >1 year previously (according to CDC criteria) or >2 years previously (according to WHO criteria) [ 7 ] [ 8 ]

The patient is not known to have been seronegative within the past year (according to CDC criteria) or past 2 years (according to WHO criteria). [ 7 ] [ 8 ]

It is estimated that 14% to 40% of patients with untreated syphilis progress to tertiary syphilis (late symptomatic disease) [ 6 ]

Characterized by chronic end-organ complications, often many years after initial infection

Includes cardiovascular syphilis, neurosyphilis, and gummatous syphilis.

Congenital syphilis, classified according to likelihood of infection

An abnormal physical exam that is consistent with congenital syphilis

A serum quantitative nontreponemal serologic titer that is fourfold (or greater) higher than the mother's titer at delivery (e.g., maternal titer = 1:2, neonatal titer ≥1:8 or maternal titer = 1:8, neonatal titer ≥1:32); or

A positive darkfield test or polymerase chain reaction of placenta, cord, lesions, or body fluids or a positive silver stain of the placenta or cord.

The mother was not treated, was inadequately treated, or has no documentation of having received treatment

The mother was treated with erythromycin or a regimen other than those recommended by the CDC (i.e., a nonpenicillin G regimen)

The mother received the recommended regimen but treatment was initiated <30 days before delivery.

The mother was treated during pregnancy, treatment was appropriate for the infection stage, and the treatment regimen was initiated ≥30 days before delivery

The mother has no evidence of reinfection or relapse.

The mother's treatment was adequate before pregnancy

The mother's nontreponemal serologic titer remained low and stable (i.e., serofast) before and during pregnancy and at delivery (e.g., Venereal Disease Research Laboratory test ≤1:2 or rapid plasma reagin test ≤1:4).

Common Vignette 1

Common Vignette 2

Other Presentations

Epidemiology

Pathophysiology.

• Juan C. Salazar, MD, MPH, FAAP
• Acknowledgements
• Robert A. Larsen, MD
• William Rodriguez, MD
• Jennifer Handforth, MB ChB, MRCPCH, DTM&H

Electron micrograph of Treponema pallidum on cultures of cotton-tail rabbit epithelium cells

A primary vulvar syphilitic chancre due to Treponema pallidum bacteria

A penile chancre located on the proximal penile shaft: primary syphilitic infection

Gummatous lesions on the dorsal surface of the left hand

Secondary syphilitic papulosquamous rash on the torso and upper body

Secondary syphilitic lesions on the face

Secondary syphilis presenting pigmented macules and papules on the skin

Secondary syphilitic lesions of vagina

This was a case of congenital syphilis resulting in the death of this newborn infant

This newborn presented with symptoms of congenital syphilis that included lesions on the soles of both feet

Interstitial keratitis

Peg-shaped, notched central incisors (Hutchinson teeth)

Osteoperiostitis of the tibia ("saber shins")

Clutton joints

Signs and symptoms of primary syphilis

Signs and symptoms of secondary syphilis, latent syphilis, signs and symptoms of tertiary syphilis.

Loss of anal and bladder sphincter control

Dorsal column loss (loss of vibration and proprioception/position sense)

Romberg sign.

Behavioral changes

Memory impairment

Altered mood

Argyll-Robertson pupils.

HIV coinfection

Primary syphilis: larger, painful multiple ulcers.

Secondary syphilis: genital ulcers more common and higher titers with rapid plasma reagin (RPR) testing and Venereal Disease Research Laboratory (VDRL) testing.

Possibly more rapid progression to neurosyphilis. [ 18 ]

Serologic responses to infection may be atypical. [ 34 ]

Signs and symptoms of congenital syphilis

Identification of syphilis in the mother

Adequacy of maternal treatment

Presence of clinical, laboratory, or radiographic evidence of syphilis in the infant (testing should include paired maternal and neonatal nontreponemal serologic titers using the same test, preferably conducted at the same laboratory).

Peg-shaped central incisors, notched at the apex (Hutchinson teeth)

Eighth cranial nerve deafness

Frontal bossing of the skull

Anterior bowing of the shins (Saber shins)

Saddle nose deformity

Clutton joints (symmetric painless knee swelling).

Initial investigations for acquired syphilis 

Treponemal enzyme immunoassay (EIA)

T pallidum particle agglutination assay (TPPA)

T pallidum haemagglutination assay (TPHA)

Fluorescent antibody absorption (FTA-ABS)

Immunocapture assay (ICA).

EIA: 3 weeks

TPPA: 4-6 weeks

TPHA: 4-6 weeks.

RPR: 4 weeks

VDRL: 4 weeks.

Other initial investigations for acquired syphilis

Emerging investigations, further investigations for acquired syphilis.

CSF white blood cell (WBC) count >10 cells/mm³ (10 × 10⁶ cells/L)

CSF protein >50 mg/dL (0.50 g/L)

A positive CSF VDRL test.

Initial investigations for congenital syphilis

Further investigations for congenital syphilis.

An abnormal physical exam that is consistent with congenital syphilis (e.g., nonimmune hydrops, conjugated or direct hyperbilirubinemia or cholestatic jaundice or cholestasis, hepatosplenomegaly, rhinitis, skin rash, or pseudoparalysis of an extremity) or

A serum quantitative nontreponemal serologic titer that is fourfold higher than the mother's titer (e.g., maternal titer = 1:2, neonatal titer ≥1:8 or maternal titer = 1:8, neonatal titer ≥1:32) or

A positive dark-field test or PCR of placenta, cord, lesions or body fluids, or a positive silver stain of the placenta or cord.

The mother was not treated, was inadequately treated, or has no documentation of having received treatment or

The mother was treated with erythromycin or other nonpenicillin regimen or

The mother received treatment <4 weeks before delivery.

Infants and children ages ≥1 month with reactive serologic tests for syphilis.

sexual contact with an infected person

The risk of acquiring syphilis after sex with someone with primary or secondary syphilis is between 30% and 60%. [ 17 ]

men who have sex with men (MSM)

At higher risk, particularly if they are also HIV coinfected, use illicit drugs such as methamphetamine, or have multiple, casual sexual partners. [ 21 ] [ 22 ]

In 2021, almost half (46.5%) of all reported cases of primary and secondary syphilis in the US occurred in MSM. [ 12 ]

illicit drug use

Association due to the exchange of sex for money or drugs, particularly crack cocaine. [ 23 ]

commercial sex workers

Multiple sexual partners.

A risk factor for all STIs.

Important in syphilis epidemiology. [ 21 ]

people with HIV or other STIs

Suggests unprotected sexual intercourse, which increases the risk of STIs.

All patients who have an STI should have syphilis screening, as should patients at higher risk of STIs, irrespective of where they are seen.

syphilis during pregnancy (risk for congenital syphilis)

The fetus acquires the infection from the infected mother. Inadequate treatment of maternal syphilis accounts for up to one-third of congenital syphilis cases. [ 24 ]

This may result in miscarriage, stillbirth, or neonatal death. [ 3 ]

Screening for syphilis at the first prenatal visit aims to identify and treat asymptomatic infected women, thus preventing transplacental transmission. [ 25 ] The Centers for Disease Control and Prevention recommends repeating syphilis screening at 28 weeks' gestation and at delivery for women at high risk of syphilis infection. Risk factors for syphilis infection during pregnancy include commercial sex work, a history of substance misuse, sex with multiple partners, late entry into prenatal care (i.e., first visit during the second trimester or later) or no prenatal care, unstable housing or homelessness, and imprisonment of the woman or her partner. [ 8 ]

Initially a macule, developing into a papule and then ulcerating to form a chancre. Image

Classically appears in the anogenital area 14 to 21 days after exposure (primary infection).

Usually indurated, solitary, and painless. Image

May not always be noticed by the patient and examining physician, and it heals spontaneously.

Atypically may be multiple and painful. Coinfection with genital herpes or chancroid may cause painful ulceration. HIV coinfection may be associated with multiple ulcers.

Erosions on the genitalia may also occur in secondary syphilis. Image

Moderately enlarged, rubbery regional lymphadenopathy associated with the classical syphilitic ulcer (chancre) in primary infection.

Generalized lymphadenopathy may occur with secondary syphilis.

Symmetric macular, papular, or maculopapular rash in secondary syphilis. Image

Often widespread with mucous membrane involvement. Image

May desquamate.

Usually nonitchy, over the trunk, palms, soles, and scalp.

In dark-skinned patients may cause pruritus.

May accompany a history of constitutional symptoms such as fever and malaise.

Onset is usually 6 to 12 weeks after exposure.

Up to 25% of people who have untreated secondary syphilis develop relapsing episodes of rash and fever. [ 9 ] [ 17 ]

Rash also occurs in congenital syphilis.

Such as fever, malaise, myalgia, fatigue, and arthralgia with secondary syphilis.

May be mistaken for primary HIV infection or another intercurrent viral illness.

As a result of cardiovascular syphilis (tertiary disease), which may lead to heart failure.

May also be a constitutional symptom in secondary syphilis.

A sign of early congenital syphilis (occurring <2 years of age).

Discharge may be purulent and bloody.

Usually associated with other signs of disseminated infection (rash, mucous membrane ulceration).

May develop in secondary syphilis.

Slightly raised, or flat, round, or oval papules covered by gray exudates.

A sign of secondary syphilis.

May be present within moist areas of the perineum.

May be mistaken for genital warts.

Possible signs of neurosyphilis. [ 66 ]

Brain involvement in tertiary syphilis causes a range of syndromes, including cognitive and motor impairment, which are sometimes grouped under the broad term "general paresis".

Visual impairment may be a presenting feature of syphilitic iritis or uveitis, occurring in secondary infection.

Bilaterally small, irregular pupils, which do not constrict when exposed to bright light, but do constrict in response to accommodation.

A feature of tabes dorsalis occurring in tertiary syphilis.

Dorsal column loss is a feature of tabes dorsalis, occurring in tertiary syphilis.

Possible sign of cardiovascular syphilis (tertiary disease).

Diastolic murmur at the left sternal edge indicates aortic regurgitation, which may be due to aortitis caused by cardiovascular syphilis.

A sign of gummatous syphilis (also known as benign tertiary syphilis).

Affects skin and visceral organs.

The destructive gumma may gradually replace normal tissue.

Signs of congenital syphilis. [ 67 ]

Signs of early congenital syphilis.

May occur in early congenital syphilis (occurring <2 years of age).

This rash may be similar to the rash of secondary syphilis in adults. It may also be more widespread, bullous or papulonecrotic, or desquamating.

Initially the rash may be a vesicular rash with small blisters appearing on the palms and plantar surfaces of the feet. An erythematous or maculopapular rash, which is often copper-colored, may subsequently appear on the face, palms, and plantar surfaces of the feet. The rash may also affect the mouth, genitalia, and anus. Images

A sign of late congenital syphilis (occurring >2 years of age).

Due to neonatal osteochondritis in congenital syphilis. Image

Including frontal bossing, high cranium, and saddle nose.

Hutchinson teeth (peg-shaped incisors, notched at the apex), mulberry molars dome-shaped with small cusps at the apex.

Poorly mineralized teeth. Image

Necrotizing funisitis (inflammation of the umbilical cord) is virtually diagnostic of congenital syphilis. Usually found in preterm infants who are stillborn, or die within a few weeks of birth.

