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Syphilis

March 20, 2023

Syphilis (/ˈsɪfəlɪs/) is a sexually transmitted infection caused by the bacterium Treponema pallidum subspecies pallidum.[3] The signs and symptoms of syphilis vary depending in which of the four stages it presents (primary, secondary, latent, and tertiary).[1] 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.[1] In secondary syphilis, a diffuse rash occurs, which frequently involves the palms of the hands and soles of the feet.[1] There may also be sores in the mouth or vagina.[1] In latent syphilis, which can last for years, there are few or no symptoms.[1] In tertiary syphilis, there are gummas (soft, non-cancerous growths), neurological problems, or heart symptoms.[2] Syphilis has been known as "the great imitator" as it may cause symptoms similar to many other diseases.[1][2]

Syphilis
Electron micrograph of Treponema pallidum
SpecialtyInfectious disease
SymptomsFirm, painless, non-itchy skin ulcer[1]
CausesTreponema pallidum usually spread by sex[1]
Diagnostic methodBlood tests, dark field microscopy of infected fluid[1][2]
Differential diagnosisMany other diseases[1]
PreventionCondoms, Long-term monogamous relationships[1]
TreatmentAntibiotics[3]
Frequency45.4 million / 0.6% (2015)[4]
Deaths107,000 (2015)[5]

Syphilis is most commonly spread through sexual activity.[1] It may also be transmitted from mother to baby during pregnancy or at birth, resulting in congenital syphilis.[1][6] Other diseases caused by Treponema bacteria include yaws (T. pallidum subspecies pertenue), pinta (T. carateum), and nonvenereal endemic syphilis (T. pallidum subspecies endemicum).[2] These three diseases are not typically sexually transmitted.[7] Diagnosis is usually made by using blood tests; the bacteria can also be detected using dark field microscopy.[1] The Centers for Disease Control and Prevention (U.S.) recommend all pregnant women be tested.[1]

The risk of sexual transmission of syphilis can be reduced by using a latex or polyurethane condom.[1] Syphilis can be effectively treated with antibiotics.[3] The preferred antibiotic for most cases is benzathine benzylpenicillin injected into a muscle.[3] In those who have a severe penicillin allergy, doxycycline or tetracycline may be used.[3] In those with neurosyphilis, intravenous benzylpenicillin or ceftriaxone is recommended.[3] During treatment people may develop fever, headache, and muscle pains, a reaction known as Jarisch–Herxheimer.[3]

In 2015, about 45.4 million people had syphilis infections,[4] of which six million were new cases.[8] During 2015, it caused about 107,000 deaths, down from 202,000 in 1990.[5][9] 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).[2][10] This is believed to be partly due to increased sexual activity, prostitution, and decreasing use of condoms.[11][12][13]

Signs and symptoms

Syphilis can present in one of four different stages: primary, secondary, latent, and tertiary,[2] and may also occur congenitally.[14] It was referred to as "the great imitator" by Sir William Osler due to its varied presentations.[2][15][16]

Primary

Primary syphilis is typically acquired by direct sexual contact with the infectious lesions of another person.[17] Approximately 2–6 weeks after contact (with a range of 10–90 days) a skin lesion, called a chancre, appears at the site and this contains infectious spirochetes.[18][19] This is classically (40% of the time) a single, firm, painless, non-itchy skin ulceration with a clean base and sharp borders approximately 0.3–3.0 cm in size.[2] The lesion may take on almost any form.[20] In the classic form, it evolves from a macule to a papule and finally to an erosion or ulcer.[20] Occasionally, multiple lesions may be present (~40%),[2] with multiple lesions being more common when coinfected with HIV.[20] Lesions may be painful or tender (30%), and they may occur in places other than the genitals (2–7%).[20] The most common location in women is the cervix (44%), the penis in heterosexual men (99%), and anally and rectally in men who have sex with men (34%).[20] Lymph node enlargement frequently (80%) occurs around the area of infection,[2] occurring seven to 10 days after chancre formation.[20] The lesion may persist for three to six weeks if left untreated.[2]

Secondary

 
Typical presentation of secondary syphilis with a rash on the palms of the hands
 
Reddish papules and nodules over much of the body due to secondary syphilis

Secondary syphilis occurs approximately four to ten weeks after the primary infection.[2] While secondary disease is known for the many different ways it can manifest, symptoms most commonly involve the skin, mucous membranes, and lymph nodes.[21] There may be a symmetrical, reddish-pink, non-itchy rash on the trunk and extremities, including the palms and soles.[2][22] The rash may become maculopapular or pustular.[2] It may form flat, broad, whitish, wart-like lesions on mucous membranes, known as condyloma latum.[2] All of these lesions harbor bacteria and are infectious.[2] Other symptoms may include fever, sore throat, malaise, weight loss, hair loss, and headache.[2] Rare manifestations include liver inflammation, kidney disease, joint inflammation, periostitis, inflammation of the optic nerve, uveitis, and interstitial keratitis.[2][23] The acute symptoms usually resolve after three to six weeks;[23] about 25% of people may present with a recurrence of secondary symptoms.[21][24] 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.[21]

