Syphilis

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Not to be confused with Sisyphus.

Syphilis
Antibiotics[4]
Frequency45.4 million / 0.6% (2015, global)[5]
Deaths107,000 (2015, global)[6]

Syphilis (

latent or tertiary.[1][2] The primary stage classically presents with a single chancre (a firm, painless, non-itchy skin ulceration usually between 1 cm and 2 cm in diameter), though there may be multiple sores.[2] In secondary syphilis, a diffuse rash occurs, which frequently involves the palms of the hands and soles of the feet.[2] There may also be sores in the mouth or vagina.[2] Latent syphilis has no symptoms and can last years.[2] In tertiary syphilis, there are gummas (soft, non-cancerous growths), neurological problems, or heart symptoms.[3] Syphilis has been known as "the great imitator", because it may cause symptoms similar to many other diseases.[2][3]

Syphilis is most commonly spread through

dark field microscopy.[2] The Centers for Disease Control and Prevention (U.S.) recommends for all pregnant women to be tested.[2]

The risk of sexual transmission of syphilis can be reduced by using a

intravenous benzylpenicillin or ceftriaxone is recommended.[4] During treatment, people may develop fever, headache, and muscle pains, a reaction known as Jarisch–Herxheimer.[4]

In 2015, about 45.4 million people had syphilis infections,[5] of which six million were new cases.[9] During 2015, it caused about 107,000 deaths, down from 202,000 in 1990.[6][10] After decreasing dramatically with the availability of penicillin in the 1940s, rates of infection have increased since the turn of the millennium in many countries, often in combination with human immunodeficiency virus (HIV).[3][11] This is believed to be partly due to unsafe drug use, increased prostitution, and decreased use of condoms.[12][13][14]

Signs and symptoms

Primary syphilis on a tongue

Syphilis can

Sir William Osler due to its varied presentations.[3][17][18]

Primary

Chancre on a penis due to primary syphilis, 1978

Primary syphilis is typically acquired by direct sexual contact with the infectious lesions of another person.

rectally in men who have sex with men (34%).[22] Lymph node enlargement frequently (80%) occurs around the area of infection,[3] occurring seven to 10 days after chancre formation.[22] The lesion may persist for three to six weeks if left untreated.[3]

Secondary

Typical presentation of secondary syphilis with a rash on the palms of the hands, 1967
nodules
over much of the body due to secondary syphilis

Secondary syphilis occurs approximately four to ten weeks after the primary infection.

condyloma latum.[3] All of these lesions harbor bacteria and are infectious.[3] Other symptoms may include fever, sore throat, malaise, weight loss, hair loss, and headache.[3] Rare manifestations include liver inflammation, kidney disease, joint inflammation, periostitis, inflammation of the optic nerve, uveitis, and interstitial keratitis.[3][25] The acute symptoms usually resolve after three to six weeks;[25] about 25% of people may present with a recurrence of secondary symptoms.[23][26] Many people who present with secondary syphilis (40–85% of women, 20–65% of men) do not report previously having had the classical chancre of primary syphilis.[23]

Latent

Latent syphilis is defined as having serologic proof of infection without symptoms of disease.[19] It develops after secondary syphilis and is divided into early latent and late latent stages.[27] Early latent syphilis is defined by the World Health Organization as less than 2 years after original infection.[27] Early latent syphilis is infectious as up to 25% of people can develop a recurrent secondary infection (during which bacteria are actively replicating and are infectious).[27] Two years after the original infection the person will enter late latent syphilis and is not as infectious as the early phase.[25][28] The latent phase of syphilis can last many years after which, without treatment, approximately 15–40% of people can develop tertiary syphilis.[29]

Tertiary

Model of a head of a person with tertiary (gummatous) syphilis, Musée de l'Homme, Paris

Tertiary syphilis may occur approximately 3 to 15 years after the initial infection and may be divided into three different forms: gummatous syphilis (15%), late neurosyphilis (6.5%), and cardiovascular syphilis (10%).[3][25] Without treatment, a third of infected people develop tertiary disease.[25] People with tertiary syphilis are not infectious.[3]

Gummatous syphilis or late

benign syphilis usually occurs 1 to 46 years after the initial infection, with an average of 15 years.[3] This stage is characterized by the formation of chronic gummas, which are soft, tumor-like balls of inflammation which may vary considerably in size.[3] They typically affect the skin, bone, and liver, but can occur anywhere.[3]

Cardiovascular syphilis usually occurs 10–30 years after the initial infection.[3] The most common complication is syphilitic aortitis, which may result in aortic aneurysm formation.[3]

general paresis or tabes dorsalis.[3]

Meningovascular syphilis involves inflammation of the small and medium arteries of the central nervous system. It can present between 1–10 years after the initial infection. Meningovascular syphilis is characterized by stroke, cranial nerve palsies and

pupillary reflex
).