The umbilical cord has a specific appearance known as the "barberpole" cord as a result of inflammation of the matrix of the umbilical cord. [ 37 ]

May coexist with genital ulceration.

Occurs in both primary and secondary infection.

In secondary infection the mouth ulcers (snail track ulcers) will usually be coexistent with other symptoms or signs, such as rash, fever.

Latent syphilis is defined as positive serology in the absence of clinical features of syphilis.

Ulcers in primary syphilis may not be noticed by the patient and examining physician.

Possible sign of tertiary disease with brain involvement.

May indicate neurologic involvement.

May occur with neck stiffness.

May be a presenting feature of syphilitic iritis or uveitis, occurring in secondary infection.

The eighth cranial nerve is the most commonly affected cranial nerve in neurosyphilis.

Hearing loss may be a symptom and a sign of both early and late neurosyphilis.

Deafness may also occur as a result of late congenital syphilis (occurring >2 years of age).

Suggest neurologic involvement.

Occurs with nephrotic syndrome that may develop due to vasculitis in secondary syphilis.

May indicate hepatitis, due to vasculitis in secondary syphilis.

Sign of neurosyphilis.

Usually affecting lower limbs.

May occur in all forms of neurosyphilis.

As a result of cardiovascular syphilis (tertiary disease).

Aortic aneurysm caused by syphilis almost always affects the thoracic aorta (usually the ascending part of the thoracic aorta), resulting in heart failure.

Lesions in gummatous syphilis may cause organomegaly, and become infiltrative or destructive.

May occur as a result of gummatous syphilis.

May include a wide range of problems such as seizures, meningitis, obstructive hydrocephalus, and cranial nerve palsies.

coiled spirochete bacterium with a corkscrew appearance and motility

Performed to identify Treponema pallidum .

Can provide a definitive diagnosis of syphilis, but is not usually available outside specialist settings.

The lesion is cleansed and abraded with a gauze pad until serous exudates appear, which are collected onto a glass slide for microscopic analysis.

A single negative result does not exclude infection; ideally 3 negative examinations on different days are required.

Primary syphilis: sensitivity of dark-field microscopy is 74% to 86%, specificity is 85% to 100%. [ 5 ] [ 6 ] [ 39 ]

Secondary syphilis: dark-field microscopy may be positive from ulcerative anogenital lesions.

Gummata in tertiary syphilis have few, if any, identifiable T pallidum organisms.

Congenital syphilis: test suspicious lesions (e.g., bullous rash or nasal discharge). [ 8 ]

A treponemal serology test.

A patient with a positive treponemal test result will remain positive for life. Therefore, a positive result alone cannot distinguish between an active infection or past (treated) infection.

The most common approach is to use a treponemal test as the initial serologic test, followed by a nontreponemal test to confirm diagnosis and provide evidence of active disease or reinfection (i.e., a "reverse sequence screening algorithm"). [ 40 ]

False-positive results may occur with other nonsexually transmitted treponemal infection (e.g., yaws, pinta, bejel).

False-negative results may occur in incubating and early primary syphilis. It usually takes 3 weeks for an EIA IgG/IgM test to become positive after infection with  Treponema pallidum .

EIA is the test generally used for screening. [ 10 ]

Primary syphilis: EIA sensitivity 82% to 100%, and specificity 97% to 100%. [ 68 ]

Secondary syphilis: EIA sensitivity is 100%. [ 68 ]

Late latent syphilis: EIA sensitivity is 98% to 100%. [ 68 ]

A patient with a positive treponemal test result will remain positive for life. Therefore, a positive result alone cannot distinguish between an active or past (treated) infection.

Primary syphilis: TPPA sensitivity is 85% to 100%, and specificity is 98% to 100%. [ 69 ] [ 70 ]

Secondary and late latent syphilis: TPPA sensitivity is 98% to 100%. [ 70 ]

FTA-ABS is used less often than TPHA and TPPA because it is less specific.

LIA serologic tests (e.g., INNO-LIA syphilis test) can be used to confirm syphilis infection following initial serologic treponemal testing. A single LIA test can confirm infection, making it more convenient than traditional methods of serologic confirmation (which usually require multiple assays). Studies evaluating the performance of LIA tests for syphilis infection have demonstrated higher sensitivity and specificity compared with FTA-ABS and TPHA serology tests. [ 49 ] [ 50 ]

A nontreponemal serology test.

Provides a quantitative measure of disease activity and can be used to monitor treatment response (RPR titers decrease or become nonreactive with effective treatment).

Despite adequate treatment, some patients maintain a persisting low level positive antibody titer (known as a serofast reaction). [ 44 ]

False positives may occur due to the presence of a variety of medical conditions (e.g., pregnancy, autoimmune disorders, and infections).

A false-negative test may occasionally occur in an undiluted specimen (the prozone phenomenon).

Primary syphilis: RPR sensitivity is 70% to 73%. [ 5 ] [ 71 ]

Secondary syphilis: RPR sensitivity is 100%. [ 71 ]

Preferred test over the serum Venereal Disease Research Laboratory test.

Congenital syphilis: include paired maternal and neonatal nontreponemal serologic titers using the same test, preferably conducted at the same laboratory. [ 8 ]

The Food and Drug Administration (FDA) has issued a warning of false-positive RPR results linked to COVID-19 vaccination. RPR false reactivity has been observed in some individuals for at least 5 months following the vaccine. The issue has been identified in the Bio-Rad BioPlex 2200 Syphilis Total & RPR test kit. It is not yet known if other RPR tests are affected similarly. For healthcare professionals who use the Bio-Rad BioPlex 2200 Syphilis Total & RPR test kit, the FDA recommends performing confirmatory testing for all reactive results. In patients previously treated for syphilis who received a COVID-19 vaccine, and whose clinical presentation and epidemiologic considerations do not support syphilis reinfection, reactive RPR results obtained from the BioPlex 2200 Syphilis Total & RPR test kit should be confirmed using an RPR test from a different manufacturer. [ 45 ]

Provides a quantitative measure of disease activity and can be used to monitor treatment response (VDRL titers decrease or become nonreactive with effective treatment).

Primary syphilis: VDRL sensitivity is 44% to 76%. [ 5 ]

VDRL is positive in 77% of cases of late latent syphilis. [ 5 ]

VDRL sensitivity in secondary syphilis is 100%. [ 71 ]

WBC count >10 cells/mm³; CSF protein >50 mg/dL; CSF VDRL positive; CSF TPHA/TPPA/FTA-ABS positive

Indicated for any patient with clinical evidence of neurologic involvement (e.g., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, or loss of vibration sense).

Indicated if syphilis of unknown duration exists in the presence of HIV coinfection.

Indicated in any child with congenital syphilis and neurologic symptoms or signs. [ 8 ]

An elevated CSF WBC count and positive CSF Venereal Disease Research Laboratory (VDRL) suggests neurologic involvement. [ 31 ]

Some patients with neurosyphilis have an isolated elevated CSF WBC count and negative rapid plasma reagin/VDRL.

Neurosyphilis is unlikely at CSF Treponema pallidum hemagglutination assay (TPHA)/ T pallidum particle agglutination assay (TPPA) titers <1:320.

A nonreactive CSF-TPHA test result usually excludes neurosyphilis.

possible widened thoracic aorta, aortic calcification

May detect possible thoracic aortic aneurysm or aortic calcification.

Required in people with symptoms or signs of aortic regurgitation, heart failure, or aortic aneurysm.

may show evidence of heart failure, aortic regurgitation, or thoracic aortic aneurysm

Required if cardiovascular syphilis is strongly suspected (e.g., a patient has symptoms or signs of aortic regurgitation, heart failure, or aortic aneurysm).

usually normal

Performed before lumbar puncture to exclude elevated intracranial pressure, to ensure that a lumbar puncture procedure will be safe.

Elevated intracranial pressure is rarely caused by syphilis itself.

positive or negative

All patients with syphilis should be tested for HIV.

In geographic areas in which the prevalence of HIV is high, patients who have syphilis should be retested for HIV after 3 months, even if the first HIV test result is negative, and be offered HIV pre-exposure prophylaxis (PrEP). [ 8 ]

All infants and children at risk for congenital syphilis should be tested for HIV. [ 8 ]

may show hepatomegaly, ascites, hydrops fetalis, intrauterine growth retardation

Should be performed on all pregnant women with syphilis or suspected of having syphilis.

Presence of fetal or placental syphilis indicates a greater risk of treatment failure for congenital syphilis. [ 65 ]

may show anemia, thrombocytopenia, leukopenia, possible neutrophilia

Performed in infants with possible congenital syphilis.

may demonstrate osteochondritis

May be indicated in infants with suspected congenital syphilis. [ 8 ]

Performed if osteochondritis suspected.

aspartate aminotransferase and alanine aminotransferase may be elevated

Performed if clinical findings suggestive of liver involvement (e.g., hepatomegaly).

may detect deafness

Performed if clinically indicated.

may detect hearing deficit

Neurosyphilis may involve cranial nerves (particularly the 8th cranial nerve).

osseous lesions

Might aid diagnosis of congenital syphilis in stillborn infants. [ 8 ]

T pallidum PCR has been shown to have moderate sensitivity (70% to 80%) and high specificity >90% in the diagnosis of primary or secondary syphilis, when compared with adequate reference tests (e.g., serology, dark-field microscopy). [ 51 ]

The Centers for Disease Control and Prevention considers PCR testing a valid method for diagnosing primary, secondary, and congenital syphilis, and its use is likely to increase. [ 8 ] [ 52 ]

positive; however, a positive result for treponemal antibodies alone does not distinguish between current, past, or treated infection

POC syphilis testing has been assessed in the setting of high-risk regions, where rapid and early diagnosis may be more important than accuracy. Several clinical trials have shown promise and POC testing has been recommended as part of the Pan American Health Organization strategy to diagnose and treat syphilis. [ 53 ] [ 54 ]

Genital herpes

Differentiating Signs/Symptoms

There may be a history of fever, genital blisters or sores, and lymphadenopathy with first episode herpes simplex.

The patient may describe previous episodes of genital ulceration.

On physical exam there are typically multiple, painful vesicular or ulcerative lesions on or around the genitals or rectum.

Differentiating Tests

If lesions are present, clinical diagnosis should be confirmed by swabbing lesions for herpes simplex virus (HSV) culture or HSV polymerase chain reaction (PCR). [ 8 ]

Because of the higher sensitivity of PCR, this is the preferred test when available. [ 8 ]

Glycoprotein G-based type-specific serology may be indicated in certain patient groups and can differentiate between infection with HSV-1 and HSV-2. [ 8 ]

Characterized by painful genital ulcers and painful inguinal lymphadenopathy. Lesions of primary syphilis are typically not painful.

Usually occurs in discrete outbreaks.

On physical exam there may be an erythematous papule, pustule, or painful ulcer, as well as painful unilateral inguinal lymphadenopathy (bubo formation), which may rupture.