Latent

Latent syphilis is defined as having serologic proof of infection without symptoms of disease.[17] It develops after secondary syphilis and is divided into early latent and late latent stages.[25] Early latent syphilis is defined by the World Health Organization as less than 2 years after original infection.[25] Early latent syphilis is infectious as up to 25% of people can develop a recurrent secondary infection (during which spirochetes are actively replicating and are infectious).[25] Two years after the original infection the person will enter late latent syphilis and is not as infectious as the early phase.[23][26] The latent phase of syphilis can last many years after which, without treatment, approximately 15-40% of people can develop tertiary syphilis.[27]

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%).[2][23] Without treatment, a third of infected people develop tertiary disease.[23] People with tertiary syphilis are not infectious.[2]

Gummatous syphilis or late benign syphilis usually occurs 1 to 46 years after the initial infection, with an average of 15 years.[2] This stage is characterized by the formation of chronic gummas, which are soft, tumor-like balls of inflammation which may vary considerably in size.[2] They typically affect the skin, bone, and liver, but can occur anywhere.[2]

Cardiovascular syphilis usually occurs 10–30 years after the initial infection.[2] The most common complication is syphilitic aortitis, which may result in aortic aneurysm formation.[2]

Neurosyphilis refers to an infection involving the central nervous system. Involvement of the central nervous system in syphilis (either asymptomatic or symptomatic) can occur at any stage of the infection.[19] It may occur early, being either asymptomatic or in the form of syphilitic meningitis; or late as meningovascular syphilis, manifesting as general paresis or tabes dorsalis.[2]

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 spinal cord inflammation.[28] Late symptomatic neurosyphilis can develop decades after the original infection and includes 2 types; general paresis and tabes dorsalis. General paresis presents with dementia, personality changes, delusions, seizures, psychosis and depression.[28] Tabes dorsalis is characterized by gait instability, sharp pains in the trunk and limbs, impaired positional sensation of the limbs as well as having a positive Romberg's sign.[28] Both tabes dorsalis and general paresis may present with Argyll Robertson pupil which are pupils that constrict when the person focuses on near objects (accommodation reflex) but do not constrict when exposed to bright light (pupillary reflex).

Congenital

Main article: Congenital syphilis

Congenital syphilis is that which is transmitted during pregnancy or during birth.[6] Two-thirds of syphilitic infants are born without symptoms.[6] Common symptoms that develop over the first couple of years of life include enlargement of the liver and spleen (70%), rash (70%), fever (40%), neurosyphilis (20%), and lung inflammation (20%).[6] If untreated, late congenital syphilis may occur in 40%, including saddle nose deformation, Higouménakis' sign, saber shin, or Clutton's joints among others.[6] Infection during pregnancy is also associated with miscarriage.[29] The three main dental defects in congenital syphilis are Hutchinson's incisors (screwdriver shaped incisors), Moon's molars or bud molars, and Fournier's molars or mulberry molars (molars with abnormal occlusal anatomy resembling a mulberry).[30]

Cause

Bacteriology

 
Histopathology of Treponema pallidum spirochetes using a modified Steiner silver stain
Main article: Treponema pallidum

Treponema pallidum subspecies pallidum is a spiral-shaped, Gram-negative, highly mobile bacterium.[10][20] Three other human diseases are caused by related Treponema pallidum subspecies, including yaws (subspecies pertenue), pinta (subspecies carateum) and bejel (subspecies endemicum).[2] Unlike subspecies pallidum, they do not cause neurological disease.[6] Humans are the only known natural reservoir for subspecies pallidum.[14] It is unable to survive more than a few days without a host.[20] This is due to its small genome (1.14Mbp) failing to encode the metabolic pathways necessary to make most of its macronutrients.[20] It has a slow doubling time of greater than 30 hours.[20] The bacterium is known for its ability to evade the immune system and its invasiveness.[31]

Transmission

Syphilis is transmitted primarily by sexual contact or during pregnancy from a mother to her baby; the spirochete is able to pass through intact mucous membranes or compromised skin.[2][14] It is thus transmissible by kissing near a lesion, as well as oral, vaginal, and anal sex.[2][32] Approximately 30% to 60% of those exposed to primary or secondary syphilis will get the disease.[23] Its infectivity is exemplified by the fact that an individual inoculated with only 57 organisms has a 50% chance of being infected.[20] Most new cases in the United States (60%) occur in men who have sex with men; and in this population 20% of syphilis cases were due to oral sex alone.[2][32] Syphilis can be transmitted by blood products, but the risk is low due to screening of donated blood in many countries.[2] The risk of transmission from sharing needles appears to be limited.[2]

It is not generally possible to contract syphilis through toilet seats, daily activities, hot tubs, or sharing eating utensils or clothing.[33] This is mainly because the bacteria die very quickly outside of the body, making transmission by objects extremely difficult.[34]

Diagnosis

 
This poster acknowledges the social stigma of syphilis, while urging those who possibly have the disease to be tested (circa 1936).
 