Congenital

Main article: Congenital syphilis

Congenital syphilis is that which is transmitted during pregnancy or during birth.

mulberry.[32]

Cause

Bacteriology

Main article: Treponema pallidum
Steiner silver stain
, 1986

Treponema pallidum subspecies pallidum is a spiral-shaped,

Gram-negative, highly mobile bacterium.[11][22] Two other human diseases are caused by related Treponema pallidum subspecies, yaws (subspecies pertenue) and bejel (subspecies endemicum), and one further caused by the very closely related Treponema carateum, pinta.[3][33] Unlike subspecies pallidum, they do not cause neurological disease.[7] Humans are the only known natural reservoir for subspecies pallidum.[34] It is unable to survive more than a few days without a host.[22] This is due to its small genome (1.14Mbp) failing to encode the metabolic pathways necessary to make most of its macronutrients.[22] It has a slow doubling time of greater than 30 hours.[22] The bacterium is known for its ability to evade the immune system and its invasiveness.[35]

Transmission

Syphilis is transmitted primarily by sexual contact or during

sharing needles appears to be limited.[3]

It is not generally possible to contract syphilis through toilet seats, daily activities, hot tubs, or sharing eating utensils or clothing.[38] This is mainly because the bacteria die very quickly outside of the body, making transmission by objects extremely difficult.[39]

Diagnosis

Poster for testing of syphilis, showing a man and a woman bowing their heads in shame
This Works Progress Administration poster (c. 1936) acknowledges the social stigma of syphilis, while urging those who possibly have the disease to be tested
Micrograph of secondary syphilis skin lesions. (A/B) H&E stain of SS lesions. (C/D) IHC staining reveals abundant bacteria embedded within a mixed cellular inflammatory infiltrate (shown in the red box) in the papillary dermis. The blue arrow points to a tissue histiocyte and the read arrows to two dermal lymphocytes[40]

Syphilis is difficult to diagnose clinically during early infection.

blood tests or direct visual inspection using dark field microscopy.[3][41] Blood tests are more commonly used, as they are easier to perform.[3] Diagnostic tests are unable to distinguish between the stages of the disease.[42]

Blood tests

Blood tests are divided into nontreponemal and treponemal tests.[22]

Nontreponemal tests are used initially and include

varicella (chickenpox) and measles. False positives can also occur with lymphoma, tuberculosis, malaria, endocarditis, connective tissue disease, and pregnancy.[19]

Because of the possibility of false positives with nontreponemal tests, confirmation is required with a treponemal test, such as

lymphocytes) and high protein levels in the cerebrospinal fluid in the setting of a known syphilis infection.[3][19]

Direct testing

antibodies tagged with fluorescein, which attach to specific syphilis proteins, while PCR uses techniques to detect the presence of specific syphilis genes.[22] These tests are not as time-sensitive, as they do not require living bacteria to make the diagnosis.[22]

Prevention

Vaccine

As of 2018[update], there is no

animal model but research continues.[44][45]

Sex

Condom use reduces the likelihood of transmission during sex, but does not eliminate the risk.[46] The Centers for Disease Control and Prevention (CDC) states, "Correct and consistent use of latex condoms can reduce the risk of syphilis only when the infected area or site of potential exposure is protected.[47] However, a syphilis sore outside of the area covered by a latex condom can still allow transmission, so caution should be exercised even when using a condom."[48]

monogamous relationship with a partner who has been tested and is known to be uninfected."[48]

Congenital disease

Portrait of a man affected with what is now believed to have been congenital syphilis, c. 1820[49]

Congenital syphilis in the newborn can be prevented by screening mothers during early pregnancy and treating those who are infected.

antenatal care at all, and the antenatal care others receive does not include screening.[50][54] It still occasionally occurs in the developed world, as those most likely to acquire syphilis are least likely to receive care during pregnancy.[50] Several measures to increase access to testing appear effective at reducing rates of congenital syphilis in low- to middle-income countries.[52] Point-of-care testing to detect syphilis appeared to be reliable, although more research is needed to assess its effectiveness and into improving outcomes in mothers and babies.[55]

Screening

The CDC recommends that sexually active men who have sex with men be tested at least yearly.[56] The USPSTF also recommends screening among those at high risk.[57]