Haemophilus ducreyi is identified on specialist culture medium, which is not widely commercially available and has a sensitivity of <80%. [ 72 ]

Polymerase chain reaction testing is up to 100% sensitive but is not universally approved. [ 72 ] [ 73 ]

Therefore a positive diagnosis of chancroid is suggested by the presence of one or more painful genital ulcers with no evidence of syphilis or herpes simplex virus. [ 8 ] Regional lymphadenopathy is also confirmatory, if present. [ 8 ]

Primary HIV infection

Not preceded by genital ulceration.

However, genital ulceration may be present at the same time as primary HIV infection and the rash associated with the ulceration.

Laboratory tests positive for HIV, including antigen (P24 antigen) tests.

Other acute viral exanthems

Laboratory tests positive for specific virus.

Skin lesions are usually pruritic.

Typical distribution: interdigital, wrists, nipples, ankles, buttocks.

Diagnosis is usually clinical, but skin scrapings and microscopy for Sarcoptes scabiei may be performed.

Skin lesions are usually absent on palms and plantar aspects of feet.

Not associated with signs of systemic infection.

Diagnosis is usually clinical.

Skin biopsy can be undertaken to confirm diagnosis.

Lichen planus

Skin lesions are usually absent on palms and plantar aspect of feet.

Genital warts

Pink lumps, in genital and/or perianal skin and mucous membranes. Not necessarily confined to opposing membranes.

Not associated with other signs of secondary syphilis (rash, constitutional symptoms, generalized lymphadenopathy).

Exclusion of syphilis (negative syphilis serology).

Alzheimer dementia

Progressive dementia.

No specific differentiating symptoms and signs compared with neurosyphilis.

Less likely to have a history of possible signs and symptoms of earlier stages of syphilis infection.

Vascular dementia

Multi-infarct dementia often associated with other evidence of arteriopathy.

Syphilis infection is often asymptomatic but highly transmissible

If untreated, it causes in-utero mortality and considerable morbidity many years after initial infection

Treatment of syphilis in the early stage of infection is curative and aims to halt disease progression and eliminate further transmission of infection

Syphilis is an important facilitator of HIV transmission.

Asymptomatic patients who are at risk of syphilis infection [ 1 ] [ 74 ]

Pregnant women [ 8 ] [ 29 ] [ 62 ] [ 63 ] [ 75 ]

Blood donors. [ 76 ]

Screening tests

Screening in sti clinic, prenatal screening, screening low-risk asymptomatic population, screening for hiv and other stis, treatment approach, without neurosyphilis, neurosyphilis, infection in pregnancy, coinfection with hiv, congenital syphilis.

Presence of clinical, laboratory, or radiographic evidence of syphilis in the infant (testing should include paired maternal and neonatal non-treponemal serological titres using the same test, preferably conducted at the same laboratory).

Potential adverse effects of therapy

Primary Options

penicillin G benzathine

2.4 million units intramuscularly as a single dose

Secondary Options

100 mg orally twice daily for 14 days

Empiric therapy may be considered in those with suspected early infection (a rash or ulceration) before results of serology are available. Empiric therapy may be appropriate if there are concerns regarding re-attendance. The benefits of empiric therapy (prompt therapy) and risks (potentially unnecessary treatment) should be discussed with the patient.

Intramuscular benzathine penicillin G as a single dose is given. If the patient is allergic to penicillin and is not pregnant, oral doxycycline may be offered.

Sexual contacts of patients with confirmed syphilis should be screened and offered presumptive treatment if follow-up may be problematic.

intramuscular benzathine penicillin G

primary/secondary/early latent syphilis (nonpregnant): 2.4 million units intramuscularly as a single dose; primary/secondary/early latent syphilis (pregnant): 2.4 million units intramuscularly as a single dose, may repeat in 1 week; late-latent/tertiary syphilis with normal cerebrospinal fluid examination: 2.4 million units intramuscularly once weekly for 3 weeks

The first-line treatment for primary, secondary, and early latent syphilis (without neurosyphilis) is intramuscular benzathine penicillin G as a single dose. [ 8 ]  Note that the dose may be split and administered at two discrete injection sites.

The first-line treatment of late latent and tertiary (gummatous, cardiovascular, psychiatric manifestations, late neurosyphilis) syphilis with normal cerebrospinal fluid (CSF) examination is intramuscular benzathine penicillin G (once weekly for 3 weeks).

All patients who have tertiary syphilis should undergo cerebrospinal fluid examination before treatment is started. Patients with abnormal CSF findings should be treated with a neurosyphilis regimen. [ 8 ]

Pregnant women should receive penicillin-based treatment according to their stage of syphilis. For pregnant women with primary, secondary, or early latent syphilis, certain evidence suggests that administering two injections of intramuscular benzathine penicillin G, rather than one, can help prevent congenital syphilis. Pregnant women with late latent or tertiary syphilis with normal CSF examination should receive three injections of intramuscular benzathine penicillin G, as per the guidance for nonpregnant individuals. [ 8 ]

Most clinicians treat HIV-positive and HIV-negative individuals with the same penicillin regimens, according to the stage of syphilis. [ 8 ]

Antibiotic therapy for cardiovascular syphilis does not reverse cardiovascular disease, which may continue to progress after treatment. Discussion with a cardiologist is advised.

40-60 mg orally once daily for 3 days; start 24 hours before penicillin

Corticosteroid therapy may be considered to minimize the risk of Jarisch-Herxheimer reaction in nonpregnant patients with neurosyphilis. [ 10 ]   However, evidence of effectiveness is unclear and it is not routinely recommended in the US.

Jarisch-Herxheimer reaction is an acute febrile illness that can occur within the first 24 hours after initiation of antibiotic treatment for syphilis. Symptoms include acute fever, headache, and myalgia, usually occurring in patients with early syphilis. [ 8 ]

oral doxycycline

100 mg orally twice daily for 14 days (primary/secondary/early latent syphilis) or 28 days (late latent/tertiary syphilis with normal cerebrospinal fluid examination)

If the patient is allergic to penicillin, the first-line treatment in nonpregnant patients is oral doxycycline.

Adherence and patient compliance may influence treatment outcome if oral therapy is administered.

Patients who are allergic to penicillin, with primary or secondary syphilis and HIV coinfection, should receive antibiotic therapy as recommended for penicillin-allergic, HIV-negative patients. [ 8 ]

40-60 mg orally once daily for 3 days; start 24 hours before doxycycline

Corticosteroid therapy may be considered to minimize the risk of Jarisch-Herxheimer reaction in nonpregnant patients with neurosyphilis. [ 10 ]  However, evidence of effectiveness is unclear and it is not routinely recommended in the US.

desensitization

Penicillin desensitization is recommended for all patients with penicillin hypersensitivity in pregnancy. The evidence for the use of nonpenicillin regimens is relatively weak. [ 8 ]

Penicillin allergy skin testing identifies patients at high risk for penicillin reactions. Skin reagents used should include major and minor allergens. [ 97 ] Those who are skin-test negative can receive penicillin therapy. However, some clinicians perform desensitization without skin testing, particularly if the skin reagents for both minor and major determinants of penicillin allergy are not available.

Acute desensitization can be performed in patients who have a positive skin test to one of the penicillin determinants, and should be performed in a hospital setting. Oral or intravenous desensitization can be performed, and is usually completed in 4 hours, following which the first dose of penicillin is administered. [ 98 ]

postdesensitization intramuscular benzathine penicillin G

primary/secondary/early latent syphilis: 2.4 million units intramuscularly as a single dose, may repeat in 1 week; late-latent/tertiary syphilis with normal cerebrospinal fluid examination: 2.4 million units intramuscularly once weekly for 3 weeks

Desensitization is usually completed in 4 hours, following which the first dose of penicillin is administered. [ 98 ]

Pregnant women should receive penicillin-based treatment according to their stage of syphilis. For pregnant women with primary, secondary, or early latent syphilis, certain evidence suggests that administering two injections of intramuscular benzathine penicillin G, rather than one, can help prevent congenital syphilis. Pregnant women with late latent or tertiary syphilis with normal cerebrospinal fluid examination should receive three injections of intramuscular benzathine penicillin G, as per the guidance for nonpregnant individuals. [ 8 ]

adults with neurosyphilis

intravenous aqueous penicillin G

penicillin G sodium

18-24 million units/day intravenously given in divided doses every 4 hours (or by continuous infusion) for 10-14 days

Central nervous system involvement can occur at any stage of syphilis and can range from asymptomatic meningeal involvement to dementia and sensory neuropathy. [ 18 ] First-line treatment for neurosyphilis is intravenous aqueous penicillin G. [ 8 ]

Pregnant women should receive penicillin-based treatment according to their stage of syphilis.

Most clinicians treat HIV-positive and HIV-negative patients with the same penicillin regimens, according to the stage of syphilis. [ 8 ]

subsequent intramuscular benzathine penicillin G

2.4 million units intramuscularly once weekly for 1-3 weeks

Some specialists administer benzathine penicillin G once weekly for up to 3 weeks after the intravenous aqueous penicillin G regimen for neurosyphilis has been completed.

This ensures the duration of treatment is comparable with that of late syphilis in the absence of neurosyphilis. [ 8 ]

intramuscular procaine penicillin G plus oral probenecid

penicillin G procaine

2.4 million units intramuscularly once daily for 10-14 days

500 mg orally four times daily for 10-14 days

Second-line treatment for neurosyphilis is intramuscular procaine penicillin G plus oral probenecid.

Most clinicians treat HIV-positive and HIV-negative patients with the same penicillin regimens according to the stage of syphilis.

Pregnant women should receive penicillin-based treatment according to their stage of syphilis. [ 8 ]

with penicillin allergy

Penicillin desensitization is recommended for all patients with neurosyphilis who have penicillin hypersensitivity. The evidence for the use of nonpenicillin regimens is relatively weak. [ 8 ]

postdesensitization penicillin G

subsequent postdesensitization intramuscular benzathine penicillin G

Some specialists administer benzathine penicillin G once weekly for up to 3 weeks after the treatment regimen for neurosyphilis has been completed (only if first-line intravenous therapy was chosen as the initial therapy).

high-dose oral doxycycline

200 mg orally twice daily for 28 days

The evidence for the use of nonpenicillin regimens is relatively weak. However, high-dose doxycycline is used by some clinicians in this situation. [ 7 ] [ 18 ]

congenital syphilis

neonate: confirmed proven or highly probable congenital syphilis

intravenous aqueous penicillin G or intramuscular procaine penicillin G

100,000 to 150,000 units/kg/day intravenously, administered as 50,000 units/kg/dose every 12 hours during the first 7 days of life and then every 8 hours thereafter for a total of 10 days

50,000 units/kg intramuscularly once daily for 10 days

All neonates born to mothers who have reactive nontreponemal and treponemal tests results should be evaluated with a quantitative nontreponemal serologic test (rapid plasma reagin tests [RPR] or Venereal Disease Research Laboratory [VDRL]) performed on the neonate's serum. The nontreponemal test performed on the neonate should be the same type of nontreponemal test performed on the mother. [ 8 ]

Confirmed proven or highly probable syphilis includes any neonate with: an abnormal physical exam that is consistent with congenital syphilis (e.g., nonimmune hydrops, conjugated or direct hyperbilirubinemia or cholestatic jaundice or cholestasis, hepatosplenomegaly, rhinitis, skin rash, or pseudoparalysis of an extremity); a serum quantitative nontreponemal serologic titer that is fourfold (or greater) higher than the mother's titer at delivery (e.g., maternal titer = 1:2, neonatal titer ≥1:8 or maternal titer = 1:8, neonatal titer ≥1:32); or a positive darkfield test or polymerase chain reaction (PCR) of placenta, cord, lesions, or body fluids or a positive silver stain of the placenta or cord. [ 8 ]

First-line treatment of confirmed proven or highly probable congenital syphilis is intravenous aqueous penicillin G or intramuscular procaine penicillin G. [ 8 ] [ 100 ] ​ 

Discussion with an obstetric specialist and neonatologist is recommended. Subsequently, close clinical and serologic follow-up by a pediatric specialist is recommended.

