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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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• Mayo Clinic Minute: Syphilis surge is cause for concern Feb. 03, 2024, 12:00 p.m. CDT
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Syphilis is an infectious disease caused by a germ (bacterium) called Treponema pallidum . There are several stages of syphilis. The earliest stage usually causes an ulcer on your genital region. If the infection is not successfully treated, you can go on to develop symptoms in other parts of your body.

In this article

Syphilis symptoms, how do you get syphilis, classification of syphilis, syphilis symptoms in detail, how is syphilis diagnosed, are any other tests needed, syphilis treatment, can syphilis be prevented, what should i do if i think i have syphilis, what is syphilis.

The symptoms of syphilis infection vary depending on how long ago you were infected. You can find out more about the symptoms of each stage in detail later in this leaflet, but in summary the symptoms include:

Primary syphilis (2-3 weeks to three months after contact with the germ)

One or more ulcers on your genital region or mouth, which are usually painless and go away on their own after about six weeks.

Secondary syphilis (if the infection wasn't treated, usually a month after first contact)

This is a non-painful rash, especially on hands and feet; feeling generally unwell and tired; swollen glands; joint pains and warty lumps on the genitals.

Tertiary syphilis (many years after first infection)

This is a serious complication affecting the nervous system, heart, blood vessels and skin.

What does syphilis look like?

The first two images below show what primary syphilis looks like.

The first image (below) shows white skin on the penis, with a single ulcer sitting in the middle of a reddened area.

Syphilis single chancre - primary infection

By Original uploader Pygmalion at German Wikipedia, CC BY-SA 3.0 , via Wikimedia Commons

The next image also shows primary syphilis but there are two ulcers visible on the black skin of the penis.

Syphilis chancres - primary infection

By CDC/M. Rein, VD, Public domain, via Wikimedia Commons

The next image shows the rash on the palm of the hands and fingers in secondary syphilis.

Syphilis - secondary infection presentation

By CDC/Robert Sumpter, Public domain, via Wikimedia Commons

Sexual contact with an infected person

of people would be worried about contracting syphilis from a casual sexual encounter.

Source: Patient Sexual Health Survey

Syphilis is a sexually transmitted infection (STI). The infection is passed from person to person through contact with a syphilis sore (ulcer) - described below. So, depending where the ulcer is, the infection can be passed on during vaginal, anal, or oral sex without a condom.

Syphilis is one of the less common STIs in the UK. The number of cases are, however, rising. In the UK, the rates of infection are highest amongst men who have sex with men.

Syphilis is much more common in countries outside the UK, especially in developing parts of the world.

Note : syphilis is not spread by toilet seats, door knobs, bathtubs, shared clothing or eating utensils, etc. You need to have very intimate and direct contact with an infected person.

Syphilis infection in pregnancy

If you have syphilis and become pregnant, you can pass on syphilis to your unborn baby (fetus). It is passed on via the placenta. Infection in the fetus can lead to serious problems in pregnancy (see later) and/or congenital syphilis .

Blood transmission

Syphilis is also transmitted in the blood. Syphilis can be transmitted through receiving infected blood products (a blood transfusion). In the UK, all blood products are rigorously screened for infections, including syphilis and human immunodeficiency virus (HIV) . However, syphilis can also be passed from person to person through sharing needles between injecting intravenous drug users (IVDUs).

Syphilis infection is divided up into:

Acquired syphilis

This is generally transmitted through sex with an infected partner. There are several stages:

• Primary syphilis . This is the earliest stage and generally occurs from ten days to three months after infection. It typically causes a painless ulcer on your genitals.
• Secondary syphilis . This is the second stage of syphilis. Many different symptoms can occur (see later) but usually last several weeks. They can, however, come and go for up to two years.
• Early latent syphilis . This lasts for a year or so and you are still infectious - that is, you can pass syphilis on to other people.
• Late latent syphilis . About two years after secondary syphilis has cleared you can become non-infectious and are no longer able to pass syphilis on to others.
• Tertiary syphilis . This is the final stage of syphilis. It can affect many organs of the body, including your brain and heart. It can result in death.

Congenital syphilis

This means syphilis infection that is passed from a pregnant mother to her unborn baby. It is divided into:

• Early congenital syphilis. This is diagnosed in the first two years of life.
• Late congenital syphilis. This is diagnosed after the age of 2 years.

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What are the stages of syphilis?

If left untreated, the infection typically follows the pattern of four stages as described above - primary, secondary, latent and final-stage (tertiary) syphilis. Neurosyphilis (syphilis affecting your brain) is considered separately, as it can occur at any stage of syphilis.

Primary syphilis

Typically, one small ulcer (sore) develops where syphilis germs (bacteria) enter your body. This ulcer is called a chancre. It is commonly on the penis in men, on the vulva or vagina in women, or on the back passage (anus) in either men or women. The ulcer usually appears about 2-3 weeks after having sex with an infected person but it may appear at any time up to three months later.

The ulcer is usually painless and about the size of a small coin. A clear fluid (serum) oozes from the ulcer. This fluid is highly infectious and teeming with germs. The ulcer lasts up to six weeks, then heals - but this does not mean the infection has gone.

When you have a syphilis ulcer, the nearby glands (lymph nodes) in your groin may swell. These feel like small lumps at the top of your legs in the groin crease.

Sometimes the primary stage is non-typical. For example:

• You may have more than one ulcer.
• The ulcer may be painful.
• Pus may come from an ulcer.
• The ulcer may be in your mouth (if you catch the infection during oral sex), or in the rectum (from anal sex).
• The ulcer may be on the cervix in women and is not seen or felt.
• You may have no symptoms, or very mild symptoms that you take little notice of.

People with HIV infection as well as syphilis tend to get multiple, deep, large chancres.

Secondary syphilis

If the primary ulcer is not treated, or not noticed, the germs may spread to many parts of your body. Symptoms of secondary syphilis may then develop. These tend to appear a few weeks after the ulcer has healed but may develop whilst the ulcer is healing. Symptoms of secondary syphilis are numerous and vary from person to person. Some symptoms are nonspecific and are similar to those that can occur with other medical problems.

Symptoms of secondary syphilis may include:

• Rash . This is a common symptom of secondary syphilis. The rash consists of dark patches that appear on your skin, each about the size of a penny. The rash may occur in many areas of the body, or be only in a few areas. However, the palms of the hands and the soles of the feet are almost always involved. The rash is not usually itchy or painful.
• Condylomata lata are wart-like growths that may develop around the penis in men, or vagina in women.
• A feeling of 'unwellness' (general malaise) and tiredness (lethargy).
• Mild high temperature (mild fever) and headaches are common.
• Sore throat .
• Joint pains.
• Swollen lymph nodes may develop in various places in your body (such as your groin, armpits or neck).
• Patchy hair loss (alopecia) can occur but is not that common.
• Less commonly, inflammation may develop in other parts of your body such as the liver, eyes, brain, or kidneys.

Without treatment, the rash and other symptoms from secondary syphilis usually go after several weeks. However, they may come and go for up to two years.