Syphilis is a notifiable disease in many countries, including Canada,[58] the European Union,[59] and the United States.[60] This means health care providers are required to notify public health authorities, which will then ideally provide partner notification to the person's partners.[61] Physicians may also encourage patients to send their partners to seek care.[62] Several strategies have been found to improve follow-up for STI testing, including email and text messaging of reminders for appointments.[63]

Treatment

Historic use of mercury

As a form of

mercury (II) chloride were still in prominent medical use as late as 1916, and considered effective and worthwhile treatments.[67]

Early infections

The first-line treatment for uncomplicated syphilis (primary or secondary stages) remains a single dose of

Resistance to macrolides, rifampicin, and clindamycin is often present.[34] Ceftriaxone, a third-generation cephalosporin antibiotic, may be as effective as penicillin-based treatment.[3] It is recommended that a treated person avoid sex until the sores are healed.[38] In comparison to azithromycin for treatment in early infection, there is lack of strong evidence for superiority of azithromycin to benzathine penicillin G.[70]

Late infections

For neurosyphilis, due to the poor penetration of benzathine penicillin into the

penicillin G for a minimum of 10 days.[3][34] If a person is allergic to penicillin, ceftriaxone may be used or penicillin desensitization attempted.[3] Other late presentations may be treated with once-weekly intramuscular benzathine penicillin for three weeks.[3] Treatment at this stage solely limits further progression of the disease and has a limited effect on damage which has already occurred.[3] Serologic cure can be measured when the non-treponemal titers decline by a factor of 4 or more in 6–12 months in early syphilis or 12–24 months in late syphilis.[21]

Jarisch–Herxheimer reaction

Jarisch–Herxheimer reaction in a person with syphilis and human immunodeficiency virus[71]

One of the potential side effects of treatment is the Jarisch–Herxheimer reaction.[3] It frequently starts within one hour and lasts for 24 hours, with symptoms of fever, muscle pains, headache, and a fast heart rate.[3] It is results from the release of pro-inflammatory cytokines by the immune system in response to lipoproteins released from rupturing syphilis bacteria.[72]

Pregnancy

Penicillin is an effective treatment for syphilis in pregnancy[73] but there is no agreement on which dose or route of delivery is most effective.[74]

Epidemiology

Main article: Epidemiology of syphilis
Syphilis deaths per million persons in 2012
  0–0
  1–1
  2–3
  4–10
  11–19
  20–28
  29–57
  58–138
disability adjusted life years from syphilis per 100,000 inhabitants in 2004[75]

In 2012, about 0.5% of adults were infected with syphilis, with 6 million new cases.

African Americans accounted for almost half of all cases in 2010.[77] As of 2014, syphilis infections continue to increase in the United States.[78][79] In the United States as of 2020, rates of syphilis have increased by more than threefold; in 2018 approximately 86% of all cases of syphilis in the United States were in men.[21] In 2021, preliminary CDC data illustrated that 2,677 cases of congenital syphilis were found in the population of 332 million in the United States.[80]

Syphilis was very common in Europe during the 18th and 19th centuries.[11] Flaubert found it universal among 19th-century Egyptian prostitutes.[81] In the developed world during the early 20th century, infections declined rapidly with the widespread use of antibiotics, until the 1980s and 1990s.[11] Since 2000, rates of syphilis have been increasing in the US, Canada, the UK, Australia and Europe, primarily among men who have sex with men.[34] Rates of syphilis among US women have remained stable during this time, while rates among UK women have increased, but at a rate less than that of men.[82] Increased rates among heterosexuals have occurred in China and Russia since the 1990s.[34] This has been attributed to unsafe sexual practices, such as sexual promiscuity, prostitution, and decreasing use of barrier protection.[34][82][83]

Left untreated, it has a mortality rate of 8% to 58%, with a greater death rate among males.[3] The symptoms of syphilis have become less severe over the 19th and 20th centuries, in part due to widespread availability of effective treatment, and partly due to virulence of the bacteria.[23] With early treatment, few complications result.[22] Syphilis increases the risk of HIV transmission by two to five times, and coinfection is common (30–60% in some urban centers).[3][34] In 2015, Cuba became the first country to eliminate mother-to-child transmission of syphilis.[84]

History

Main article: History of syphilis

Origin, spread and discovery

Rembrandt van Rijn, circa 1665–67, oil on canvas. De Lairesse, himself a painter and art theorist, had congenital syphilis that deformed his face and eventually blinded him[85]