Neonates with reactive nontreponemal tests should be followed up to ensure that the nontreponemal test returns to negative. [ 8 ]

Neonates with a penicillin allergy or those who develop an allergic reaction presumed secondary to penicillin should be desensitized and treated with penicillin. [ 8 ] The evidence for the use of nonpenicillin regimens is relatively weak.

Skin testing is not possible in neonates with congenital syphilis as the procedure has not been standardized in this age group. [ 8 ]

neonate: possible congenital syphilis

intravenous aqueous penicillin G or intramuscular procaine penicillin G or intramuscular benzathine penicillin G

50,000 units/kg intramuscularly as a single dose

All neonates born to mothers who have reactive nontreponemal and treponemal test results should be evaluated with a quantitative nontreponemal serologic test (rapid plasma reagin [RPR] or Venereal Disease Research Laboratory [VDRL]) performed on the neonate's serum. The nontreponemal test performed on the neonate should be the same type of nontreponemal test performed on the mother.

Possible congenital syphilis includes any neonate who has a normal physical exam and a serum quantitative nontreponemal serologic titer equal to or less than fourfold of the maternal titer at delivery (e.g., maternal titer = 1:8, neonatal titer ≤1:16) and one of the following: the mother was not treated, was inadequately treated, or has no documentation of having received treatment; the mother was treated with erythromycin or a regimen other than those recommended by the Centers for Disease Control and Prevention (i.e., a nonpenicillin G regimen); the mother received the recommended regimen but treatment was initiated <30 days before delivery. [ 8 ]

Treatment of possible congenital syphilis is intravenous aqueous penicillin G, intramuscular procaine penicillin G, or intramuscular benzathine penicillin G. [ 8 ] [ 100 ]

Single-dose benzathine penicillin G may be used if follow up is certain and the following investigations are normal: cerebrospinal fluid analysis for VDRL test, cell count, and protein; complete blood count including differential and platelet count; and long-bone radiographs. [ 8 ] Single-dose benzathine penicillin G may also be considered if the risk of untreated maternal syphilis is considered low and the neonate's nontreponemal test is nonreactive. If the mother had untreated early syphilis at the time of delivery, the neonate is at increased risk for congenital syphilis and the 10-day course of aqueous penicillin G should be considered, even if investigations are normal, nontreponemal test is nonreactive, and follow-up is assured. [ 8 ]

neonate: congenital syphilis less likely

Congenital syphilis is less likely in any neonate who has a normal physical exam and a serum quantitative nontreponemal serologic titer equal or less than fourfold of the maternal titer at delivery (e.g., maternal titer = 1:8, neonatal titer ≤1:16) and both of the following are true: the mother was treated during pregnancy, treatment was appropriate for the infection stage, and the treatment regimen was initiated ≥30 days before delivery; the mother has no evidence of reinfection or relapse. [ 8 ]

Recommended treatment is with intramuscular benzathine penicillin G. [ 8 ]

If the mother's nontreponemal titers decreased at least fourfold after therapy for early syphilis, or remained stable for low-titer, latent syphilis (e.g., VDRL test <1:2 or RPR <1:4), an alternative approach is to provide close serologic follow-up every 2-3 months for 6 months. [ 8 ]

neonate: congenital syphilis unlikely

observation

Congenital syphilis is unlikely if the neonate has a normal physical exam and a serum quantitative nontreponemal serologic titer equal to or less than fourfold of the maternal titer at delivery and both of the following are true: the mother's treatment was adequate before pregnancy; and the mother's nontreponemal serologic titer remained low and stable (i.e., serofast) before and during pregnancy and at delivery (e.g., VDRL test ≤1:2 or RPR ≤1:4). [ 8 ]

No treatment is required. However, neonates with reactive nontreponemal tests should be followed up to ensure that the nontreponemal test returns to negative. [ 8 ]

Intramuscular benzathine penicillin G may be considered, particularly if the neonate has a reactive nontreponemal test and follow up is not certain. [ 8 ]

infant or child

intravenous aqueous penicillin G or intramuscular benzathine penicillin G

200,000 to 300,000 units/kg/day intravenously, administered as 50,000 units/kg/dose every 4-6 hours for 10 days

50,000 units/kg intramuscularly once weekly for up to 3 weeks, maximum 2.4 million units/dose

​​Infants and children ages ≥1 month who have reactive serologic tests for syphilis (e.g., serum rapid plasma reagin reactive, serum treponemal enzyme immunoassay reactive, or serum Treponema pallidum particle agglutination reactive) should be examined thoroughly for clinical manifestations of congenital syphilis. [ 8 ] ​ Maternal records should be reviewed for evidence of maternal infection. Maternal serologic tests may have been negative in cases of extremely early or incubating syphilis. [ 8 ]

Evaluation should include: cerebrospinal fluid analysis for Venereal Disease Research Laboratory test, cell count, and protein; complete blood count, including differential and platelet count; and other tests if clinically indicated (e.g., long-bone x-rays, chest x-ray, liver enzymes, neuroimaging, auditory brain-stem response). [ 8 ]

Infants and children with clinical manifestations of congenital syphilis or abnormal evaluation should be treated with intravenous aqueous penicillin G. A single dose of intramuscular benzathine penicillin G may be considered after the 10-day treatment course of intravenous aqueous penicillin G to provide a more comparable duration as treatment for late syphilis. [ 8 ]

Infants and children with no clinical manifestations of congenital syphilis and normal evaluation (including normal cerebrospinal fluid evaluation) may be treated with up to 3 weekly doses of intramuscular benzathine penicillin G. [ 8 ]

Infants and children ages >1 month with acquired primary or secondary syphilis should be managed by a pediatric infectious disease specialist and evaluated for sexual abuse. [ 8 ] See Sexual abuse and assault .

Infants and children with a penicillin allergy or those who develop an allergic reaction presumed secondary to penicillin should be desensitized and treated with penicillin. [ 8 ] Skin testing may be used in children ages ≥2 years. The evidence for the use of nonpenicillin regimens is relatively weak.

Azithromycin 

Ceftriaxone, primary prevention, secondary prevention.

People exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis in a sexual partner should be treated presumptively, on the basis that they may be infected even if seronegative. It is estimated that 30% to 60% of sexual partners of people with early syphilis will develop the infection. [ 17 ]

People exposed more than 90 days before diagnosis of primary, secondary, or early latent syphilis in a sexual partner should be treated presumptively if syphilis serology is not available immediately and if follow-up may be problematic.

Treatment of long-term sexual partners of patients with latent syphilis is dependent on clinical evaluation and serology results.

For primary syphilis: exposure 3 months before treatment, plus duration of symptoms.

For secondary syphilis: 6 months plus duration of symptoms.

For early latent syphilis: 1 year.

Follow-Up Overview

Natural course of infection

Serology test results

Jarisch-Herxheimer reaction

Occurs within the first 24 hours after antibiotic therapy due to the rapid killing of treponemes.

Characterized by acute fever, headache, and myalgia, usually in patients with early syphilis. [ 8 ]

The likelihood of reaction is high in early syphilis but low in late syphilis. However, all patients should be advised of a possible reaction prior to receiving antibiotic treatment.

In pregnant women, Jarisch-Herxheimer reaction may cause fetal distress and premature labor. [ 8 ]

Treatment is supportive with oral fluids, acetaminophen, and nonsteroidal anti-inflammatory drugs.

Corticosteroid therapy may be considered to minimize the risk of a Jarisch-Herxheimer reaction in nonpregnant patients with cardiovascular syphilis or neurosyphilis. [ 10 ]  However, the evidence of effectiveness is unclear and it is not routinely recommended in the US.

allergic reaction to penicillin

May arise in patients not previously known to be allergic.

In patients with penicillin allergy, alternative treatment options may be offered, dependent on the stage of syphilis.

Penicillin allergy skin testing and desensitization may be required (e.g., in the treatment of pregnant women).

Penicillin-allergic responses may include urticaria, angioedema, and anaphylaxis.

Treatment of allergic reaction is determined by the severity of the reaction.

asymptomatic progression of disease

Organ-specific complications can occur in untreated infection of unknown duration.

Specialist opinion should be sought depending on the nature of the complication (e.g., ophthalmology specialist opinion for ocular infection, cardiovascular specialist opinion for aortic regurgitation).

HIV infection

Syphilis facilitates the acquisition of HIV. [ 17 ]

iatrogenic procaine reaction

Occurs when intramuscular procaine penicillin G (e.g., used to treat neurosyphilis) is mistakenly administered intravenously.

Patients may develop penicillin allergic responses, including anaphylactic shock. [ 23 ]

Key Articles

Stoltey JE, Cohen SE. Syphilis transmission: a review of the current evidence. Sex Health. 2015 Apr;12(2):103-9. [Abstract] [Full Text]

British Association for Sexual Health and HIV (BASHH). UK national guidelines on the management of syphilis. December 2015 [internet publication]. [Full Text]

World Health Organization. Guidelines for the treatment of Treponema pallidum (syphilis). 2016 [internet publication]. [Full Text]

Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm Rep. MMWR Recomm Rep. 2021 Jul 23;70(4):1-187. [Abstract] [Full Text]

World Health Organization. WHO guideline on syphilis screening and treatment for pregnant women. 2017 [internet publication].  [Full Text]

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92. Parkes R, Renton A, Meheus A, et al. Review of current evidence and comparison for effective syphilis treatment in Europe. Int J STD AIDS. 2004 Feb;15(2):73-88. [Abstract]

93. Hook EW 3rd, Martin DH, Stephens J, et al. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis. 2002 Aug;29(8):486-90. [Abstract]

94. Riedner G, Rusizoka M, Todd J, et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med. 2005 Sep 22;353(12):1236-44. [Abstract] [Full Text]

95. Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med. 2004 Jul 8;351(2):154-8. [Abstract] [Full Text]

96. World Health Organization. Guidelines for the treatment of Treponema pallidum (syphilis). 2016 [internet publication]. [Full Text]

97. Ansotegui IJ, Melioli G, Canonica GW, et al. IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper. World Allergy Organ J. 2020 Feb;13(2):100080. [Abstract] [Full Text]

98. Chastain DB, Hutzley VJ, Parekh J, et al. Antimicrobial desensitization: a review of published protocols. Pharmacy (Basel). 2019 Aug 9;7(3):112. [Abstract] [Full Text]

99. World Health Organization. WHO guideline on syphilis screening and treatment for pregnant women. 2017 [internet publication].  [Full Text]