Latent syphilis

After the symptoms of secondary syphilis have cleared, you may not have any symptoms for several years. In this 'hidden' (latent) period you may think that the disease has gone. In some cases, there is no further development. In the first year or so of latent syphilis you can still pass the infection on. After this time, you are no longer infectious to others but you still have syphilis infection. If left untreated, the germs can slowly damage various parts of your body and symptoms of the final (tertiary) stage may eventually appear.

Tertiary syphilis

Tertiary syphilis can develop many years after the initial syphilis infection. Some manifestations of the disease can occur up to 50 years later. Many of these complications are potentially very serious and can make you extremely unwell. Some problems are life-threatening and can lead to death if untreated.

Syphilis is not considered to be infectious in its tertiary stage. Tertiary complications are slowly progressive and can affect any organ of your body.

Tertiary syphilis may cause several types of complications:

• Brain (neurological) complications . This is also called neurosyphilis (see next section).
• Cardiovascular complications . These are problems affecting your heart and blood vessels (the cardiovascular system). Most commonly, syphilis affects the main blood vessel leading out of your heart (the aorta). Inflammation here can cause weakening of your aorta, which can stretch, forming an aneurysm. Aneurysms have thin weak walls and can burst (rupture), potentially leading to death. Even if an aneurysm does not rupture, it can seriously affect one of your heart valves (the aortic valve), leading to a heart murmur. In turn, the heart does not pump very well and becomes swollen (distended) with blood. This condition is known as heart failure. See the separate leaflets called Congestive Heart Failure and Anatomy of the heart for more details.
• Gummatous disease . Gummas are soft growths (tumours) caused by inflammation. They are not cancerous (malignant) tumours but are long-term (chronic) and can affect any part of the body. They can grow on your skeleton and affect your joints; they can also cause large lumps in or under the skin. Gummas can grow on your internal organs (such as your liver) and affect organ function. Quite commonly they appear on your leg, below your knee. Gummas may be single or multiple and can vary in size between one and several centimetres. They can cause bone pain at night and the chronic inflammation can cause a high temperature and a low blood count (anaemia).

Neurosyphilis

This means that the syphilis infection is affecting your central nervous system (CNS). The CNS includes your brain, your spinal cord and their coverings (the meninges).

Neurosyphilis can occur at any stage of syphilis infection . However, commonly it is thought of as a tertiary complication, occurring late on in untreated disease. Neurosyphilis is generally a slow and gradual loss of mental and physical function, with alterations in mood and personality. It is possible to have a more acute illness which is quicker in onset and more severe. On average it occurs between one and ten years after the initial infection.

Neurosyphilis used to be a lot more common in the days before antibiotic treatment was widely available. Probably between 2 and 4 people in every 10 with syphilis infection, developed neurosyphilis. Neurosyphilis is now more common in people who also have HIV infection.

The four main types of neurosyphilis are:

• Asymptomatic neurosyphilis (no symptoms). Before effective antibiotic treatment was available, 3-4 people in every 10 with secondary syphilis had neurosyphilis which did not cause any symptoms.
• Meningovascular syphilis . This involves inflammation of the coverings and small blood vessels in your brain. On average, this complication occurs about seven years after initial syphilis infection. It can cause headaches and dizziness and can result in a stroke. Meningitis - inflammation of the coverings of the brain (the meninges) - can also occur as a more sudden-onset (acute) complication. Total loss of vision (severe sight impairment) and deafness can also occur.
• General paresis . This is also known (historically) as 'general paresis of the insane'. It is a chronic dementia that represents a severe complication of neurosyphilis, usually in its late stages. On average, death follows within only 2-3 years. There is progressive personality change, memory loss and confusion. Sometimes depression or hallucinations occur.
• Tabes dorsalis . This is another, late form of neurosyphilis, more common before antibiotic treatment. The nerves in the spinal cord are damaged, leading to poor balance and co-ordination and problems with walking. Additionally, there is loss of pain and temperature sensation in the feet. As a result, deep foot ulcers can occur.

Syphilis in pregnancy and congenital syphilis

Syphilis infection can be passed from a pregnant mother to her unborn baby (fetus), via the placenta. This can result in serious pregnancy complications such as:

• Miscarriage . This means death of the fetus before 24 weeks of gestation.
• Stillbirth. This means death of the fetus after 24 weeks of gestation.
• Hydrops. This is a condition of severe swelling due to fluid (oedema) in the fetus. It is a serious condition that can result in death of the fetus.
• Placental abruption (where the placenta suddenly detaches from the uterus).
• Postpartum haemorrhage (PPH) when there is excessive bleeding at delivery.
• Preterm (premature) labour . This is labour and delivery of the baby before 37 weeks of gestation.

Congenital syphilis is syphilis infection in the baby or the child, transmitted from the mother. It is divided into early and late cases, dependent on when the child shows symptoms of syphilis infection. (See 'Classification of syphilis' section, above.)

Early symptoms and signs of untreated congenital syphilis occur before the age of 2 years. They include:

• Rashes - typically a peeling rash of the palms, the soles and around the mouth and back passage (anus).
• An enlarged liver and/or spleen.
• Abnormal bone X-rays.
• Enlarged glands (lymph nodes).
• Yellowing of the skin or the whites of the eyes (jaundice).

Late congenital syphilis is rare. It can cause symptoms similar to neurosyphilis in an adult. Problems affecting the eyes and joints are seen, as well as deafness, gummas and dental abnormalities.

Syphilis can be difficult to diagnose just based on symptoms. This is because there are very many different symptoms and often these symptoms can occur with other conditions. This is why syphilis used to be called 'the Great Imitator' because it mimics many other illnesses.

Now, however, there are specific tests for syphilis. So, as long as it is suspected as a possibility, it can be easily diagnosed with a syphilis test.

Genitourinary medicine (GUM) clinics often also perform STI screening in order to look for other sexually transmitted infections. Testing for syphilis is part of this. There are two main types of test:

• A small sample (swab) from the sore can be looked at under the microscope. The typical germs (bacteria) can be seen.
• If the sore (ulcer) has gone, a blood test can detect if you have syphilis. The blood test looks for proteins in your blood, called antibodies. These antibodies are made by your immune system in order to fight infection. The antibody test can be positive or negative. A negative result might mean the test has been carried out too early. It can take a while for the antibodies to be present in the blood. If this is the case, a repeat test will usually be advised after a period of about three months. A positive test will either mean that you have syphilis or have had syphilis in the past.

Additionally, all pregnant women are screened for syphilis. This is part of the routine antenatal blood tests that are usually done between 8 and 16 weeks of pregnancy.

In primary and secondary syphilis, generally no other tests are required. However, in the final stage (tertiary syphilis), where there are complications affecting other parts of the body, further tests may be required.

Other tests may include a chest X-ray or ultrasound of the heart (echocardiogram, or 'echo') in cardiovascular syphilitic disease. Brain scans (such as computerised tomography (CT) or magnetic resonance imaging (MRI) may be needed if there is suspected brain (neurological) involvement.

Because syphilis is caused by bacteria (germs), it is treatable with antibiotics.