Paleopathologists have known for decades that syphilis was present in the Americas before European contact.[86][87] The situation in Afro-Eurasia has been murkier and caused considerable debate.[88] According to the Columbian theory, syphilis was brought to Spain by the men who sailed with Christopher Columbus in 1492 and spread from there, with a serious epidemic in Naples beginning as early as 1495. Contemporaries believed the disease sprang from American roots, and in the 16th century physicians wrote extensively about the new disease inflicted on them by the returning explorers.[89]

Most evidence supports the Columbian origin hypothesis.[90] However, beginning in the 1960s, examples of probable treponematosis—the parent disease of syphilis, bejel, and yaws—in skeletal remains shifted the opinion of some towards a "pre-Columbian" origin.[91][92] A 2024 study published in Nature supported an emergence postdating human occupation in the Americas.[93]

When living conditions changed with urbanization, elite social groups began to practice basic hygiene and started to separate themselves from other social tiers. Consequently, treponematosis was driven out of the age group in which it had become endemic. It then began to appear in adults as syphilis. Because they had never been exposed as children, they were not able to fend off serious illness. Spreading the disease via sexual contact also led to victims being infected with a massive bacterial load from open sores on the genitalia. Adults in higher socioeconomic groups then became very sick with painful and debilitating symptoms lasting for decades. Often, they died of the disease, as did their children who were infected with congenital syphilis. The difference between rural and urban populations was first noted by Ellis Herndon Hudson, a clinician who published extensively about the prevalence of treponematosis, including syphilis, in times past.[94] The importance of bacterial load was first noted by the physician Ernest Grin in 1952 in his study of syphilis in Bosnia.[95]

The most compelling evidence for the validity of the pre-Columbian hypothesis is the presence of syphilitic-like damage to bones and teeth in medieval skeletal remains. While the absolute number of cases is not large, new ones are continually discovered, most recently in 2015.[96] At least fifteen cases of acquired treponematosis based on evidence from bones, and six examples of congenital treponematosis based on evidence from teeth, are now widely accepted. In several of the twenty-one cases the evidence may also indicate syphilis.[97]

A healthy man and a diseased man torture Christ before his crucifixion. From a Frensh book of hours, c. 1375–1435

In 2020, a group of leading paleopathologists concluded that enough evidence had been collected to prove that treponemal disease, almost certainly including syphilis, had existed in Europe prior to the voyages of Columbus.[98] There is an outstanding issue, however. Damaged teeth and bones may seem to hold proof of pre-Columbian syphilis, but there is a possibility that they point to an endemic form of treponemal disease instead. As syphilis, bejel, and yaws vary considerably in mortality rates and the level of human disease they elicit, it is important to know which one is under discussion in any given case, but it remains difficult for paleopathologists to distinguish among them. (The fourth of the treponemal diseases is pinta, a skin disease and therefore unrecoverable through paleopathology.) Ancient DNA (aDNA) holds the answer, because just as only aDNA suffices to distinguish between syphilis and other diseases that produce similar symptoms in the body, it alone can differentiate spirochetes that are 99.8 percent identical with absolute accuracy.[99] Progress on uncovering the historical extent of syndromes through aDNA remains slow, however, because the bacterium responsible for treponematosis is rare in skeletal remains and fragile, making it notoriously difficult to recover and analyse. Precise dating to the medieval period is not yet possible but work by Kettu Majander et al. uncovering the presence of several different kinds of treponematosis at the beginning of the early modern period argues against its recent introduction from elsewhere. Therefore, they argue, treponematosis—possibly including syphilis—almost certainly existed in medieval Europe.[100]

Despite significant progress in tracing the presence of syphilis in past historic periods, definitive findings from paleopathology and aDNA studies are still lacking for the medieval period. Evidence from art is therefore helpful in settling the issue. Research by Marylynn Salmon has demonstrated that deformities in medieval subjects can be identified by comparing them to those of modern victims of syphilis in medical drawings and photographs.[101] One of the most typical deformities, for example, is a collapsed nasal bridge called saddle nose. Salmon discovered that it appeared often in medieval illuminations, especially among the men tormenting Christ in scenes of the crucifixion. The association of saddle nose with evil is an indication that the artists were thinking of syphilis, which is typically transmitted through sexual intercourse with promiscuous partners, a mortal sin in medieval times.