100. Walker GJ, Walker D, Molano Franco D, et al. Antibiotic treatment for newborns with congenital syphilis. Cochrane Database Syst Rev. 2019 Feb 15;(2):CD012071. [Abstract] [Full Text]

101. Liang Z, Chen YP, Yang CS, et al. Meta-analysis of ceftriaxone compared with penicillin for the treatment of syphilis. Int J Antimicrob Agents. 2016 Jan;47(1):6-11. [Abstract]

102. Liu HY, Han Y, Chen XS, et al. Comparison of efficacy of treatments for early syphilis: A systematic review and network meta-analysis of randomized controlled trials and observational studies. PLoS One. 2017 Jun 28;12(6):e0180001. [Abstract] [Full Text]

103. Faculty of Sexual and Reproductive Healthcare. Barrier methods for contraception and STI prevention. August 2015 [internet publication]. [Full Text]

104. Ng BE, Butler LM, Horvath T, et al. Population-based biomedical sexually transmitted infection control interventions for reducing HIV infection. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD001220. [Abstract] [Full Text]

105. de Walque D, Dow WH, Nathan R, et al. Incentivising safe sex: a randomised trial of conditional cash transfers for HIV and sexually transmitted infection prevention in rural Tanzania. BMJ Open. 2012 Feb 8;2(1):e000747. [Abstract] [Full Text]

106. British Association for Sexual Health and HIV (BASHH). BASHH National Guideline on the Management of Sexually Transmitted Infections and Related Conditions in Children and Young People 2021. 2021 [internet publication]. [Full Text]

Published by

Centers for Disease Control and Prevention

World Health Organization

International Union against Sexually Transmitted Infections 

British Association for Sexual Health and HIV

International Union against Sexually Transmitted Infections

National Institute for Health and Care Excellence (UK)

Faculty of Sexual and Reproductive Healthcare (UK)

Topic last updated: 2023-12-11

Juan C. Salazar , MD, MPH, FAAP

Professor and Chair

Department of Pediatrics

University of Connecticut School of Medicine

Physician in Chief

Connecticut Children's

Acknowledgements :

Dr Juan C. Salazar would like to gratefully acknowledge Adriana R. Cruz, Jairo M. Montezuma-Rusca, Nicholas Bennett, Patrick French, and Nooshin Barmania, previous contributors to this topic. We would also like to acknowledge our infectious diseases expert panel member, Dr Elisabeth Adderson, for her contribution to this topic.

Peer Reviewers

Robert A. Larsen , MD

Associate Professor of Medicine

University of Southern California

Keck School of Medicine

Los Angeles

William Rodriguez , MD

Assistant Professor of Medicine

Harvard Medical School

Director of Research

Global Health Delivery Project

Harvard School of Public Health

Jennifer Handforth , MB ChB, MRCPCH, DTM&H

Consultant Paediatrician

Croydon University Hospital

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

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

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The U.S. Syphilis Spike Has Been Brewing for Decades

Annalies Winny

Syphilis cases in the U.S. are skyrocketing even as rates for other STIs like gonorrhea and chlamydia are flat or declining.

Alarming numbers released by the CDC are the latest marker in a decades-long rise of the disease, showing the highest case numbers since the 1950s.

From 2018 to 2022, reported cases rose 80% in the U.S . In 2022, cases of congenital syphilis among newborns were 10 times higher than in 2012, at 3,700 cases. Black and American Indian populations bear a disproportionate share of the burden—and women are making up a rising share of cases.

Left untreated, the disease can be devastating, causing serious heart and brain damage, blindness, deafness, and paralysis. Congenital cases can cause miscarriage, lifelong medical issues, and infant death.

Khalil Ghanem , MD, PhD ’08, a professor of Medicine with a joint appointment in Population, Family and Reproductive Health, discusses how the country—which just decades ago seemed on the brink of defeating syphilis—lost momentum.

How is syphilis transmitted, and what are the symptoms?

Syphilis can be transmitted through sexual contact (anal, genital, or oral), from mother to fetus, and in very rare cases, through blood transfusion or organ transplantation. Only during its early stages—around the first four months—can it be transmitted sexually, but it can be passed to a fetus at any stage.

The first clinical signs are known as primary syphilis, which usually don’t show up until two to six weeks after infection. In sexually transmitted syphilis, the first symptoms are ulcers at the site of exposure. They are generally painless, and therefore much harder to detect inside the vagina or anus than on the penis.

The immune system usually kicks in and clears those symptoms—but it doesn’t cure the disease—and eventually it escalates to secondary syphilis. At this stage, the organism is replicating very quickly and affecting many organs in the body. It can bring on fevers, skin lesions, mucosal lesions, and even hepatitis. Again, the immune system can clear these symptoms and the infection reaches its next stage: latent syphilis.

Sixty percent of people with latent syphilis will never have symptoms again. The other 40% suffer devastating complications including neurological problems, cardiovascular issues, and inflammatory masses all over the body. Overall, 10% of patients who are not treated for syphilis wind up dying from this infection.

Currently, there’s no way of knowing who will fall into what category.  

How are congenital cases different from adult cases?

It's the same [disease] process, but in a tiny person whose immune system is not yet functional.

The disease can lead to miscarriage or stillbirth, and up to 40% of babies born to women with untreated syphilis die from the infection. 

If the infant is born, early manifestations include horrifying skin peeling, enlarged liver and spleen, and impacts on the blood and central nervous system.

A newborn with syphilis may only present symptoms years later, when the disease can cause incredibly brittle bones that essentially break when the child begins to put on weight. And there’s nothing you can do about it if the disease reaches that stage without prior treatment.

Every case of congenital syphilis in this country is a black mark on public health. The reality is that a lot of pregnant patients are not seeking care until late or don’t have access to care—and the later you wait, the more likely you are to have transmission to the fetus.

How is syphilis treated?

Syphilis is a cruel disease. Left untreated, it can affect any and every organ system and evade the immune response. Penicillin and other antibiotics can cure it, but it’s essential to treat it early when the least damage has been done.

There is only one drug recommended for the treatment of uncomplicated syphilis during pregnancy: benzathine penicillin G (BPG), and we are experiencing a national shortage of it. The FDA has temporarily approved the importation and sale of the nearly identical French version of the drug to shore up supplies—but this episode highlights the country’s dependence on a single manufacturer for BPG and the dire implications when that manufacturer experiences production issues.

Why is syphilis on the rise in the U.S. now?

The syphilis rates in the U.S. started going up in 2000 and have not stopped.

Initially, this increase was mainly among men who have sex with men. Today, we have parallel epidemics in two sexual networks: one in MSM, and one among heterosexuals, which has been linked to drug use. The rise of syphilis cases among women is now surpassing the rise among men.

It’s harder to break down by region. We have good data from cities but very poor data from rural areas, where there’s less access to health care and more missed diagnoses. But there have been multiple outbreaks reported in rural areas.

What changed in 2000?

In the late 1990s, there was a belief that the U.S. was on track to beat syphilis—in 1999 we achieved the lowest rates of syphilis recorded in the country.

During that time, people were scared of HIV—it was a death sentence—and that helped change sexual behaviors. Now you can treat HIV as a chronic disease, and you can prevent it with pre-exposure prophylaxis. That has impacted sexual behavior and taken some of the pressure off of syphilis prevention overall, which has been deprioritized and underfunded.

Why hasn’t the U.S. been able to beat syphilis?

We should be able to eradicate this entirely preventable disease through the basic tenets of infection control: widespread screening, testing, finding the sexual partners of infected individuals, treating those who have the disease, and educating the public.

We have good diagnostics, we know how it’s transmitted, there’s no animal reservoir, and we know how to treat it. 

But there are wider public health challenges. Screening is inadequate: While some women get routinely tested for STIs at their annual exam, men are far less likely to get routine screenings. And because many people with syphilis have no symptoms, they won’t seek out screening. Plus, many at-risk patients don’t have access to health care, and a lot of sexual health clinics have closed over the last decade.

Also, the stigma of STIs doesn’t just happen from the patient side, it also comes from clinicians —many physicians think, “my patient doesn’t have syphilis.”

Finding patients’ partners has also become more difficult in the online dating era—partners are often identified with an online handle, not a physical location.

What’s the global picture?

Any place where you look, syphilis rates are going up. The only place that I know is seeing some declines in rates in some populations is China, which in the last 15 years had a massive outbreak in both gay and heterosexual populations. In recent years they’ve seen steady declines after spending a lot of money screening, testing, and treating the disease.

What can the U.S. learn from that? Has this outbreak drawn more attention to the issue?

I gave a talk on syphilis at a conference 10 years ago, and there were about 40 people in the room. They just reinvited me to speak at that same meeting, and there were over 700 people in the room. There is more interest because we’re seeing a lot more patients, and clinicians need to relearn how to treat them.

The one major thing that has an impact on the rate is money. The U.S. government through the CDC has had relatively flat spending on STD prevention over the last 20 years—and with inflation, that amounts to a significant decrease in spending.

The problem with public health is that when disease rates go down, we have to take the limited funds we have, and move them somewhere else.  

Annalies Winny is a writer and producer at the Johns Hopkins Bloomberg School of Public Health

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HOPE Challenge: Heart of the Matter Recap

KATHERINE A. M. SNYDER, MD, AND ADAM D. VOELCKERS, MD

Am Fam Physician. 2024;109(3):212-216

This is part I of a two-part article on newborn skin. “ Newborn Skin: Part II. Birthmarks ,” appears in this issue of AFP .

Author disclosure: No relevant financial relationships.

Rashes in the newborn period are common and most are benign. Infections should be suspected in newborns with pustules or vesicles, especially in those who are not well-appearing or have risk factors for congenital infection. Congenital cytomegalovirus infection can cause sensorineural hearing loss and neurodevelopmental delay. Skin manifestations of cytomegalovirus may include petechiae due to thrombocytopenia. The most common skin manifestations of early congenital syphilis are small, copper-red, maculopapular lesions located primarily on the hands and feet that peel and crust over three weeks. Erythema toxicum neonatorum and neonatal pustular melanosis are transient pustular rashes with characteristic appearance and distribution. Neonatal acne is self-limited, whereas infantile acne may benefit from treatment. Milia can be differentiated from neonatal acne by their presence at birth. Cutis marmorata and harlequin color change are transient vascular phenomena resulting from inappropriate or exaggerated dilation of capillaries and venules in response to stimuli.

Skin findings in newborns can present a diagnostic challenge in distinguishing common, benign rashes from those associated with infection, malignancy, or systemic syndromes. When clinicians evaluate the newborn rash, the most important skill is to recognize when further evaluation is necessary because early diagnosis and treatment can have a significant impact on morbidity and mortality. Part I of this article reviews the presentation, prognosis, and treatment of the most common rashes and skin changes that present during the first four weeks of life. Part II of this article, which appears in this issue of American Family Physician , discusses the identification and management of birthmarks that appear in newborns. 1

Transient Rashes

Infectious causes of transient rashes, such as Candida infections or congenital cytomegalovirus, should be a primary consideration. A rash consistent with one of the classic benign presentations in the well-appearing newborn can be monitored for resolution. Risk factors for congenital infections should be considered before the diagnosis of a benign rash.