• Antibiotic injections are the usual treatment. Benzathine or procaine penicillin are the antibiotics usually used. This kills the syphilis bacteria and prevents the disease from progressing any further. The injections are given intramuscularly (IM), usually into the buttock. A single dose can be given for primary and secondary syphilis. Later stages may need a course of three injections, at weekly intervals. Neurosyphilis usually requires more frequent, daily doses for a couple of weeks.
• Other antibiotics are sometimes used if you are allergic to penicillin. Azithromycin may be used in this situation but there is an increasing problem of resistance to this type of antibiotic.

Note : it is important to avoid any type of sexual activity until the syphilis sores are completely healed and until two weeks have passed after your treatment was completed.

Remember : it is not just penetration and ejaculation that lead to transmission of syphilis. It is caught by close skin-to-skin (sexual) contact with the oozing fluid (serum) from the ulcer (chancre).

Treatment during the primary or secondary stages of the disease will usually prevent any permanent long-term damage.

Some of the problems associated with the final stage (tertiary syphilis) cannot be completely cured with antibiotics. However, antibiotic treatment may prevent further worsening of your condition. Heart and blood vessel (cardiovascular) complications may still become worse, despite treatment.

If you have syphilis, you should usually be investigated , treated and followed up by a GUM clinic. If you have caught syphilis, there is a good chance that you may also have another STI. A GUM clinic will take small samples (swabs) and blood tests to exclude other STIs such as chlamydia, gonorrhoea and HIV. Local and national information is also available on the internet - for example, from the Family Planning Association's 'Find a clinic' service.

The GUM clinic can organise contact tracing. This means informing your previous sexual partners (confidentially and anonymously) that they need testing for STIs, including syphilis. This is especially important if you are unable or unwilling to do this yourself.

It is important to tell your current sexual partner(s) so that they can also be tested and treated if necessary.

If you practise safe sex, and always use a condom , your risk of catching syphilis (and other STIs) is very much reduced. However, condoms do not provide complete protection, as syphilis ulcers can sometimes be on areas not covered by a condom.

If you have had syphilis and had it treated, you can still be re-infected if you have sex with an infected person. (The antibodies in your blood are not sufficient to protect you from another infection if you come into contact with syphilis again.)

If you suspect that you have syphilis, or another STI, see your GP or contact your local GUM clinic.

In the UK you can go to the local GUM clinic without a referral from your GP and many clinics offer a 'walk-in' service. All treatment at a GUM clinic is completely confidential and your GP does not have to be informed, if you do not wish them to be. (However, sometimes this can be very helpful as part of your continuing 'whole body' (holistic) medical care.) You can find out where your nearest GUM clinic is by the following methods:

• Asking your GP practice.
• Contacting your local hospital.
• Checking in the telephone directory.
• Search the NHS 'Find a clinic' service.

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Further reading and references

UK national guidelines on the management of syphilis 2015 ; British Association for Sexual Health and HIV (2015, updated 2019)

Syphilis ; NICE CKS (Clinical Knowledge Summaries) December 2019. UK access only.

O'Byrne P, MacPherson P ; Syphilis. BMJ. 2019 Jun 28365:l4159. doi: 10.1136/bmj.l4159.

Hussain SA, Vaidya R ; Congenital Syphilis

Tracking the syphilis epidemic in England: 2010 to 2019 ; An update on progress towards the Syphilis Action Plan prevention priorities, Public Health England, January 2021

WHO Guideline on Syphilis Screening and Treatment for Pregnant Women ; Recommendations on syphilis screening and treatment for pregnant women, World Health Organization, 2017

Satyaputra F, Hendry S, Braddick M, et al ; The Laboratory Diagnosis of Syphilis. J Clin Microbiol. 2021 Sep 2059(10):e0010021. doi: 10.1128/JCM.00100-21. Epub 2021 May 12.

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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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• Published: 12 October 2017
• Rosanna W. Peeling 1 ,
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• Mary L. Kamb 2 ,
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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-d213640486e3628">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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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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Syphilis numbers still high in Idaho as states grapple with less funding for prevention

This story originally appeared in The Idaho Press

In the '90s, the U.S. had almost completely eliminated cases of syphilis, a sexually transmitted disease that can be devastating if left untreated.

Today, rates of syphilis in the U.S. are at a 74-year high; rates increased 80% between 2018-2022, according to data published by the Centers for Disease Control in January.

Though Idaho’s incidence rate is lower than the nation, and peaked in 2022, the state continues to see high levels of cases, local public health experts told the Idaho Press. And while additional federal funding was given to states to keep cases in check in 2021, federal leaders decided to rescind it in summer 2023, leaving health districts in Idaho and nationwide to determine how to fund such efforts going forward.

Local public health leaders told the Idaho Press about the rise of the infection in Idaho, and how to prevent its spread.

A ‘SNEAKY’ INFECTION

Syphilis is a sexually transmitted infection, or STI, caused by the bacterium Triponema pallidum. Most prominent symptoms occur in the early stages of the disease, in the first year following exposure, said Jessica McClenahan, a staff epidemiologist with Central District Health, the health district covering Ada, Boise, Elmore, and Valley counties.

Syphilis is transmitted through skin-to-skin contact with an infected person’s chancre, a type of ulcer and early indication of infection.

Other symptoms can include swollen lymph nodes, white patches in the mouth, and a rash on the palms and soles of feet, although McClenahan said people are more frequently reporting the rash on their trunk and extremities instead. The rashes people get are not infectious, she said.

“There are always caveats with syphilis, and we are continually humbled by the sneaky, strange things it does to people,” McClenahan said.

If a pregnant person has syphilis, they are at risk of transmitting the bacteria to the fetus. Symptoms in newborns include deafness and blindness, but babies can be born without symptoms and develop complications later, she said.

Syphilis is treatable with penicillin, but if left untreated, it can enter a latent phase where it stays in the body, sometimes emerging decades later, causing complications like damage to the eyes, ears, and other organs .

But sometimes people skip the latent phase, with the worst complications appearing within the first year, McClenahan said.

In general, people with multiple sexual partners should get full STI testing every six months, including blood work, said Heather Averett, a disease intervention specialist with Southwest District Health.

Using condoms and dental dams during sexual contact helps prevent syphilis’s spread, Averett said.

“If they are consistent in that use, they are protecting themselves,” she said.

McClenahan noted that condom use was popularized in 1500s Europe, not to prevent pregnancies, but to prevent syphilis.

SYPHILIS IN IDAHO

As a disease intervention specialist, Averett spends her day investigating potential cases of syphilis, HIV, and other sexually transmitted infections for Southwest District Health, the health district that encompasses Canyon, Owyhee, Adams, Gem, Payette, and Washington counties.

For Averett, that involves looking at lab results, trying to determine the stage of a person’s syphilis, and referring them and their sexual partners to treatment, she said.

Averett’s position was made possible with increased funding from the Centers for Disease Control to track and prevent the spread of STIs like syphilis.