Micrograph of secondary syphilis skin lesions. (A/B) H&E stain of SS lesions. (C/D) IHC staining reveals abundant spirochetes 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.[35]

Syphilis is difficult to diagnose clinically during early infection.[20] Confirmation is either via blood tests or direct visual inspection using dark field microscopy.[2][36] Blood tests are more commonly used, as they are easier to perform.[2] Diagnostic tests are unable to distinguish between the stages of the disease.[37]

Blood tests

Blood tests are divided into nontreponemal and treponemal tests.[20]

Nontreponemal tests are used initially, and include venereal disease research laboratory (VDRL) and rapid plasma reagin (RPR) tests. False positives on the nontreponemal tests can occur with some viral infections, such as varicella (chickenpox) and measles. False positives can also occur with lymphoma, tuberculosis, malaria, endocarditis, connective tissue disease, and pregnancy.[17]

Because of the possibility of false positives with nontreponemal tests, confirmation is required with a treponemal test, such as treponemal pallidum particle agglutination (TPHA) or fluorescent treponemal antibody absorption test (FTA-Abs).[2] Treponemal antibody tests usually become positive two to five weeks after the initial infection.[20] Neurosyphilis is diagnosed by finding high numbers of leukocytes (predominately lymphocytes) and high protein levels in the cerebrospinal fluid in the setting of a known syphilis infection.[2][17]

Direct testing

Dark field microscopy of serous fluid from a chancre may be used to make an immediate diagnosis.[20] Hospitals do not always have equipment or experienced staff members, and testing must be done within 10 minutes of acquiring the sample.[20] Two other tests can be carried out on a sample from the chancre: direct fluorescent antibody (DFA) and polymerase chain reaction (PCR) tests.[20] DFA uses antibodies tagged with fluorescein, which attach to specific syphilis proteins, while PCR uses techniques to detect the presence of specific syphilis genes.[20] These tests are not as time-sensitive, as they do not require living bacteria to make the diagnosis.[20]

Prevention

Vaccine

As of 2018, there is no vaccine effective for prevention.[14] Several vaccines based on treponemal proteins reduce lesion development in an animal model but research continues.[38][39]

Sex

Condom use reduces the likelihood of transmission during sex, but does not eliminate the risk.[40] 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.[41] 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."[42]

Abstinence from intimate physical contact with an infected person is effective at reducing the transmission of syphilis. The CDC states, "The surest way to avoid transmission of sexually transmitted diseases, including syphilis, is to abstain from sexual contact or to be in a long-term mutually monogamous relationship with a partner who has been tested and is known to be uninfected."[42]

Congenital disease

 
Portrait of Mr. J. Kay, affected with what is now believed to have been congenital syphilis c. 1820[43]

Congenital syphilis in the newborn can be prevented by screening mothers during early pregnancy and treating those who are infected.[44] The United States Preventive Services Task Force (USPSTF) strongly recommends universal screening of all pregnant women,[45] while the World Health Organization (WHO) recommends all women be tested at their first antenatal visit and again in the third trimester.[46][47] If they are positive, it is recommended their partners also be treated.[46] Congenital syphilis is still common in the developing world, as many women do not receive antenatal care at all, and the antenatal care others receive does not include screening.[44][48] It still occasionally occurs in the developed world, as those most likely to acquire syphilis are least likely to receive care during pregnancy.[44] Several measures to increase access to testing appear effective at reducing rates of congenital syphilis in low- to middle-income countries.[46] 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.[49]

Screening

The CDC recommends that sexually active men who have sex with men be tested at least yearly.[50] The USPSTF also recommends screening among those at high risk.[51]

Syphilis is a notifiable disease in many countries, including Canada,[52] the European Union,[53] and the United States.[54] This means health care providers are required to notify public health authorities, which will then ideally provide partner notification to the person's partners.[55] Physicians may also encourage patients to send their partners to seek care.[56] Several strategies have been found to improve follow-up for STI testing, including email and text messaging of reminders for appointments.[57]

Treatment

Historic use of mercury

As a form of chemotherapy, elemental mercury had been used to treat skin diseases in Europe as early as 1363.[58] As syphilis spread, preparations of mercury were among the first medicines used to combat it. Mercury is in fact highly anti-microbial: by the 16th century it was sometimes found to be sufficient to halt development of the disease when applied to ulcers as an inunction or when inhaled as a suffumigation. Once the disease had gained a strong foothold, however, the amounts and forms of mercury necessary to control its development exceeded the human body's ability to tolerate it, and the treatment became worse and more lethal than the disease. Nevertheless, medically directed mercury poisoning became widespread through the 17th, 18th, and 19th centuries in Europe, North America, and India.[59] Mercury salts such as mercury (II) chloride were still in prominent medical use as late as 1916, and considered effective and worthwhile treatments.[60]

Early infections

The first-line treatment for uncomplicated syphilis (primary or secondary stages) remains a single dose of intramuscular benzathine benzylpenicillin.[61] The bacterium is highly vulnerable to penicillin when treated early, and a treated individual is typically rendered non-infective in about 24 hours.[62] Doxycycline and tetracycline are alternative choices for those allergic to penicillin; due to the risk of birth defects, these are not recommended for pregnant women.[61] Resistance to macrolides, rifampicin, and clindamycin is often present.[14] Ceftriaxone, a third-generation cephalosporin antibiotic, may be as effective as penicillin-based treatment.[2] It is recommended that a treated person avoid sex until the sores are healed.[33] In comparison to azithromycin for treatment in early infection, there is lack of strong evidence for superiority of azithromycin to benzathine penicillin G.[63]

Late infections

For neurosyphilis, due to the poor penetration of benzathine penicillin into the central nervous system, those affected are given large doses of intravenous penicillin G for a minimum of 10 days.[2][14] If a person is allergic to penicillin, ceftriaxone may be used or penicillin desensitization attempted.[2] Other late presentations may be treated with once-weekly intramuscular benzathine penicillin for three weeks.[2] Treatment at this stage solely limits further progression of the disease and has a limited effect on damage which has already occurred.[2] 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.[19]