INFECTIOUS CAUSES

Congenital infections may present with vesicles or pustules and can generally be distinguished based on presentation ( Table 1 ) . 2 – 8 Diffuse papular or vesicular rashes due to bacterial infections will often be associated with clinical signs of sepsis. 2

Congenital Candida infections are rare and cause a desquamating, maculopapular, papulopustular, or erythematous diffuse rash that presents at birth or in the first week of life. Prompt treatment with systemic antifungals can prevent disseminated candidemia. 3

Herpes simplex virus (HSV) is a potentially devastating infection for the newborn and can be effectively treated with prompt recognition. Most newborns who are infected with HSV in the peripartum period have a birthing parent with no known history of HSV. Neonatal HSV can present with disseminated disease, central nervous system disease, or cutaneous infection of the skin, eyes, and mouth. HSV skin vesicles typically present at approximately 12 days of life and are associated with lethargy and fever in an ill-appearing child. 4 An evaluation for HSV in these cases should not be delayed.

Congenital cytomegalovirus infections can cause sensorineural hearing loss and neurodevelopmental delay. Presentation is variable; 90% of newborns affected by cytomegalovirus are asymptomatic. Skin manifestations may include petechiae due to thrombocytopenia. Newborns with symptoms are more likely to suffer permanent sequelae. 5 Diagnostic testing in newborns is performed with a saliva sample in the first two to three weeks of life. 6

Previously considered a rare disease, congenital syphilis has steadily increased in incidence and geographic distribution since 2013. 7 The most common skin manifestations of early congenital syphilis are small, copper-red, maculopapular lesions located primarily on the hands and feet that peel and crust over three weeks. 7 Diagnosis is based on a quantitative comparison of nontreponemal serologic titers in the birthing parent and neonate. 7 Penicillin is the treatment of choice. 8

ERYTHEMA TOXICUM NEONATORUM

Erythema toxicum is a benign rash that may cause a caregiver to have concern that it is a more serious condition ( Figure 1 ) . It is the most common pustular newborn rash and affects approximately one-half of newborns; it is more common in those who are full-term. 9 , 10 Lesions may be present at birth but more often appear in the first few days of life. 11 Lesions may present as papules, followed by the development of small pustules with a large red base that are not in groups and are located on the face, trunk, and extremities. Lesions are not found on the palms or soles. 2 Diagnosis is made clinically in well-appearing newborns, although a peripheral smear that contains eosinophils may help confirm the diagnosis. 2 No treatment is required, and the rash should resolve with no scarring in one to two weeks.

TRANSIENT NEONATAL PUSTULAR MELANOSIS

Transient neonatal pustular melanosis is more common in newborns with skin containing higher levels of melanin. It is a pustular rash that is present at birth. The pustules rupture and leave a characteristic pigmented macule ( Figure 2 ) . The rash is diagnosed clinically by lesions that may appear on the forehead, behind the ears, and on the neck, trunk, and extremities, including the palms and soles. 12 Hyperpigmentation may persist for weeks to months before fading. 2

NEONATAL AND INFANTILE ACNE

Neonatal acne presents with closed comedones on the forehead, nose, and cheeks that may appear pustular ( Figure 3 ) . It is not present at birth, but develops in the first four weeks of life. 13 Neonatal acne is thought to be a result of sebaceous gland stimulation from newborn exposure to adult levels of endogenous hormones. Infantile acne generally presents after six weeks, lasts for six to 12 months, and may be more inflammatory in nature. 14 Infantile acne does not require further evaluation in the absence of other signs of hormonal excess. Infantile acne rarely requires treatment; however, topical antimicrobials or retinoids may be used in consultation with a specialist for severe or refractory cases and concerns for scarring. 15

Milia consists of tiny, pearly white to yellow cysts located on the forehead, nose, and cheeks, although they can appear in other locations ( Figure 4 ) . They are secondary to retained keratin and present at birth in up to one-half of newborns. Treatment is not needed. 2 , 16

Transient Vascular Phenomena

Transient vascular phenomena are visual representations of inappropriate or exaggerated dilation of normally formed blood vessels in response to an environmental stimulus.

CUTIS MARMORATA

Cutis marmorata is a physiologic phenomenon that presents as a reticular, bluish rash with symmetrical distribution on the trunk and extremities ( Figure 5 ) . It is caused by the dilation of capillaries and venules in response to cold temperatures. It can occur for weeks after birth and will disappear in warm temperatures. 17

Cutis marmorata telangiectatica congenita is a serious vascular anomaly that mimics physiologic cutis marmorata. Although the rash may appear similar in both conditions, cutis marmorata telangiectatica congenita should be considered if there is skin atrophy, ulceration, or unilateral distribution. 17 Referral is indicated when the diagnosis is uncertain.

HARLEQUIN COLOR CHANGE

Harlequin color change affects up to 10% of newborns, especially those who are preterm or small for gestational age. 18 It presents as transient, clearly demarcated areas in which one-half of the body is pale, and the other is plethoric. It generally appears between the third and fifth day of life, can persist from 30 seconds to 20 minutes, and may disappear when the newborn cries. 19 It is a benign, cutaneous condition that is thought to be secondary to vasomotor instability from an immature hypothalamus. It requires no specific evaluation or treatment. 19 , 20

This article updates a previous article on this topic by O’Connor, et al. 2

Data Sources: A PubMed search was completed using the terms congenital infections, erythema toxicum neonatorum, transient neonatal pustular melanosis, neonatal and infantile acne, milia, cutis marmorata, harlequin color change, and key terms for diagnosis and management. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. The Cochrane database, UpToDate, Essential Evidence Plus, and the TRIP database were also searched. Search dates: November 2022 to February 2023, May to June 2023, and December 2023.

The authors thank the patients’ families who allowed their newborns to be photographed for this article.

Snyder KAM, Voelckers AD. Newborn skin: part II. Birthmarks. Am Fam Physician. 2024;109(3):217-221.

O’Connor NR, McLaughlin MR, Ham P. Newborn skin: part I. Common rashes. Am Fam Physician. 2008;77(1):47-52.

Kaufman DA, Coggins SA, Zanelli SA, et al. Congenital cutaneous candidiasis: prompt systemic treatment is associated with improved outcomes in neonates [published correction appears in Clin Infect Dis . 2017; 65(8): 1431–1433]. Clin Infect Dis. 2017;64(10):1387-1395.

Kabani N, Kimberlin DW. Neonatal herpes simplex virus infection. Neoreviews. 2018;19(2):e89-e96.

Kabani N, Ross SA. Congenital cytomegalovirus infection. J Infect Dis. 2020;221(suppl1):S9-S14.

Fowler KB, Boppana SB. Congenital cytomegalovirus infection. Semin Perinatol. 2018;42(3):149-154.

Woods CR. Syphilis in children: congenital and acquired. Semin Pediatr Infect Dis. 2005;16(4):245-257.

Centers for Disease Control and Prevention. Congenital syphilis. Accessed July 1 1, 2023. https://cdc.gov/std/treatment-guidelines/congenital-syphilis.htm

Erdle SC, O’Brien K. A neonate with blisters. Pediatr Rev. 2020;41(suppl 1):S27-S29.

Kanada KN, Merin MR, Munden A, et al. A prospective study of cutaneous findings in newborns in the United States: correlation with race, ethnicity, and gestational status using updated classification and nomenclature. J Pediatr. 2012;161(2):240-245.

Haveri FTTS, Inamadar AC. A cross-sectional prospective study of cutaneous lesions in newborn. ISRN Dermatol. 2014;2014:360590.

Dinulos JG, Graham EA. Influence of culture and pigment on skin conditions in children. Pediatr Rev. 1998;19(8):268-275.

Greydanus DE, Azmeh R, Cabral MD, et al. Acne in the first three decades of life: an update of a disorder with profound implications for all decades of life. Dis Mon. 2021;67(4):101103.

Serna-Tamayo C, Janniger CK, Micali G, et al. Neonatal and infantile acne vulgaris: an update. Cutis. 2014;94(1):13-16.

Eichenfield LF, Krakowski AC, Piggott C, et al.; American Acne and Rosacea Society. Evidence-based recommendations for the diagnosis and treatment of pediatric acne. Pediatrics. 2013;131(suppl 3):S163-S186.

Gallardo Avila PP, Mendez MD. Milia. StatPearls . Updated January 31, 2023. Accessed November 15, 2022. https://www.ncbi.nlm.nih.gov/books/NBK560481/

Null E, Clarey D, Warrack S. Diffuse reticulated rash in a newborn. Pediatr Rev. 2021;42(suppl2):151-154.

Januário G, Salgado M. The harlequin phenomenon. J Eur Acad Dermatol Venereol. 2011;25(12):1381-1384.

Velayuthan S, Sankararaman S. Visual diagnosis: newborn who has unilateral color change. Diagnosis: harlequin color change. Pediatr Rev. 2013;34(7):e25-e26.

Valerio E, Barlotta A, Lorenzon E, et al. Harlequin color change: neonatal case series and brief literature review. AJP Rep. 2015;5(1):e73-e76.

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Syphilis Infections, Reinfections and Serological Response in a Large Italian Sexually Transmitted Disease Centre: A Monocentric Retrospective Study

Valentina marchese.

1 Unit of Infectious and Tropical Diseases, Department of Clinical and Experimental Sciences, ASST Spedali Civili di Brescia and University of Brescia, 25123 Brescia, Italy

2 Unit of Infectious and Tropical Diseases, ASST Spedali Civili di Brescia, 25123 Brescia, Italy

Giorgio Tiecco

Samuele storti, melania degli antoni, stefano calza.

3 Unit of Biostatistics and Bioinformatics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy

Maurizio Gulletta

Francesca viola, emanuele focà, alberto matteelli, francesco castelli, eugenia quiros-roldan, associated data.

Data presented in this manuscript are available from the corresponding authors on reasonable request.

Background: Syphilis infection does not confer definitive and protective immunity against reinfection, and crucial aspects of repeated episodes of syphilis are far from being understood, especially among people living with HIV (PLWH). Methods: In order to explore the burden of syphilis in a large cohort of HIV-negative patients and PLWH, this retrospective study describes the demographics, clinical presentation and treatment outcome of patients with syphilis treated at our clinic from 2013 to 2021. Results: Within the study period, 1859 syphilis episodes (827, 44.5% first infections and 1032, 55.5% reinfections) were recorded. A total of 663 patients, of whom 347 (52%) had PLWH, were considered. Syphilis was mostly diagnosed in males (77%) and European (79%) patients. More than half of syphilis episodes were recorded during the late latent stage (64%) or during follow-up/screening visits for other diseases, while symptomatic stages led to a diagnosis in almost half of HIV-negative patients ( p < 0.001). PLWH with syphilis infection were predominantly homo/bisexual ( p < 0.001). A significantly higher rate of syphilis reinfection was observed in PLWH, who also demonstrated a higher range of subsequent episodes. The serofast state was found to be similar at the 6- and 12-month follow-up visits. The multivariate analysis carried out in the HIV-positive group showed that an RPR titre >1:16 was an independent predictor for serological non-response. Conclusions: Syphilis reinfections are predominantly diagnosed in HIV-positive MSM. The high rate of asymptomatic presentation among PLWH supports the role of periodical syphilis screening. In PLWH, the only baseline factor associated with an increased risk of non-response was an RPR titre >1:16, while assessment at 12 months after treatment increased the possibility of detecting a serological response, indicating that PLWH have a slower serological response to treatment.