Health districts had leeway to use the funding as they saw fit, with Central District Health electing to have their disease intervention specialist do educational presentations in schools and juvenile detention centers, said Surabhi Malesha, program manager for communicable diseases with the district.

States have received federal funding for years to fund prevention of sexually transmitted infections, said Lindsay Haskell, a health programs specialist with the Idaho Department of Health and Welfare. In 2021, part of the American Rescue Plan Act directed additional funds toward STI prevention.

In 2020, public health entities were tasked with mitigating the effects of the COVID-19 pandemic, leaving few people to focus on STIs like syphilis, McClenahan said.

Idaho’s health districts are funded by the Idaho Department of Health and Welfare, which is funded entirely with federal money, Haskell said. The infusion of additional federal dollars helped health districts locally and nationally to respond to the rise in syphilis, she said.

Southwest District Health declared an outbreak in Feb. 2021 . That year, 43 people had tested positive for syphilis by July, compared to just 18 total in 2017. The district said the outbreak was over in October 2023, as cases dropped to a level that is considered contained, Averett said.

Idaho’s syphilis cases peaked in 2022, with 183 early-stage cases and 169 late or unknown stage cases, according to data from the Idaho Department of Health and Welfare. The following year saw 110 early-stage cases and 98 late or unknown-stage cases.

QUESTIONS OF FUTURE FUNDING

Through the American Rescue Plan Act, Idaho was to receive an additional $5 million in funds to use for STI prevention and mitigation through 2025, Haskell said.

But in 2023, as part of a legislation to address the debt ceiling, the federal government rescinded subsequent funding for the program, according to reporting by the Associated Press . And because published data of STIs lags by a year, public health officials across the country are concerned that case numbers for 2023 could worsen, according to reporting by National Public Radio .

Idaho received $3 million of the $5 million, and has through 2025 to use it, Haskell said. After that time, the health department will have to get creative to decide how it will fund work like Averett’s.

“We’re not sure what that will look like on an ongoing basis,” Haskell said, “and any time we’re using other funding streams, those other projects we had planned may not come to fruition.”

Some of Haskell’s colleagues at the national level are also pushing for additional federal funding to continue supplementing disease intervention programs, she said.

HOPE IN EDUCATION

McClenahan, the epidemiologist with Central District Health, emphasized that getting an STI is “very, very common.” Having an STI does not define someone, nor does it reflect their identity or character, she said.

“The current rates of STIs are more a reflection of lack of access to care and education than some sort of national moral failure,” she said. “We’re hardwired to seek connection and pleasure, and so I think if we bring it to the surface, and talk about it, and normalize sexual health as part of your emotional and physical health, overall, that will make more gains in reducing the STI epidemic.”

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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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Rapid rise in syphilis hits native americans hardest.

From her base in Gallup, New Mexico, Melissa Wyaco supervises about two dozen public health nurses who crisscross the sprawling Navajo Nation searching for patients who have tested positive for or been exposed to a disease once nearly eradicated in the U.S.: syphilis.

Infection rates in this region of the Southwest — the 27,000-square-mile reservation encompasses parts of Arizona, New Mexico, and Utah — are among the nation’s highest. And they’re far worse than anything Wyaco, who is from Zuni Pueblo (about 40 miles south of Gallup) and is the nurse consultant for the Navajo Area Indian Health Service, has seen in her 30-year nursing career.

Syphilis infections nationwide have climbed rapidly in recent years, reaching a 70-year high in 2022, according to the most recent data from the Centers for Disease Control and Prevention. That rise comes amid a shortage of penicillin , the most effective treatment. Simultaneously, congenital syphilis — syphilis passed from a pregnant person to a baby — has similarly spun out of control. Untreated, congenital syphilis can cause bone deformities, severe anemia, jaundice, meningitis, and even death. In 2022, the CDC recorded 231 stillbirths and 51 infant deaths caused by syphilis, out of 3,761 congenital syphilis cases reported that year.

And while infections have risen across the U.S., no demographic has been hit harder than Native Americans. The CDC data released in January shows that the rate of congenital syphilis among American Indians and Alaska Natives was triple the rate for African Americans and nearly 12 times the rate for white babies in 2022.

“This is a disease we thought we were going to eradicate not that long ago, because we have a treatment that works really well,” said Meghan Curry O’Connell, a member of the Cherokee Nation and chief public health officer at the Great Plains Tribal Leaders’ Health Board, who is based in South Dakota.

Instead, the rate of congenital syphilis infections among Native Americans ( 644.7 cases per 100,000 people in 2022) is now comparable to the rate for the entire U.S. population in 1941 ( 651.1 ) — before doctors began using penicillin to cure syphilis. (The rate fell to 6.6 nationally in 1983.)

O’Connell said that’s why the Great Plains Tribal Leaders’ Health Board and tribal leaders from North Dakota, South Dakota, Nebraska, and Iowa have asked federal Health and Human Services Secretary Xavier Becerra to declare a public health emergency in their states. A declaration would expand staffing, funding, and access to contact tracing data across their region.

“Syphilis is deadly to babies. It’s highly infectious, and it causes very severe outcomes,” O’Connell said. “We need to have people doing boots-on-the-ground work” right now.

In 2022, New Mexico reported the highest rate of congenital syphilis among states. Primary and secondary syphilis infections, which are not passed to infants, were highest in South Dakota , which had the second-highest rate of congenital syphilis in 2022. In 2021, the most recent year for which demographic data is available, South Dakota had the second-worst rate nationwide (after the District of Columbia) — and numbers were highest among the state’s large Native population .

In an October news release , the New Mexico Department of Health noted that the state had “reported a 660% increase in cases of congenital syphilis over the past five years.” A year earlier, in 2017, New Mexico reported only one case — but by 2020, that number had risen to 43, then to 76 in 2022.

Starting in 2020, the covid-19 pandemic made things worse. “Public health across the country got almost 95% diverted to doing covid care,” said Jonathan Iralu, the Indian Health Service chief clinical consultant for infectious diseases, who is based at the Gallup Indian Medical Center. “This was a really hard-hit area.”

At one point early in the pandemic, the Navajo Nation reported the highest covid rate in the U.S. Iralu suspects patients with syphilis symptoms may have avoided seeing a doctor for fear of catching covid. That said, he doesn’t think it’s fair to blame the pandemic for the high rates of syphilis, or the high rates of women passing infections to their babies during pregnancy, that continue four years later.

Native Americans are more likely to live in rural areas , far from hospital obstetric units , than any other racial or ethnic group. As a result, many do not receive prenatal care until later in pregnancy, if at all. That often means providers cannot test and treat patients for syphilis before delivery.

In New Mexico, 23% of patients did not receive prenatal care until the fifth month of pregnancy or later, or received fewer than half the appropriate number of visits for the infant’s gestational age in 2023 (the national average is less than 16%).

Inadequate prenatal care is especially risky for Native Americans, who have a greater chance than other ethnic groups of passing on a syphilis infection if they become pregnant. That’s because, among Native communities, syphilis infections are just as common in women as in men. In every other ethnic group , men are at least twice as likely to contract syphilis, largely because men who have sex with men are more susceptible to infection. O’Connell said it’s not clear why women in Native communities are disproportionately affected by syphilis.