Jarisch–Herxheimer reaction

 
Jarisch–Herxheimer reaction in a person with syphilis and human immunodeficiency virus[64]

One of the potential side effects of treatment is the Jarisch–Herxheimer reaction.[2] It frequently starts within one hour and lasts for 24 hours, with symptoms of fever, muscle pains, headache, and a fast heart rate.[2] It is caused by cytokines released by the immune system in response to lipoproteins released from rupturing syphilis bacteria.[65]

Pregnancy

Penicillin is an effective treatment for syphilis in pregnancy[66] but there is no agreement on which dose or route of delivery is most effective.[67]

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
 
Age-standardized disability adjusted life years from syphilis per 100,000 inhabitants in 2004[68]

In 2012, about 0.5% of adults were infected with syphilis, with 6 million new cases.[8] In 1999, it is believed to have infected 12 million additional people, with greater than 90% of cases in the developing world.[14] It affects between 700,000 and 1.6 million pregnancies a year, resulting in spontaneous abortions, stillbirths, and congenital syphilis.[6] During 2015, it caused about 107,000 deaths, down from 202,000 in 1990.[5][9] In sub-Saharan Africa, syphilis contributes to approximately 20% of perinatal deaths.[6] Rates are proportionally higher among intravenous drug users, those who are infected with HIV, and men who have sex with men.[11][12][13] In the United States about 55,400 people are newly infected each year.[69] 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.[19] African Americans accounted for almost half of all cases in 2010.[70] As of 2014, syphilis infections continue to increase in the United States.[71][72]

Syphilis was very common in Europe during the 18th and 19th centuries.[10] Flaubert found it universal among nineteenth-century Egyptian prostitutes.[73] In the developed world during the early 20th century, infections declined rapidly with the widespread use of antibiotics, until the 1980s and 1990s.[10] 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.[14] 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.[74] Increased rates among heterosexuals have occurred in China and Russia since the 1990s.[14] This has been attributed to unsafe sexual practices, such as sexual promiscuity, prostitution, and decreasing use of barrier protection.[14][74][75]

Left untreated, it has a mortality rate of 8% to 58%, with a greater death rate among males.[2] 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.[21] With early treatment, few complications result.[20] Syphilis increases the risk of HIV transmission by two to five times, and coinfection is common (30–60% in some urban centers).[2][14] In 2015, Cuba became the first country to eliminate mother-to-child transmission of syphilis.[76]

History

Main article: History of syphilis
 
Portrait of Gerard de Lairesse by 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.[77]

Paleopatholgists have known for decades that syphilis was present in the Americas before European contact.[78] The situation in Europe and Afro-Eurasia has been murkier and caused considerable debate.[79] 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 sixteenth century physicians wrote extensively about the new disease inflicted on them by the returning explorers.[80]

Most historians and paleopathologists initially accepted the Columbian theory, but over several decades beginning in the 1960s examples of probable treponematosis—the parent disease of syphilis, bejel, and yaws—in skeletal remains have shifted opinion.[81] As a result the pre-Columbian hypothesis is now more widely accepted.[82] It argues that treponemal disease in the form of bejel and yaws was a common childhood ailment in Europe and Afro-Eurasia beginning in ancient times. Largely benign if still unpleasant, infections occurred among the young, transmitted via shared drinking vessels or bedding with only a small bacterial load. In adulthood, people infected as children had a certain degree of immunity that prevented serious symptoms upon reinfection. Once living conditions began to change with urbanization, however, and certain more elite social groups separated themselves from their inferiors and regularly practiced better hygiene, 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.[83] The importance of bacterial load was first noted by the physician Ernest Grin in 1952 in his study of syphilis in Bosnia.[84]

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, they keep turning up, most recently in 2015.[85] 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.[86] 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.[87]

 
A healthy man and a diseased man torture Christ before his crucifixion. Books of Hours, c. 1375-1435 (detail). France. (Getty Museum Open Content Program).
 
A man with a diseased penis torments Christ. Diptych with the Passion of Christ c. 1400 (detail). Austria, Styria. (Cleveland Museum of Art Open Access Program)

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 disgust 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.[88] Progress on uncovering the historical extent of syndromes through aDNA remains slow, however, because the spirochete responsible for treponematosis is rare in skeletal remains and fragile, making it notoriously difficult to recover and analyze. 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.[89]

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.[90] 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 men perceived to be so evil they would kill the son of God indicates the artists were thinking of syphilis, which is typically transmitted through sexual intercourse with promiscuous partners, a mortal sin in medieval times. One illuminator goes so far as to show a flagellant with an exposed penis, red at the tip as though infected with a syphilitic sore. Others show the deformed teeth associated with congenital syphilis—Hutchinson's incisors—or the eye deformity ptosis that often appears in victims of the disease.