1. Background

Syphilis is one of the oldest sexually transmitted diseases, for which curative and inexpensive treatment is available [ 1 ]. However, the annual rate of primary and secondary syphilis has risen in recent years, both in Europe and the USA [ 2 ]. In Italy, the estimated notification rate is 2.5/100,000, and syphilis disproportionately affects men, with an overall gender ratio of 7:1 (male-to-female) in 2018 [ 3 ]. Previous Italian national data (1991–2017) confirm the major burden in males, demonstrating that they account for 91% of all primary or secondary cases and 65% of latent syphilis [ 4 ].

During the last two years of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, community containment and social distancing measures might have affected the circulation of STDs [ 5 ]. However, few and controversial data are available. A recent monocentric study carried out in Italy has shown that despite the lockdown and the fear of SARS-CoV-2 infection, risky sexual activity has not diminished; likewise, the risk of syphilis remains, raising concern for community health [ 6 ].

Syphilis is frequently encountered among people living with HIV (PLWH), with a non-uniquely defined prevalence; in Europe, the rate of HIV and syphilis coinfection (either known or newly diagnosed) is 24% overall and may reach 35% when specifically considering the bisexual population and other men who have sex with men (MSM) [ 2 , 7 ]. Moreover, syphilis facilitates both HIV transmission and HIV acquisition, and with the consolidation of the evidence that a stable virological suppression of plasmatic HIV-RNA does not lead to HIV transmission (U = U or undetectable = untransmittable), this bond is intended to last [ 1 ]. Coinfection is dangerous because HIV infection may modulate the clinical presentation and the serologic response to syphilis treatment [ 7 ]. PLWH with a syphilis infection seem to have a higher risk of developing neurosyphilis and mount an abnormal serological response [ 8 , 9 ]. Many diagnostic and therapeutic challenges remain, as there are currently no controlled trials focused on syphilis–HIV coinfection management. Standard HIV care should always include regular syphilis serology, but new models for testing and prevention will be crucial next steps in controlling this coinfection [ 10 ].

Syphilis infection does not lead to immunity against reinfection, making repeated episodes of syphilis a concrete reality, especially in MSM with a high rate of partner change [ 11 ]. Moreover, data regarding serological response in patients with syphilis reinfection are discordant, and crucial aspects of the interpretation of non-treponemal test trends are far from being resolved [ 1 ]. The non-uniquely defined serological response in syphilis reinfections, together with the altered immunologic response in PLWH, represents a challenge for clinicians.

In order to explore the burden of syphilis in a large cohort of HIV-negative patients and PLWH, this retrospective study describes the demographics, clinical presentation and treatment outcomes of patients with syphilis treated at our clinic from 2013 to 2021. It also aims at assessing possible factors associated with serological response to treatment for syphilis reinfections among PLWH, for whom a higher frequency of reinfection was recorded during the study period. We also aimed to assess relevant factors associated with a serological response to treatment and syphilis reinfection among our HIV/syphilis coinfected population.

2. Materials and Methods

2.1. study population and setting.

The study was conducted at the Department of Infectious Disease of the ASST Spedali Civili, Brescia, Italy. In 2021, our department provided care to 3841 PLWH and hosted a clinic for sexually transmitted diseases (STDs) as part of the Italian Sentinel Surveillance System.

We retrospectively evaluated all cases of syphilis reported by our clinic to the Italian Sentinel Syphilis Surveillance System from January 2013 to December 2021, matching them with our electronic health record system. Incomplete or uncertain records were excluded. The study population was split into 2 groups: the HIV-positive group and HIV-negative group or control group, according to the presence of HIV/syphilis coinfection. All cases of syphilis (first diagnosis or reinfection), either among PLWH or HIV-negative patients aged >18 years, were included.

2.2. Data Collection

Demographic and clinical/laboratory characteristics were collected from medical records. The variables included sex, age, area of origin according to the United Nations (UN) classification [ 12 ], sexual orientation, HIV infection and, among PLWH, HIV viral load and lymphocyte CD4+ T-cell count. For detected cases, data regarding clinical classification (primary, secondary, tertiary, early latent, late latent or neurosyphilis) and reasons for testing were collected (screening for PLWH, pregnancy, other STDs or partner tracing or presence of symptoms). Incomplete or uncertain cases were excluded. Moreover, only records with at least one follow-up consultation at 6 and/or 12 months after treatment, reporting signs or symptoms and non-treponemal test results were included to assess the serological response to treatment.

2.3. Clinical Management

We considered indirect methods to assess a syphilis diagnosis; TPHA (Treponema pallidum haemagglutination assay) as a treponemal test and RPR (rapid plasma reagin) as a non-treponemal test were the principally used assays. PLWH underwent syphilis screening at their first HIV clinical evaluation with both treponemal and non-treponemal tests. Patients with positive results received the appropriate supervised treatment. Screening was repeated annually (with an RPR test being used only in previously treated patients), or earlier in the case of reported symptoms or at-risk sexual intercourse. A thorough anamnesis and physical examination were performed in the case of a syphilis diagnosis to assess its stage, even performing a lumbar puncture according to current ongoing guidelines if needed [ 13 ]. All patients received appropriate treatment (mostly benzathine penicillin or doxycycline in the case of allergy). In HIV-negative individuals, indications for testing for syphilis infection in Italy include clinical suspicion, contact with syphilis, pregnant women and risk factors for sexually transmitted diseases. Follow-up visits were scheduled at 6 months and 12 months after treatment. During these visits, clinicians assessed risk factors for syphilis re-exposure and serological data were obtained to monitor the RPR titre trends. Patients with a serological non-response or a serofast status were asked for risk factors, and in doubtful cases, a new treatment was given.

2.4. Definitions

A first syphilis case was defined as a patient with positive treponemal and non-treponema tests without a previous history of treated syphilis infection whether in combination with clinical signs of syphilis or not. Reinfection was defined in patients having more than 2 diagnoses of syphilis infection during the study period in the case of having been previously diagnosed as having syphilis, having received adequate treatment and having demonstrated a seroreversion from negative to positive or a ≥4-fold increase in non-treponemal titre. Patients with undocumented treatment during the study period and patients with missing, incomplete or uncertain data were excluded from the study.

In accordance with the current literature, we considered patients with a complete seroreversion in RPR titres (from positive to negative) or with a ≥4-fold decline in nontreponemal antibody titres as serological responders [ 13 , 14 ]. Patients who, after an effective treatment, showed a ≤4-fold titre decline were defined as serological non-responders, whereas patients with a persistently reactive RPR titre despite adequate treatment and an initial ≥4-fold decline were defined as serofast.

2.5. Ethical Aspects

The study protocol received ethical approval from the Ethics Committee of the province of Brescia (code number NP 4847). All data were collected and analysed according to current Italian laws for the management of sensitive data and principles of the Declaration of Helsinki. The standard clinical practice at all healthcare services included providing thorough information and receiving verbal consent to any of the offered practices.

2.6. Statistical Analysis

Descriptive analysis of the characteristics of the two cohorts at baseline was performed. The median values and interquartile ranges (IQRs) were used to describe numerical variables, while the counts and percentages were employed for qualitative variables. A chi-square (χ2) test with p -values computed using Monte–Carlo simulations (B = 2000) or the Wilcoxon–Mann–Whitney test were used to compare the groups for categorical or continuous variables, respectively.

The number of reinfections was modelled using a generalised linear model (GLM) with a negative binomial family. The results are reported as incidence rate ratio (IRR) estimates and corresponding 95% confidence intervals (CIs 95%). Serological non-responses or serofast statuses were modelled as binary outcomes in a longitudinal setting using generalised linear mixed models (GLMMs) with a binomial family (also known as logistic regression). The results are reported as odds ratios (ORs) and corresponding 95% confidence intervals (CIs 95%). All tests were two-sided (apart from χ2), and a 5% significance level was assumed.

3.1. Prevalence of Syphilis Episodes in the Study Period

In the study period, 1859 syphilis episodes were recorded. A total of 827 patients were diagnosed with a first episode of syphilis infection (44.5%) and divided according to their HIV infection status ( Table 1 ). Between 2019 and 2021, we observed a decrease in first syphilis infection diagnoses among HIV-negative subjects. Approximately 1032 (55.5%) syphilis reinfections were recorded, especially in the HIV-positive population.

Number of first syphilis infections and reinfections per year during the study period.

Approximately 164 (19.8%) records regarding first syphilis infections were incomplete. Thus, 95 (11%) HIV-negative and 69 (8%) HIV-positive patients were excluded due to missing data ( Figure 1 ), whereas 650 (63%) subsequent episodes of syphilis infection were excluded due to patients being lost to follow-up. As shown in Figure 1 , 61 HIV-negative and 209 HIV-positive patients had at least 1 new episode of syphilis during the follow-up visits at 6 and/or 12 months. A total of 54 and 328 episodes of syphilis reinfection were recorded among HIV-negative and HIV-positive patients, respectively.

Study design (Ep. = episodes).

3.2. Demographic and Clinical Characteristics of Included Patients

The study included 663 patients, 316 (48%) HIV-negative and 347 (52%) HIV-positive patients with a median CD4 count of 295.5 cells/mcL (range 4 to 1038). As shown in Table 2 , syphilis was mostly diagnosed in males (508, 77%) with a median age of 39 years old (IQR, 12–83 years). Most patients were of European origin (522, 79%) and self-declared a homo/bisexual orientation (299, 45%). More than half of syphilis episodes were recorded during the late latent stage (424, 64%), followed by the secondary (107, 16%), primary (63, 10%) and early latent (53, 8%) stages. Neurosyphilis was observed in 16 (2%) episodes. Most syphilis episodes (426, 64%) were detected during follow-up/screening visits for other diseases (HIV, other STIs or partner tracing), whereas (237) 36% were detected due to the appearance of symptoms (skin rash, chancre or neurologic symptoms).

Demographic characteristics of the study population.

We found statistical differences between the HIV-positive group and the control group in several aspects of the demographic analysis. PLWH with syphilis infection were predominantly (260, 75%) homo/bisexual ( p < 0.001), while most heterosexuals with syphilis (184, 58%) were in the control group. Almost half (163, 53%) of HIV-negative syphilis infections were diagnosed during symptomatic stages, while, considering the longer median follow-up (88.9 months, p < 0.001), PLWH were diagnosed mainly with syphilis (278, 80%) due to screening/follow-up reasons during asymptomatic stages ( p < 0.001). Regarding syphilis reinfection, a significantly higher rate ( p < 0.001) was observed in the HIV-positive group (209, 60%), who had a higher rate of subsequent episodes (1 to 7), whereas sporadic (61, 19%) episodes of syphilis reinfections were recorded in the control group.

Among PLWH, the logistic regression model to assess factors associated with the number of syphilis reinfections showed a protective association with age (IRR 0.65, 95% CI 0.47–0.91 for range 40–50 years, p = 0.011 and IRR 0.55, 95% CI 0.35–0.86, p = 0.009 for age > 50 years), while being homosexual/bisexual increased the risk of syphilis reinfections (IRR 1.52, 95% CI 1.09, 2.18, p = 0.017). In our model, gender, geographical origin and CD4 nadir were not associated with an increased risk of syphilis reinfection in PLWH ( Table 3 ).