“The Navajo Nation is a maternal health desert,” said Amanda Singer, a Diné (Navajo) doula and lactation counselor in Arizona who is also executive director of the Navajo Breastfeeding Coalition/Diné Doula Collective. On some parts of the reservation, patients have to drive more than 100 miles to reach obstetric services. “There’s a really high number of pregnant women who don’t get prenatal care throughout the whole pregnancy.”

She said that’s due not only to a lack of services but also to a mistrust of health care providers who don’t understand Native culture. Some also worry that providers might report patients who use illicit substances during their pregnancies to the police or child welfare. But it’s also because of a shrinking network of facilities: Two of the Navajo area’s labor and delivery wards have closed in the past decade. According to a recent report , more than half of U.S. rural hospitals no longer offer labor and delivery services.

Singer and the other doulas in her network believe New Mexico and Arizona could combat the syphilis epidemic by expanding access to prenatal care in rural Indigenous communities. Singer imagines a system in which midwives, doulas, and lactation counselors are able to travel to families and offer prenatal care “in their own home.”

O’Connell added that data-sharing arrangements between tribes and state, federal, and IHS offices vary widely across the country, but have posed an additional challenge to tackling the epidemic in some Native communities, including her own. Her Tribal Epidemiology Center is fighting to access South Dakota’s state data.

In the Navajo Nation and surrounding area, Iralu said, IHS infectious disease doctors meet with tribal officials every month, and he recommends that all IHS service areas have regular meetings of state, tribal, and IHS providers and public health nurses to ensure every pregnant person in those areas has been tested and treated.

IHS now recommends all patients be tested for syphilis yearly, and tests pregnant patients three times. It also expanded rapid and express testing and started offering DoxyPEP, an antibiotic that transgender women and men who have sex with men can take up to 72 hours after sex and that has been shown to reduce syphilis transmission by 87% . But perhaps the most significant change IHS has made is offering testing and treatment in the field.

Today, the public health nurses Wyaco supervises can test and treat patients for syphilis at home — something she couldn’t do when she was one of them just three years ago.

“Why not bring the penicillin to the patient instead of trying to drag the patient in to the penicillin?” said Iralu.

It’s not a tactic IHS uses for every patient, but it’s been effective in treating those who might pass an infection on to a partner or baby.

Iralu expects to see an expansion in street medicine in urban areas and van outreach in rural areas, in coming years, bringing more testing to communities — as well as an effort to put tests in patients’ hands through vending machines and the mail.

“This is a radical departure from our past,” he said. “But I think that’s the wave of the future.”

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF .

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Neurosyphilis, Ocular Syphilis, and Otosyphilis

Neurosyphilis, ocular syphilis, otosyphilis, evaluation and treatment, for more information.

• Be aware of neurosyphilis, ocular syphilis, and otosyphilis.
• Screen for neurologic, visual, and auditory signs and symptoms in patients at risk for syphilis (e.g., men who have sex with men, people with HIV, and people with multiple or anonymous partners).
• Screen patients for syphilis if they present with neurologic, visual, or auditory complaints.
• Conduct a careful neurological exam, including an evaluation of all cranial nerves, for patients with reactive nontreponemal and treponemal serology and clinical signs of early syphilis.
• Conduct an immediate ophthalmologic evaluation for patients with syphilis and ocular complaints.
• Evaluate and manage patients with syphilis and otologic symptoms in collaboration with an otolaryngologist.

Neurosyphilis is a result of invasion of the central nervous system by Treponema pallidum, which can occur at any stage of syphilis. It is unknown whether certain T. pallidum  strains are neurotropic.

Early neurologic clinical manifestations (e.g., cranial nerve dysfunction, meningitis, meningovascular syphilis, stroke, and altered mental status) are usually present within the first few months or years of infection. Late neurologic manifestations (e.g., tabes dorsalis and general paresis) occur 10–30 years after infection but can occur earlier in people who are immunocompromised.

Invasion of cerebrospinal fluid (CSF) by T. pallidum can occur during any stage of syphilis and CSF laboratory abnormalities are common among people with early syphilis regardless of neurologic signs or symptoms. No evidence supports variation from the CDC-recommended treatment regimen for syphilis at any stage for people without clinical neurologic findings. If clinical signs or symptoms of neurologic involvement are present (e.g., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, or motor or sensory deficits), CSF examination should be performed.

Infection of the visual system (ocular syphilis) or auditory system (otosyphilis) can also occur at any stage of syphilis.

Ocular syphilis can occur at any stage of syphilis, with variable clinical presentations, including isolated ocular abnormalities or with neurologic manifestations. Ocular syphilis can involve almost any eye structure, but posterior uveitis and panuveitis are the most common clinical manifestations. Additional ocular manifestations may include anterior uveitis, optic neuropathy, retinal vasculitis, and interstitial keratitis. Ocular syphilis may lead to decreased visual acuity with subsequent permanent blindness.

Ocular syphilis may be the initial presentation of syphilis in a patient. Screening for syphilis should be considered in new onset vision changes.

Otosyphilis is caused by an infection of the cochleovestibular system with T. pallidum and typically presents with sensorineural hearing loss, tinnitus, or vertigo. Hearing loss can be unilateral or bilateral, have a sudden onset, and progress rapidly. Otosyphilis can result in permanent hearing loss.

Otosyphilis may be the initial presentation of syphilis in a patient. Screening for syphilis should be considered in new onset sensorineural hearing loss, tinnitus, and vertigo.

Patients who present with otosyphilis may also have manifestations of ocular and neurosyphilis (especially involving cranial nerve VIII) and should be evaluated accordingly.

Patients who receive a diagnosis of syphilis and have neurologic, ocular, and/or otologic symptoms should be evaluated for neurosyphilis, ocular syphilis, or otosyphilis according to their clinical presentation.

Patients who have syphilis and symptoms or signs suggestive of neurologic disease (e.g., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, or motor or sensory deficits) should have an evaluation that includes CSF analysis before treatment. Patients with syphilis who have symptoms or signs of ocular syphilis (e.g., uveitis, iritis, neuroretinitis, or optic neuritis) should have a full ocular slit-lamp and ophthalmologic examination, including a thorough cranial nerve evaluation; if cranial nerve dysfunction is present, CSF examination is indicated.

Patients with syphilis, isolated ocular symptoms (no cranial nerve dysfunction or other neurologic abnormalities), and confirmed ocular abnormalities on examination, CSF analysis is not necessary before treatment. CSF examination may be helpful in evaluating patients with syphilis who have ocular symptoms and do not have abnormalities on ocular examination.

Patients with syphilis, isolated auditory symptoms, and normal neurologic examination, CSF examination is not recommended before treatment since it is usually normal. If there are signs and symptoms of otosyphilis, then otologic examination is needed.

All patients with syphilis should receive an HIV test if status is unknown or previously HIV-negative.

Treatment for neurosyphilis should be managed according to the STI Treatment Guidelines, 2021 – Neurosyphilis, Ocular Syphilis, and Otosyphilis .