It remains mysterious why the authors of medieval medical treatises so uniformly refrained from describing syphilis or commenting on its existence in the population. Probably many 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 appears, 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 twentieth 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.[91]

The first written records of an outbreak of syphilis in Europe occurred in 1495 in Naples, Italy, during a French invasion (Italian War of 1494–98).[10][37] Since it was claimed to have been spread by French troops, it was initially called the "French disease" by the people of Naples.[92] The disease reached London in 1497 and was recorded at St Batholomew's Hospital as infected 10 out of the 20 patients.[93] In 1530, the pastoral name "syphilis" (the name of a character) was first used by the Italian physician and poet Girolamo Fracastoro as the title of his Latin poem in dactylic hexameter Syphilis sive morbus gallicus (Syphilis or The French Disease) describing the ravages of the disease in Italy.[94][95] In Great Britain it was also called the "Great Pox".[96][97]

In the 16th through 19th centuries, syphilis was one of the largest public health burdens in prevalence, symptoms, and disability,[98]: 208–209 [99] although records of its true prevalence were generally not kept because of the fearsome and sordid status of sexually transmitted infections in those centuries.[98]: 208–209  According to a 2020 study, more than 20% of individuals in the age range 15–34 years in late 18th century London were treated for syphilis.[100] At the time the causative agent was unknown but it was well known that it was spread sexually and also often from mother to child. Its association with sex, especially 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.[96]

The causative organism, Treponema pallidum, was first identified by Fritz Schaudinn and Erich Hoffmann, in 1905.[101] The first effective treatment for syphilis was arsphenamine, discovered by Sahachiro Hata in 1909, during a survey of hundreds of newly synthesized organic arsenical compounds led by Paul Ehrlich. It was manufactured and marketed from 1910 under the trade name Salvarsan by Hoechst AG.[102] This organoarsenic compound was the first modern chemotherapeutic agent.

During the 20th century, as both microbiology and pharmacology advanced greatly, syphilis, like many other infectious diseases, became more of a manageable burden than a scary and disfiguring mystery, at least in 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,[96] at which time it became the main treatment.[103]

Many famous historical figures, including Franz Schubert, Arthur Schopenhauer, Édouard Manet,[10] Charles Baudelaire,[104] and Guy de Maupassant are believed to have had the disease.[105] Friedrich Nietzsche was long believed to have gone mad as a result of tertiary syphilis, but that diagnosis has recently come into question.[106]

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 Albrecht Dürer's Syphilitic Man (1496), a woodcut believed to represent a Landsknecht, a Northern European mercenary.[107] 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".[108][109]

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.[110]

Tuskegee and Guatemala studies

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

The "Tuskegee Study of Untreated Syphilis in the Negro Male" was an infamous, unethical and racist clinical study conducted between 1932 and 1972 by the U.S. Public Health Service.[111][112] 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.[113]

The Public Health Service started working on this study in 1932 in collaboration with Tuskegee University, a historically black college in Alabama. Researchers enrolled 600 poor, African-American sharecroppers from Macon County, Alabama in the study. Of these men, 399 had contracted syphilis before the study began, and 201 did not have the disease.[112] Medical care, hot meals and free burial insurance were given to those who participated. The men were told that the study would last six months, but in the end it continued for 40 years.[112] After funding for treatment was lost, the study was continued without informing the men that they were only being studied and would not be treated. Facing insufficient participation, the Macon County Health Department nevertheless wrote to subjects to offer them a "last chance" to get a special "treatment", which was not a treatment at all, but a spinal tap administered exclusively for diagnostic purposes.[111] None of the men infected were ever told that they had the disease, and none were treated with penicillin even after the antibiotic had been proven to successfully treat syphilis. According to the 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.[112]

The 40-year study became a textbook example of poor medical ethics because researchers had knowingly withheld treatment with penicillin and because the subjects had been misled concerning the purposes of the study. The revelation in 1972 of these study failures by a 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,[114] communication of diagnosis, and accurate reporting of test results.[115]

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

Similar experiments were carried out in Guatemala from 1946 to 1948. It was done during the administration of American President Harry S. Truman and Guatemalan President Juan José Arévalo with the cooperation of some Guatemalan health ministries and officials.[116] Doctors infected soldiers, prostitutes, prisoners and 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.[117][118] 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."[119] The experiments were led by physician John Charles Cutler who also participated in the late stages of the Tuskegee syphilis experiment.[120]

Names

It 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.[121][122] Since it was a disgraceful disease, the disease was known in several countries by the name of their neighbouring country.[103] 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".[103] To the Turks it was known as the "Christian disease", whilst in India, the Hindus and Muslims named the disease after each other.[103]

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Further reading

  • Ghanem KG, Ram S, Rice PA (February 2020). "The Modern Epidemic of Syphilis". N. Engl. J. Med. 382 (9): 845–54. doi:10.1056/NEJMra1901593. PMID 32101666. S2CID 211537893.
  • Ropper AH (October 2019). "Neurosyphilis". N. Engl. J. Med. 381 (14): 1358–63. doi:10.1056/NEJMra1906228. PMID 31577877. S2CID 242487360.

External links

 
Wikipedia's health care articles can be viewed offline with the Medical Wikipedia app.
  • "Syphilis - CDC Fact Sheet" Centers for Disease Control and Prevention (CDC)
  • UCSF HIV InSite Knowledge Base Chapter: Syphilis and HIV 20 January 2013 at the Wayback Machine
  • Recommendations for Public Health Surveillance of Syphilis in the United States
  • Pastuszczak, M.; Wojas-Pelc, A. (2013). "Current standards for diagnosis and treatment of syphilis: Selection of some practical issues, based on the European (IUSTI) and U.S. (CDC) guidelines". Advances in Dermatology and Allergology. 30 (4): 203–210. doi:10.5114/pdia.2013.37029. PMC 3834708. PMID 24278076.