Generalised linear model to assess factors associated with the number of syphilis reinfections among PLWH.

1 IRR = incidence rate ratio, CI = confidence interval.

3.3. Serological Response to Treatment in Syphilis Reinfection

Among the patients with syphilis reinfection effectively treated according to their syphilis stage, no significant statistical difference was observed in the serological response between PLWH and HIV-negative patients at 6-month and 12-month follow-up visits ( p = 0.2 at 6 months, p = 0.1 at 12 months). Among PLWH, the serologic response and seroreversion rate increased over time, while the serological non-response rate decreased during the follow-up assessment at 6 and 12 months after treatment. Conversely, the serofast status rate was found to be similar at both the 6- and at 12-month follow-up in PLWH, without any significant difference with the control group ( Table 4 ).

Serological response to treatment after syphilis reinfection at 6- and 12-month follow-up (SNR = serological non-response).

Multivariate analysis was performed considering syphilis reinfection in the HIV-positive group. In our study, an RPR titre > 1:16 was an independent predictor (OR 2.26, 95% CI 1.14–4.51, p = 0.020) of serological non-response, regardless of sex, age, CD4 cell count at diagnosis or HIV viral load ( Table 5 ). On the other hand, a follow-up evaluation at 12 months rather than earlier (6 months) statistically reduced the risk of serological non-response in PLWH (OR 0.38, 95% CI 0.22–0.65, p < 0.001). Among all the risk factors considered, none was statistically associated with the serofast state ( Table 5 ).

Risk factors associated with a serological non-response and a serofast status in syphilis reinfection among people living with HIV.

1 CI = confidence interval.

4. Discussion

This was a large monocentric retrospective study including over 1800 episodes of syphilis infection describing a cohort of 663 people diagnosed with a first syphilis infection, dividing them into two groups according to their HIV status and focusing on serological response in syphilis reinfection among PLWH. As previously described, syphilis infection and homo/bisexual orientation were also often accompanied by HIV coinfection in our cohort [ 14 ]. Furthermore, the introduction of successful antiretroviral therapy and the general assumption among PLWH of U = U have induced an alarming decline in the adoption of safe sexual behaviours [ 10 ].

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, community containment and social distancing measures might have affected the circulation of STDs. A recent monocentric study showed that despite the lockdown and the fear of SARS-CoV-2 infection, risky sexual activity has not diminished, nor has unprotected sexual intercourse among the increasing number of PrEP users (pre-exposure prophylaxis). Thus, the occurrence of syphilis has continued unabated [ 6 , 15 ]. However, in a COVID-19-prioritised era, an inevitably downscaled number of individuals seeking medical attention might also partially justify possible incidence reductions in STD diagnoses [ 16 ]. In our centre, a statistical difference was found in the annual trend of syphilis reinfections among HIV-positive and HIV-negative patients. The minimal non-significant decrease in diagnoses of syphilis among PLWH observed during 2020 and 2021 is also in line with the maintained continuum of care in PLWH with few missed visits, but with a reduction in new HIV diagnoses observed in our centre during the SARS-CoV-2 pandemic [ 17 , 18 ]. Interestingly, national epidemiological data report a 20% reduction in latent syphilis diagnoses in 2020 compared to 2019, and a 5% reduction in primary and secondary syphilis [ 19 ]. Further studies are needed to clarify the link between lockdown and sexual habits and the risk for syphilis.

Syphilis infection does not lead to immunity against reinfection, and repeated episodes of syphilis occur predominantly in PLWH, especially in an asymptomatic form, highlighting the crucial role of periodical screening [ 20 , 21 ]. In our centre, PLWH are screened for syphilis at least annually, regardless of their symptoms or risk factors, allowing for an earlier diagnosis and intercepting repeated episodes. In our cohort, syphilis reinfections in PLWH ranged from one to seven episodes. It is known that MSM with HIV infection present high rates of syphilis coinfection and reinfection [ 22 ]. In particular, MSM report a syphilis reinfection rate higher than one in five men (71/323; 22%), while in PLWH, approximately 21.8% of coinfected patients experience a reinfection [ 23 , 24 ]. The higher percentage of syphilis among HIV-negative females with respect to HIV-positive females (44% vs. 4%) in our cohort reflects an occasional diagnosis of syphilis during the pregnancy screening programs.

A recent study with a large cohort showed that factors associated with more than one episode of syphilis were sex (male) (OR = 4.28), age (OR = 1.02), homosexual/bisexual orientation (OR = 2.29) and absence of STI symptoms at the time of syphilis diagnosis (OR = 1.70) [ 25 ]. The extent of sexually risky behaviour over time is the strongest risk factor for repeated syphilis episodes when compared to other indicators (antiretroviral regimen or immunological status) [ 26 ]. The identification of at-risk adults and adolescents is crucial to improve syphilis screening strategies, as recommended by the latest USPSTF (US Preventive Services Task Force) statements [ 27 , 28 , 29 ]. While the interpretation of the indirect methods for syphilis diagnosis is relatively straightforward in patients without a prior history of syphilis, it becomes more complex in the case of reinfections, as treponemal antibodies mostly remain positive for their entire life cycle, tests lack sensitivity in early infection (as well as when patients are contagious), and non-treponemal titres often lead to difficult-to-interpret serological responses after treatment [ 29 ].

Although there are no controlled clinical trials focused on optimising the treatment of syphilis, all our patients were treated following literature recommendations based on laboratory results, expert opinions, clinical cases and experience [ 30 ]. HIV infection did not influence the treatment regimen used and, in line with the most recent literature reviews, no additional antibiotic doses were used in the case of anomalous serologic responses [ 31 , 32 ].

The main finding of our study regards the serological response to treatment in syphilis reinfections; no significant statistical difference was observed in the serological response between PLWH and HIV-negative patients. Like other authors, we were unable to find an association between the CD4 count, HIV viral load and serological response [ 33 , 34 , 35 ]. Serological response to treatment in coinfection syphilis/HIV is controversial as unusual serologic responses might be recorded [ 36 ]. However, our results are consistent with the current literature, since the majority of PLWH infected with syphilis achieved an adequate serologic response [ 36 ]. PLWH may just take longer to reach an adequate serologic response after treatment [ 36 ]; in our study, seroreversion and serological non-response rates in PLWH raised and decreased, respectively, over time. HIV-related immunodeficiency was hypothesised as the cause of this controversial response [ 37 ]. In our study, an apparently overall better serological response was found in PLWH; the primary explanation for this is that PLWH are chronically evaluated in our centre with scheduled visits every 6 months. This increases the detection rate of syphilis infection at earlier stages, which is linked to a better serological response [ 38 ].

A decline in the serofast status rate over time was not confirmed in our analysis. However, there is a paucity of information about the serofast status in the literature. In a recent analysis, HIV coinfection was associated with a slower serological cure, and while just 37% seroreverted within a year, more than 60% still had a positive RPR after 1 year of follow-up [ 39 ]. Here, the serofast status rate was found to be similar at 6 and 12 months, but this does not mean that this trend must be confirmed in a more prolonged observational study (at a hypothetical 18-month or 24-month follow-up visit). In our clinical practice, patients with a serofast status or a serological non-response after treatment are asked about risk factors for new syphilis exposure and, in doubtful cases, a new treatment is given. It is univocally stated that neither the choice of therapy nor the posology (single dose vs. three doses of intramuscular benzathine benzylpenicillin) in PLWH has any influence on the serofast state in early syphilis [ 40 ].

The risk factors for serofast status in HIV coinfection are only partially understood, especially in the case of syphilis reinfections [ 40 ]. As previously described, in our analysis, the serofast state in subsequent episodes of syphilis infection was not statistically associated with gender, age, CD4 at diagnosis or HIV-RNA or RPR titre in PLWH [ 41 ]. Curiously, baseline RPR titres ≤ 1:16, CD4 counts < 350 cells/µL, untreated HIV infection and a previous syphilis history are considered predictors for persistent non-treponemal titres [ 42 , 43 ].

Lastly, the multivariate analysis carried out among syphilis reinfections in PLWH showed that both a high RPR titre (>1:16) and an earlier follow-up evaluation (6 months rather than 12 months) after appropriate treatment are independent risk factors for serological non-response. In PLWH, repeated episodes of syphilis are associated with higher non-treponemal titres, influencing the serological outcome after treatment, whereas an adequate titre response is generally obtained earlier in HIV-negative people [ 37 ]. In addition, patients with a lower baseline RPR titre during syphilis infection seem to require a longer period to achieve a serological response (252 days for RPR titre ≤1:8, 78 days for RPR titres from 1:16 to 1:32 and 53 days for RPR titres ≥1:64, respectively; p < 0.001). It is unlikely that an earlier evaluation (at 6 months after treatment) is associated with complete seroreversion [ 39 ]. Although RPR is routinely used to monitor for a syphilis reinfection, our results suggest a possible role of a high RPR titre (>1:16) as a predictor of serological non-response. The ab initio role of the RPR titre in syphilis management is controversial, and further studies are needed to confirm our finding.

The findings of our study should be seen in light of some limitations. First, it goes without saying that retrospective studies are subject to innate bias. The data were collected retrospectively from the patients’ electronic medical records, and in some cases, they were lacking. Second, the study was carried out in a single healthcare centre, and the conclusions drawn might not be representative of the general population. In our database, data for sexual risk behaviours were not always recorded, and a proportion of patients, especially in the HIV-negative group, were lost to follow-up, reducing the number of evaluable data on treatment response. Lastly, 24-month follow-up visits are routinely scheduled in our centre, but the available data were not sufficient to be considered in this study. Nonetheless, the study’s main strength is the large sample size and the comparability between the HIV-positive group and the control group. Moreover, a single health centre study ensures a unique interpretation of the most recent guidelines, resulting in a specific and shared way of treating patients and scheduling follow-up visits. Our findings should, therefore, be confirmed by further studies.

5. Conclusions

Syphilis rates have continued to rise in recent years. To control this epidemic, patients at risk must follow up with periodical screening, and tests must be correctly interpreted to provide appropriate treatment. Interpretations of syphilis serology can be challenging, and misinterpretation may result in undertreatment or overtreatment. HIV infection status should not be considered a factor influencing the choice of treatment or altering the interpretation of the serological results, even in the case of repeated episodes of syphilis. Regarding the serological response to treatment, PLWH probably need more time to obtain an adequate response, once more confirming the importance of chronic follow-up both to assess the response to treatment and to track reinfection earlier.

Acknowledgments

Not applicable.

Funding Statement

This paper was supported with an unconditional grant from GILEAD.

Author Contributions

E.Q.-R.: Conceptualization and supervision; V.M., G.T. and E.Q.-R.: Methodology and original draft preparation; S.C.: formal statistical analysis; F.V.: Data curation; M.G.: Data collection and supervision; V.M., G.T., S.S., M.D.A., S.C., M.G., F.V., E.F., A.M., F.C. and E.Q.-R.: software, validation, investigation, resources, and writing—review & editing. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of or Hospital (code number NP 4847).

Informed Consent Statement

Data availability statement, conflicts of interest.

The authors declare no conflict of interest.

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