Ocular syphilis should be managed in collaboration with an ophthalmologist; immediate referral to an ophthalmologist is critical if ocular syphilis is suspected. Patients diagnosed with ocular syphilis should be managed according to the STI Treatment Guidelines, 2021 – Neurosyphilis, Ocular Syphilis, and Otosyphilis .

Otosyphilis should be managed in collaboration with an otolaryngologist. Treatment for otosyphilis should follow the STI Treatment Guidelines, 2021 – Neurosyphilis, Ocular Syphilis, and Otosyphilis .

Repeat CSF examinations are not necessary for patients without HIV infection or among patients with HIV infection who are on antiretroviral therapy and who exhibit serologic and clinical responses after treatment.

In 2018, the Council of State and Territorial Epidemiologists revised the syphilis case definition to include neurosyphilis related variables : neurologic, ocular, and otic manifestations.  Cases should be reported according to stage of infection and the clinical manifestations should be reported with the case report data. Healthcare providers should follow state or local health department’s guidance for reporting clinical manifestations of cases of syphilis.

CDC is conducting a study on ocular syphilis to determine whether specific molecular strain types of T. pallidum are associated with this type of syphilis. Healthcare providers with patients suspected of ocular syphilis can collect clinical specimens for molecular typing. Pre-antibiotic residual clinical samples (whole blood in EDTA tubes, exudate or tissue from primary and secondary lesions, CSF or ocular fluid) collected as part of routine clinical testing should be saved and stored at -80°C immediately upon collection for molecular typing.

For assistance with the collection procedure or shipment of samples, please contact Dr. Allan Pillay at 404-639-2140 or [email protected] . Submitters should notify CDC and their respective state and local public laboratory prior to sending specimens.

For additional laboratory considerations, see the Sexually Transmitted Infections Treatment Guidelines, 2021 .

Healthcare providers needing CDC advice on the clinical management of neurosyphilis, ocular syphilis, or otosyphilis can contact:

CDC-INFO 1-800-CDC-INFO (800-232-4636) TTY: 1-888-232-6348 In English , en Español

• Statement from CSTE on 2018 update to syphilis case definition pdf icon external icon
• 2021 STI Treatment Guidelines
• Ocular Syphilis — Eight Jurisdictions, United States, 2014–2015 MMWR November 4, 2016
• Keep an Eye Out For Ocular Syphilis external icon – Tom Peterman, MD, MSc; Kimberly Workowski, MD Medscape CDC Expert Commentary (Requires free membership to access commentary) (February 8, 2016)
• Notes from the Field: A Cluster of Ocular Syphilis Cases — Seattle, Washington, and San Francisco, California, 2014–2015  MMWR October 16, 2015
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• Patient-Centered Care – New Challenges in the Face of Chronic Conditions - 12/13/2017

Education | Virtual

Event Title Patient-Centered Care – New Challenges in the Face of Chronic Conditions December 13, 2017

Yale university – mayo clinic cersi, thursday, december 14, 2017  , presented by:.

Victor M. Montori, MD Professor of Medicine Mayo Clinic

About the Presentation

The care of patients with chronic conditions presents a challenge to the practice of medicine. In these cases, identifying the necessary evidence and translating it to improve patient care can be difficult. The questions facing patients and clinicians – such as what is best for me and for my family? – cannot be answered with confidence because of uncertainty about the relative impact of available interventions, uncertainty about what patients value in their life and for their care, and uncertainty about the impact of care on their lives and vice versa. Clinical science has responded with two innovations: shared decision making and minimally disruptive medicine. In this lecture, Dr. Montori presented on what is and what is not shared decision making, what kind of evidence is required to support patients and clinicians, and what challenges are associated with providing minimally disruptive care, particularly for complex patients with multiple chronic conditions.

About the Presenter

Victor M. Montori, MD is a Professor of Medicine at Mayo Clinic. An endocrinologist and health services researcher, Dr. Montori is the author of more than 590 peer-reviewed publications and is among the top 1% of researchers with most cited papers in clinical medicine worldwide in the last decade. Previously a member of the National Advisory Council of the Agency for Healthcare Research and Quality, he is now a Senior Advisor in the Center for Evidence and Practice Improvement at the Agency. He also serves in the Editorial Advisory Board for the BMJ, and as Director of Late Stage Translational Research at the Mayo Center for Clinical and Translational Science. He is a recognized expert in evidence-based medicine and shared decision making, and developer of the concept of minimally disruptive medicine. He works in Rochester, Minnesota, at Mayo Clinic's KER Unit, to advance person-centered care for patients with diabetes and other chronic conditions. He is founder and chair of the board of The Patient Revolution, a nonprofit focused on advancing careful and kind care for all. He is the author of Why We Revolt–A Patient Revolution for Careful and Kind Care.

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Please contact Amal Manseur at [email protected] .

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• PMC10094745

Neurosyphilis-Induced Psychosis: A Unique Presentation of Syphilis With a Primary Psychiatric Manifestation

Zaid taki el-din.

1 Department of Psychiatry, St. George's University School of Medicine, West Indies, GRD

Humzah Iqbal

2 Department of Internal Medicine, University of California San Francisco Fresno, Fresno, USA

Anil Sharma

3 Department of Psychiatry, St. Francis Medical Center, Lynwood, USA

Syphilis is a predominantly sexually transmitted infection caused by the spirochete Treponema pallidum. The infection presents with four different stages and although rare, can lead to behavioral symptoms if not treated in its earliest form. It can cause psychosis, mania, depression, anxiety, and personality changes. Screening and early treatment of syphilis are essential in preventing neurosyphilis and its neuropsychiatric symptoms. Neurosyphilis is rarely the initial presentation of syphilis. This is a case report of a 30-year-old female with neurosyphilis who presented with psychosis as the primary presentation.

Introduction

Primary syphilis is a sexually transmitted infection (STI) that presents with a localized painless chancre, typically on the genitals. Secondary syphilis is characterized by a disseminated disease with constitutional symptoms, maculopapular rash, condylomata lata (smooth, painless, wart-like white lesions on genitals), and lymphadenopathy. The first two stages are followed by a latent, asymptomatic phase known as latent syphilis that can either resolve or progress to the tertiary stage leading to multi-organ dysfunction and central nervous system (CNS) abnormalities known as neurosyphilis [ 1 ]. Neuropsychiatric manifestations of syphilis are rare, due to the widespread use of penicillin and its efficacy in treating the disease. Patients most often present in an early stage of syphilis, and only 10%-15% of cases progress to tertiary syphilis [ 2 ]. Of these cases, less than 20% present with psychiatric symptoms, which can include paranoia, behavioral changes, hallucinations, mania, and cognitive impairment [ 2 , 3 ]. Psychosis as the initial presentation of syphilis is exceedingly rare and has only been reported in a handful of cases. We present a unique case of neurosyphilis diagnosed during an episode of psychosis.