March 20, 2023
syphilis, sexually, transmitted, infection, caused, bacterium, treponema, pallidum, subspecies, pallidum, signs, symptoms, syphilis, vary, depending, which, four, stages, presents, primary, secondary, latent, tertiary, primary, stage, classically, presents, wi. Syphilis ˈ s ɪ f e l ɪ s is a sexually transmitted infection caused by the bacterium Treponema pallidum subspecies pallidum 3 The signs and symptoms of syphilis vary depending in which of the four stages it presents primary secondary latent and tertiary 1 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 1 In secondary syphilis a diffuse rash occurs which frequently involves the palms of the hands and soles of the feet 1 There may also be sores in the mouth or vagina 1 In latent syphilis which can last for years there are few or no symptoms 1 In tertiary syphilis there are gummas soft non cancerous growths neurological problems or heart symptoms 2 Syphilis has been known as the great imitator as it may cause symptoms similar to many other diseases 1 2 SyphilisElectron micrograph of Treponema pallidumSpecialtyInfectious diseaseSymptomsFirm painless non itchy skin ulcer 1 CausesTreponema pallidum usually spread by sex 1 Diagnostic methodBlood tests dark field microscopy of infected fluid 1 2 Differential diagnosisMany other diseases 1 PreventionCondoms Long term monogamous relationships 1 TreatmentAntibiotics 3 Frequency45 4 million 0 6 2015 4 Deaths107 000 2015 5 Syphilis is most commonly spread through sexual activity 1 It may also be transmitted from mother to baby during pregnancy or at birth resulting in congenital syphilis 1 6 Other diseases caused by Treponema bacteria include yaws T pallidum subspecies pertenue pinta T carateum and nonvenereal endemic syphilis T pallidum subspecies endemicum 2 These three diseases are not typically sexually transmitted 7 Diagnosis is usually made by using blood tests the bacteria can also be detected using dark field microscopy 1 The Centers for Disease Control and Prevention U S recommend all pregnant women be tested 1 The risk of sexual transmission of syphilis can be reduced by using a latex or polyurethane condom 1 Syphilis can be effectively treated with antibiotics 3 The preferred antibiotic for most cases is benzathine benzylpenicillin injected into a muscle 3 In those who have a severe penicillin allergy doxycycline or tetracycline may be used 3 In those with neurosyphilis intravenous benzylpenicillin or ceftriaxone is recommended 3 During treatment people may develop fever headache and muscle pains a reaction known as Jarisch Herxheimer 3 In 2015 about 45 4 million people had syphilis infections 4 of which six million were new cases 8 During 2015 it caused about 107 000 deaths down from 202 000 in 1990 5 9 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 2 10 This is believed to be partly due to increased sexual activity prostitution and decreasing use of condoms 11 12 13 Contents 1 Signs and symptoms 1 1 Primary 1 2 Secondary 1 3 Latent 1 4 Tertiary 1 5 Congenital 2 Cause 2 1 Bacteriology 2 2 Transmission 3 Diagnosis 3 1 Blood tests 3 2 Direct testing 4 Prevention 4 1 Vaccine 4 2 Sex 4 3 Congenital disease 4 4 Screening 5 Treatment 5 1 Historic use of mercury 5 2 Early infections 5 3 Late infections 5 4 Jarisch Herxheimer reaction 5 5 Pregnancy 6 Epidemiology 7 History 7 1 Arts and literature 7 2 Tuskegee and Guatemala studies 7 3 Names 8 References 9 Further reading 10 External linksSigns and symptomsSyphilis can present in one of four different stages primary secondary latent and tertiary 2 and may also occur congenitally 14 It was referred to as the great imitator by Sir William Osler due to its varied presentations 2 15 16 Primary Primary syphilis is typically acquired by direct sexual contact with the infectious lesions of another person 17 Approximately 2 6 weeks after contact with a range of 10 90 days a skin lesion called a chancre appears at the site and this contains infectious spirochetes 18 19 This is classically 40 of the time a single firm painless non itchy skin ulceration with a clean base and sharp borders approximately 0 3 3 0 cm in size 2 The lesion may take on almost any form 20 In the classic form it evolves from a macule to a papule and finally to an erosion or ulcer 20 Occasionally multiple lesions may be present 40 2 with multiple lesions being more common when coinfected with HIV 20 Lesions may be painful or tender 30 and they may occur in places other than the genitals 2 7 20 The most common location in women is the cervix 44 the penis in heterosexual men 99 and anally and rectally in men who have sex with men 34 20 Lymph node enlargement frequently 80 occurs around the area of infection 2 occurring seven to 10 days after chancre formation 20 The lesion may persist for three to six weeks if left untreated 2 Secondary Typical presentation of secondary syphilis with a rash on the palms of the hands Reddish papules and nodules over much of the body due to secondary syphilis Secondary syphilis occurs approximately four to ten weeks after the primary infection 2 While secondary disease is known for the many different ways it can manifest symptoms most commonly involve the skin mucous membranes and lymph nodes 21 There may be a symmetrical reddish pink non itchy rash on the trunk and extremities including the palms and soles 2 22 The rash may become maculopapular or pustular 2 It may form flat broad whitish wart like lesions on mucous membranes known as condyloma latum 2 All of these lesions harbor bacteria and are infectious 2 Other symptoms may include fever sore throat malaise weight loss hair loss and headache 2 Rare manifestations include liver inflammation kidney disease joint inflammation periostitis inflammation of the optic nerve uveitis and interstitial keratitis 2 23 The acute symptoms usually resolve after three to six weeks 23 about 25 of people may present with a recurrence of secondary symptoms 21 24 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 21 Latent Latent syphilis is defined as having serologic proof of infection without symptoms of disease 17 It develops after secondary syphilis and is divided into early latent and late latent