It remains mysterious why the authors of medieval medical treatises so uniformly refrained from describing syphilis or commenting on its existence in the population. Many may have confused it with other diseases such as leprosy (Hansen's disease) or elephantiasis. The great variety of symptoms of treponematosis, the different ages at which the various diseases appear, and its widely divergent outcomes depending on climate and culture, would have added greatly to the confusion of medical practitioners, as indeed they did right down to the middle of the 20th century. In addition, evidence indicates that some writers on disease feared the political implications of discussing a condition more fatal to elites than to commoners. Historian Jon Arrizabalaga has investigated this question for Castile with startling results revealing an effort to hide its association with elites.[102]

The first written records of an outbreak of syphilis in Europe occurred in 1495 in

Syphilis sive morbus gallicus (Syphilis or The French Disease) describing the ravages of the disease in Italy.[105][106] In Great Britain it was also called the "Great Pox".[107][108]

In the 16th through 19th centuries, syphilis was one of the largest public health burdens in

sexual promiscuity and prostitution, made it an object of fear and revulsion and a taboo. The magnitude of its morbidity and mortality in those centuries reflected that, unlike today, there was no adequate understanding of its pathogenesis and no truly effective treatments. Its damage was caused not so much by great sickness or death early in the course of the disease but rather by its gruesome effects decades after infection as it progressed to neurosyphilis with tabes dorsalis. Mercury compounds and isolation were commonly used, with treatments often worse than the disease.[107]

The causative organism, Treponema pallidum, was first identified by

Salvarsan by Hoechst AG.[113] This organoarsenic compound was the first modern chemotherapeutic agent
.

During the 20th century, as both

developed countries among those people who could afford to pay for timely diagnosis and treatment. Penicillin was discovered in 1928, and effectiveness of treatment with penicillin was confirmed in trials in 1943,[107] at which time it became the main treatment.[114]

Many famous historical figures, including

tertiary syphilis, but that diagnosis has recently come into question.[117]

Arts and literature

See also: List of syphilis cases
An early medical illustration of people with syphilis, Vienna, 1498

The earliest known depiction of an individual with syphilis is

Syphilitic Man (1496), a woodcut believed to represent a Landsknecht, a Northern European mercenary.[118] The myth of the femme fatale or "poison women" of the 19th century is believed to be partly derived from the devastation of syphilis, with classic examples in literature including John Keats' "La Belle Dame sans Merci".[119][120]

The Flemish artist Stradanus designed a print called Preparation and Use of Guayaco for Treating Syphilis, a scene of a wealthy man receiving treatment for syphilis with the tropical wood guaiacum sometime around 1590.[121]

Tuskegee and Guatemala studies

See also:
Guatemala syphilis experiment
Work Projects Administration
poster about syphilis c. 1940

The "Tuskegee Study of Untreated Syphilis in the Negro Male" was an infamous, unethical and racist

U.S. Public Health Service.[122][123] Whereas the purpose of this study was to observe the natural history of untreated syphilis; the African-American men in the study were told they were receiving free treatment for "bad blood" from the United States government.[124]

The Public Health Service started working on this study in 1932 in collaboration with

Centers for Disease Control, the men were told they were being treated for "bad blood"—a colloquialism describing various conditions such as fatigue, anemia and syphilis—which was a leading cause of death among southern African American men.[123]

The 40-year study became a textbook example of criminally negligent

whistleblower, Peter Buxtun, led to major changes in U.S. law and regulation on the protection of participants in clinical studies. Now studies require informed consent,[125] communication of diagnosis, and accurate reporting of test results.[126]

Preparation and Use of Guayaco for Treating Syphilis, after Stradanus, 1590

Similar experiments were carried out in

mental patients with syphilis and other sexually transmitted infections, without the informed consent of the subjects and treated most subjects with antibiotics. The experiment resulted in at least 83 deaths.[128][129] In October 2010, the U.S. formally apologized to Guatemala for the ethical violations that took place. Secretary of State Hillary Clinton and Health and Human Services Secretary Kathleen Sebelius stated "Although these events occurred more than 64 years ago, we are outraged that such reprehensible research could have occurred under the guise of public health. We deeply regret that it happened, and we apologize to all the individuals who were affected by such abhorrent research practices."[130] The experiments were led by physician John Charles Cutler who also participated in the late stages of the Tuskegee syphilis experiment.[131]

Names

Syphilis was first called grande verole or the "great pox" by the French. Other historical names have included "button scurvy", sibbens, frenga and dichuchwa, among others.[132][133] Since it was a disgraceful disease, the disease was known in several countries by the name of their neighbouring, often hostile country.[114] The English, the Germans, and the Italians called it "the French disease", while the French referred to it as the "Neapolitan disease". The Dutch called it the "Spanish/Castilian disease".[114] To the Turks it was known as the "Christian disease", whilst in India, the Hindus and Muslims named the disease after each other.[114]

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