Case presentation

A 30-year-old female patient was admitted to the hospital with a four-month history of suicidal ideation, anxiety, personality changes, and psychosis. The patient strongly believed that her family members and relatives were monitoring all of her movements and planning to kill her. She strongly suspected they were involved in a big conspiracy against her. She also reportedly engaged in violent behavior and aggression towards family members over the past several months. The patient's family reported that the patient's sleep had been disturbed, sometimes only sleeping three hours a night. The patient denied any drug or alcohol usage and denied any sexual activity for the past several years. Mental status examination (MSE) showed a disheveled young woman with pressured speech who had avoidant eye contact and was restless throughout the interview. The patient had an irritable mood, poor attention, and concentration. She had auditory hallucinations, delusions of persecution, and poor insight and judgment. She reported hearing "the man from the church" tell her "that she is a bad person" but denies suicidal or homicidal ideation. Per family, she was calm and amiable prior to a year ago. She became more easily agitated and angry, with some outbursts leading to physical altercations with family members. These altercations were unprovoked and followed an event "that she imagined in her head" per family. A careful review of the patient’s history revealed no history of psychiatric conditions and no history of STI.

The patient’s vital signs were within normal limits and the physical exam was unremarkable aside from MSE findings. Routine investigation of complete blood count, complete metabolic panel, urea, liver function tests, ammonia, urinalysis, thyroid profile, vitamin B12, and folic acid were all within normal limits. The urine drug screen and human immunodeficiency virus (HIV) screen were negative. A magnetic resonance imaging (MRI) scan of the head was unremarkable (Figures ​ (Figures1, 1 , ​ ,2 2 ).

An initial diagnosis of schizophreniform disorder with a possibility of schizophrenia given the time course given by family was unclear was presumed based on the history taken from the patient, family, and MSE. However, Venereal Disease Research Laboratory (VDRL) test returned a positive 1:16 titer, suggesting neurosyphilis as a potential cause. A lumbar puncture was performed, and the cerebrospinal fluid analysis also had a positive VDRL titer, confirming the diagnosis of neurosyphilis. The patient was administered Penicillin G intravenous (IV) for a period of 14 days, during which we observed improvement in the patient's condition. The patient's mood stabilized, agitation decreased, and they reported feeling less anxious and distressed.

Neurosyphilis is observed during tertiary syphilis, which usually presents 5-20 years after initial infection and can have a variety of neurological and psychiatric manifestations [ 4 ]. Neurosyphilis itself is rare and most cases of syphilis do not progress to this stage as they are diagnosed early and treated effectively with penicillin. Patients with neurosyphilis may present with tabes dorsalis, Argyll-Robertson pupils, lancinating pains, and uncommonly with psychiatric symptoms including psychosis, mood changes, and dementia [ 4 ]. Our patient had a unique presentation of syphilis which presented initially with psychosis, creating a challenging diagnosis. Syphilis with psychosis as the primary presentation is rare and has only been reported sparingly in the literature [ 5 - 7 ]. Our patient met the criteria for the diagnosis of schizophreniform disorder, and without screening for syphilis would likely have entered into a cycle of repeated anti-psychotic treatment, hospital readmission, and worsening of symptoms as seen in cases of syphilis-induced psychosis misdiagnosed as schizophrenia [ 3 ]. In cases of schizophrenia-like psychosis with positive testing for syphilis, it may be difficult to determine whether it is an incidental finding or the primary etiology of the presentation. Studies have shown that patients with diagnosed schizophrenia may be at higher risk for acquiring syphilis, which makes a detailed history crucial in the evaluation of these patients [ 8 ]. Our patient had no previous psychiatric history prior to this episode, making concurrent schizophreniform/schizophrenia and incidental syphilis infection unlikely, and leaving neurosyphilis as the most likely cause. Clinicians should have a high degree of suspicion for neurosyphilis and take appropriate screening measures when evaluating patients with psychosis in order to initiate timely management.

Conclusions

In this case report, we share a unique presentation of a 30-year-old female with a four-month history of suicidal ideation, anxiety, personality changes, and psychosis, later diagnosed as neurosyphilis. Syphilis with psychosis as the primary presentation is rare. This case emphasizes the importance of early screening and treatment of syphilis to prevent the progression to neurosyphilis and its neuropsychiatric symptoms. It is essential for healthcare providers to consider medical conditions in their differential diagnosis when evaluating patients with psychosis, as prompt and accurate diagnosis and treatment can significantly improve patient outcomes.

The authors have declared that no competing interests exist.

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• Case report
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• Published: 19 March 2024

Sebaceous carcinoma in a 54-year-old Black African man after cancer chemotherapy: a case report

• Olaejirinde Olaniyi Olaofe   ORCID: orcid.org/0000-0002-0074-6764 1 ,
• Bolajoko Abidemi Adewara 2 ,
• Chigozie Chidozie Okongwu 1 &
• Yusuf Olanrewaju Abdullahi 3  

Journal of Medical Case Reports volume  18 , Article number:  159 ( 2024 ) Cite this article

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Sebaceous carcinoma is a very rare malignant skin adnexal tumor that is occasionally aggressive. We have not seen a case of sebaceous carcinoma in our center in the last 10 years. It is extremely rare in Black Africans.

Case presentation

We described the case of a 55-year-old man African man who presented to our ophthalmologist with complaints of growth on the right upper eyelid for 8 months. He had surgery and chemotherapy for rectal carcinoma 6 years prior to presentation and received his last dose of chemotherapy 5 years before seeing our ophthalmologist. There was a history of spontaneous unprovoked bleeding from the lesion. He subsequently underwent surgical excision under general anesthesia. Histology of the mass showed an effaced architecture due to proliferating malignant epithelial cells disposed as trabecules, solid nests, and tongues. The microscopic features of widespread multivacuolated cytoplasm of the neoplastic cells led us to conclude that the tumor was a sebaceous carcinoma. The patient is alive and well.

Sebaceous carcinoma is a rare malignant skin adnexal tumor in Black Africans. It can present as an eyelid mass with spontaneous bleeding. It can follow cancer chemotherapy either because of its association with other tumors in Muir–Torre syndrome or because of mutagenic effects of chemotherapeutic agents.

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Introduction

Sebaceous carcinoma is a rare malignant skin adnexal tumor that is occasionally aggressive [ 1 , 2 , 3 ]. It has been reported in various parts of the world and is mainly diagnosed by histological examination of biopsies or resections of the tumor. It has been associated with other malignancies or cancer treatment modalities [ 4 ]. We have not seen a case of sebaceous carcinoma in our center in the last 10 years. We present a rare case of sebaceous carcinoma with an episode of spontaneous bleeding in a middle-aged Black African man 5 years after receiving chemotherapy for colorectal cancer.

A 55-year-old African man presented to our ophthalmologist with complaints of growth on the right upper eyelid for 8 months. Eyelid swelling started from the orbital ridge and progressed to involve the whole upper lid. There was a history of spontaneous unprovoked bleeding from the lesion noticed prior to presentation as well as eye discharge and rashes. He was unable to open the affected eye fully. He had no history of trauma, photophobia, weight loss, or tearing.