stages 25 Early latent syphilis is defined by the World Health Organization as less than 2 years after original infection 25 Early latent syphilis is infectious as up to 25 of people can develop a recurrent secondary infection during which spirochetes are actively replicating and are infectious 25 Two years after the original infection the person will enter late latent syphilis and is not as infectious as the early phase 23 26 The latent phase of syphilis can last many years after which without treatment approximately 15 40 of people can develop tertiary syphilis 27 Tertiary Model of a head of a person with tertiary gummatous syphilis Musee 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 2 23 Without treatment a third of infected people develop tertiary disease 23 People with tertiary syphilis are not infectious 2 Gummatous syphilis or late benign syphilis usually occurs 1 to 46 years after the initial infection with an average of 15 years 2 This stage is characterized by the formation of chronic gummas which are soft tumor like balls of inflammation which may vary considerably in size 2 They typically affect the skin bone and liver but can occur anywhere 2 Cardiovascular syphilis usually occurs 10 30 years after the initial infection 2 The most common complication is syphilitic aortitis which may result in aortic aneurysm formation 2 Neurosyphilis refers to an infection involving the central nervous system Involvement of the central nervous system in syphilis either asymptomatic or symptomatic can occur at any stage of the infection 19 It may occur early being either asymptomatic or in the form of syphilitic meningitis or late as meningovascular syphilis manifesting as general paresis or tabes dorsalis 2 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 spinal cord inflammation 28 Late symptomatic neurosyphilis can develop decades after the original infection and includes 2 types general paresis and tabes dorsalis General paresis presents with dementia personality changes delusions seizures psychosis and depression 28 Tabes dorsalis is characterized by gait instability sharp pains in the trunk and limbs impaired positional sensation of the limbs as well as having a positive Romberg s sign 28 Both tabes dorsalis and general paresis may present with Argyll Robertson pupil which are pupils that constrict when the person focuses on near objects accommodation reflex but do not constrict when exposed to bright light pupillary reflex Congenital Main article Congenital syphilis Congenital syphilis is that which is transmitted during pregnancy or during birth 6 Two thirds of syphilitic infants are born without symptoms 6 Common symptoms that develop over the first couple of years of life include enlargement of the liver and spleen 70 rash 70 fever 40 neurosyphilis 20 and lung inflammation 20 6 If untreated late congenital syphilis may occur in 40 including saddle nose deformation Higoumenakis sign saber shin or Clutton s joints among others 6 Infection during pregnancy is also associated with miscarriage 29 The three main dental defects in congenital syphilis are Hutchinson s incisors screwdriver shaped incisors Moon s molars or bud molars and Fournier s molars or mulberry molars molars with abnormal occlusal anatomy resembling a mulberry 30 CauseBacteriology Histopathology of Treponema pallidum spirochetes using a modified Steiner silver stain Main article Treponema pallidum Treponema pallidum subspeciespallidum is a spiral shaped Gram negative highly mobile bacterium 10 20 Three other human diseases are caused by related Treponema pallidum subspecies including yaws subspecies pertenue pinta subspecies carateum and bejel subspecies endemicum 2 Unlike subspecies pallidum they do not cause neurological disease 6 Humans are the only known natural reservoir for subspecies pallidum 14 It is unable to survive more than a few days without a host 20 This is due to its small genome 1 14Mbp failing to encode the metabolic pathways necessary to make most of its macronutrients 20 It has a slow doubling time of greater than 30 hours 20 The bacterium is known for its ability to evade the immune system and its invasiveness 31 Transmission Syphilis is transmitted primarily by sexual contact or during pregnancy from a mother to her baby the spirochete is able to pass through intact mucous membranes or compromised skin 2 14 It is thus transmissible by kissing near a lesion as well as oral vaginal and anal sex 2 32 Approximately 30 to 60 of those exposed to primary or secondary syphilis will get the disease 23 Its infectivity is exemplified by the fact that an individual inoculated with only 57 organisms has a 50 chance of being infected 20 Most new cases in the United States 60 occur in men who have sex with men and in this population 20 of syphilis cases were due to oral sex alone 2 32 Syphilis can be transmitted by blood products but the risk is low due to screening of donated blood in many countries 2 The risk of transmission from sharing needles appears to be limited 2 It is not generally possible to contract syphilis through toilet seats daily activities hot tubs or sharing eating utensils or clothing 33 This is mainly because the bacteria die very quickly outside of the body making transmission by objects extremely difficult 34 Diagnosis This poster acknowledges the social stigma of syphilis while urging those who possibly have the disease to be tested circa 1936 Micrograph of secondary syphilis skin lesions A B H amp E stain of SS lesions C D IHC staining reveals abundant spirochetes 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 35 Syphilis is difficult to diagnose clinically during early infection 20 Confirmation is either via blood tests or direct visual inspection using dark field microscopy 2 36 Blood tests are more commonly used as they are easier to perform 2 Diagnostic tests are unable to distinguish between the stages of the disease 37 Blood tests Blood tests are divided into nontreponemal and treponemal tests 20 Nontreponemal tests are used initially and include venereal disease research laboratory VDRL and rapid plasma reagin RPR tests False positives on the nontreponemal tests can occur with some