He had surgery and chemotherapy for rectal carcinoma 6 years prior to presentation and received his last dose of chemotherapy 5 years before seeing our ophthalmologist. He is a known patient with asthma. There was no family history of similar conditions.

Examination of the right eye revealed a projecting fleshy mass, measuring 3.3 × 2.0 cm, located on the upper eyelid. The mass was firm, lobulated, and nontender with irregular rough surfaces. There was a mildly tender, mobile, nonmatted, right preauricular lymph node.

He subsequently underwent surgical excision under general anesthesia. We confirmed the tumor to be malignant using frozen sections and ensured that the resection margins were free of tumors. The resected lymph node was not involved by the tumor. The surgery was followed by reconstruction of the upper eyelid using the Cutler-Beard procedure. There were no postoperative complications. The patient is alive and well 1 month after the surgery.

Histology of the mass showed an effaced architecture due to proliferating malignant epithelial cells disposed as trabecules, solid nests, and tongues. The individual malignant cells were basaloid, with marked nuclei pleomorphism, irregular nuclei outline, and open vesicular chromatin with prominent nucleoli. Mitoses were up to 11 per high power field with few atypical forms. In some areas, these cells appeared multivacuolated. Areas of squamous differentiation were also present. The features, some of which are shown in Figs.  1 , 2 , and 3 , are conclusive of sebaceous carcinoma. Microscopic examination of the lymph node showed variably sized and shaped lymphoid follicles with few prominent germinal centers. The lymph node was not infiltrated by malignant cells.

Photograph of the eyes before surgical intervention

Photomicrograph of stroma infiltration by malignant cells

Photomicrograph showing sebaceous differentiation of the malignant cells

Figure  1 shows the right eye with a projecting fleshy mass on the upper eyelid. The mass was firm, lobulated, and nontender with irregular rough surfaces.

Figure  2 shows infiltration of the fibrocollagenous stroma by malignant epithelial cells. There was reactive lymphocytic infiltration and neovascularization. Prolific vascular proliferation could explain the spontaneous bleeding experienced by the patient.

The photomicrograph shows malignant cells with multivacuolated cytoplasm in many areas of the tumor. This is strong evidence of sebaceous differentiation.

The patient’s age is within the age range for sebaceous carcinoma previously reported by some researchers. The tumor is known to occur in the age range of 43–85 years in a study performed on Koreans [ 5 ]. Like all cancers, the incidence of this tumor is expected to increase with age, probably owing to the cumulative effects of carcinogenic factors to which the patient is exposed over the years.

Although this malignant tumor is more common in Caucasians, our patient is a Black African. The tumor is very rare locally, as we have not seen any cases in the last 10 years. The rarity of the tumor in our region of the world is consistent with the low incidence of other skin tumors in our region compared with what is reported in the Western world. However, it is difficult to know the true incidence in our area, as many patients do not present to the hospital due to poverty and relatively poor accessibility of high-quality healthcare institutions.

The index case is a male patient who may have had an increased risk of the disease because of his hormonal activity. Although some studies have reported sebaceous carcinoma to be more common in female patients, a few have indicated a preponderance of the disease in male patients [ 6 ]. The tumor is known to be androgen receptor positive [ 7 , 8 , 9 ]. This can make the tumor incidence higher in male patients. The reduction in estrogen activity after menopause may also contribute to the development of the tumor in postmenopausal women. Men are known to have a more aggressive form of the disease, which may also be related to the increased proliferative effect of androgens. Men with androgen receptor-positive tumors are known to have a poorer prognosis.

Sebaceous carcinoma has been reported in various sites in the body [ 10 , 11 , 12 , 13 , 14 ]. The tumor in the index case was found in the most likely site, which was the ocular region. The mass is known to occur primarily in the ocular region, with less than half occurring in other parts of the body, most especially the head and neck region. It was also situated in the upper lid, which is the most common site for ocular cases. The location of the tumor is probably due to the greater presence of sebaceous glands in the head and neck region of the body, with particularly high concentrations in the eyelids.

Various agents have been postulated as risk factors, including Epstein–Barr virus (EBV) and ultraviolet radiation [ 13 ]. The index patient resides in Africa, which has relatively higher sunshine compared with temperate regions. This could have had a contributory role. We are unable to test for EBV to corroborate suggestions by some researchers. In our opinion, it might be necessary to evaluate any possible association of the tumor with the use of eye pencils, as they are commonly applied to the eyelids. However, any possible link is likely to be weak since there is widespread use of eye pencils and very low incidence of the tumor.

Sebaceous carcinoma has been reported following treatment of malignant tumors [ 15 ]. The index patient had chemotherapy for colorectal cancer, which could contribute to the genesis of the tumor. Cancer chemotherapeutic agents are well known to be mutagenic and capable of causing secondary malignancies. A case has been reported in a patient on ruxolitinib, a monoclonal antibody previously associated with basal cell carcinoma, Merkel cell carcinoma, and squamous cell carcinoma [ 15 ]. Some cases have been associated with Muir–Torre syndrome (MTS), a variant of Lynch syndrome [ 4 ]. It is possible that the patient has MTS syndrome. However, we could not carry out genetic tests to confirm MTS as we do not have the facilities.

As is known in typical cases of the tumor, we noticed the presence of lobules and nests that infiltrated the underlying stroma. We observed many basaloid cells. All these findings are consistent with the sebaceous differentiation of the tumor.

The patient had an episode of spontaneous bleeding from the tumor mass. From our background knowledge, this is a rare occurrence. Malignant tumors can have poorly developed leaky vessels that can be easily ruptured. Our case shows that this tumor can cause severe blood loss in patients if not adequately managed.

The individual malignant cells are basaloid (undifferentiated) with marked nuclei pleomorphism, irregular nuclei outline, and open vesicular chromatin with prominent nucleoli. The tumor can easily be identified using morphology when there is extensive sebaceous differentiation, as was seen in this case.

Sebaceous carcinoma is a rare malignant skin adnexal tumor in Black Africans. It can follow cancer chemotherapy either because of its association with other tumors in Muir–Torre syndrome or because of mutagenic effects of chemotherapeutic agents. It can present as an eyelid mass with spontaneous bleeding. The tumor can easily be identified using morphology when there is extensive sebaceous differentiation, as is seen in this case.

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The tissue blocks are available for future use.

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Olaejirinde Olaniyi Olaofe & Chigozie Chidozie Okongwu

Department of Ophthalmology, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria

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OOO and CCO reported the pathologic findings. BAA and YOA reported the clinical findings and operation notes. All authors contributed to the discussion and the final write-up.

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Correspondence to Olaejirinde Olaniyi Olaofe .

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Olaofe, O.O., Adewara, B.A., Okongwu, C.C. et al. Sebaceous carcinoma in a 54-year-old Black African man after cancer chemotherapy: a case report. J Med Case Reports 18 , 159 (2024). https://doi.org/10.1186/s13256-024-04460-z

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Received : 05 September 2023

Accepted : 13 February 2024

Published : 19 March 2024

DOI : https://doi.org/10.1186/s13256-024-04460-z

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