viral infections such as varicella chickenpox and measles False positives can also occur with lymphoma tuberculosis malaria endocarditis connective tissue disease and pregnancy 17 Because of the possibility of false positives with nontreponemal tests confirmation is required with a treponemal test such as treponemal pallidum particle agglutination TPHA or fluorescent treponemal antibody absorption test FTA Abs 2 Treponemal antibody tests usually become positive two to five weeks after the initial infection 20 Neurosyphilis is diagnosed by finding high numbers of leukocytes predominately lymphocytes and high protein levels in the cerebrospinal fluid in the setting of a known syphilis infection 2 17 Direct testing Dark field microscopy of serous fluid from a chancre may be used to make an immediate diagnosis 20 Hospitals do not always have equipment or experienced staff members and testing must be done within 10 minutes of acquiring the sample 20 Two other tests can be carried out on a sample from the chancre direct fluorescent antibody DFA and polymerase chain reaction PCR tests 20 DFA uses antibodies tagged with fluorescein which attach to specific syphilis proteins while PCR uses techniques to detect the presence of specific syphilis genes 20 These tests are not as time sensitive as they do not require living bacteria to make the diagnosis 20 PreventionVaccine As of 2018 update there is no vaccine effective for prevention 14 Several vaccines based on treponemal proteins reduce lesion development in an animal model but research continues 38 39 Sex Condom use reduces the likelihood of transmission during sex but does not eliminate the risk 40 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 41 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 42 Abstinence from intimate physical contact with an infected person is effective at reducing the transmission of syphilis The CDC states The surest way to avoid transmission of sexually transmitted diseases including syphilis is to abstain from sexual contact or to be in a long term mutually monogamous relationship with a partner who has been tested and is known to be uninfected 42 Congenital disease Portrait of Mr J Kay affected with what is now believed to have been congenital syphilis c 1820 43 Congenital syphilis in the newborn can be prevented by screening mothers during early pregnancy and treating those who are infected 44 The United States Preventive Services Task Force USPSTF strongly recommends universal screening of all pregnant women 45 while the World Health Organization WHO recommends all women be tested at their first antenatal visit and again in the third trimester 46 47 If they are positive it is recommended their partners also be treated 46 Congenital syphilis is still common in the developing world as many women do not receive antenatal care at all and the antenatal care others receive does not include screening 44 48 It still occasionally occurs in the developed world as those most likely to acquire syphilis are least likely to receive care during pregnancy 44 Several measures to increase access to testing appear effective at reducing rates of congenital syphilis in low to middle income countries 46 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 49 Screening The CDC recommends that sexually active men who have sex with men be tested at least yearly 50 The USPSTF also recommends screening among those at high risk 51 Syphilis is a notifiable disease in many countries including Canada 52 the European Union 53 and the United States 54 This means health care providers are required to notify public health authorities which will then ideally provide partner notification to the person s partners 55 Physicians may also encourage patients to send their partners to seek care 56 Several strategies have been found to improve follow up for STI testing including email and text messaging of reminders for appointments 57 TreatmentHistoric use of mercury As a form of chemotherapy elemental mercury had been used to treat skin diseases in Europe as early as 1363 58 As syphilis spread preparations of mercury were among the first medicines used to combat it Mercury is in fact highly anti microbial by the 16th century it was sometimes found to be sufficient to halt development of the disease when applied to ulcers as an inunction or when inhaled as a suffumigation Once the disease had gained a strong foothold however the amounts and forms of mercury necessary to control its development exceeded the human body s ability to tolerate it and the treatment became worse and more lethal than the disease Nevertheless medically directed mercury poisoning became widespread through the 17th 18th and 19th centuries in Europe North America and India 59 Mercury salts such as mercury II chloride were still in prominent medical use as late as 1916 and considered effective and worthwhile treatments 60 Early infections The first line treatment for uncomplicated syphilis primary or secondary stages remains a single dose of intramuscular benzathine benzylpenicillin 61 The bacterium is highly vulnerable to penicillin when treated early and a treated individual is typically rendered non infective in about 24 hours 62 Doxycycline and tetracycline are alternative choices for those allergic to penicillin due to the risk of birth defects these are not recommended for pregnant women 61 Resistance to macrolides rifampicin and clindamycin is often present 14 Ceftriaxone a third generation cephalosporin antibiotic may be as effective as penicillin based treatment 2 It is recommended that a treated person avoid sex until the sores are healed 33 In comparison to azithromycin for treatment in early infection there is lack of strong evidence for superiority of azithromycin to benzathine penicillin G 63 Late infections For neurosyphilis due to the poor penetration of benzathine penicillin into the central nervous system those affected are given large doses of intravenous penicillin G for a minimum of 10 days 2 14 If a person is allergic to penicillin ceftriaxone may be used or penicillin desensitization attempted 2 Other late presentations may be treated with once weekly intramuscular benzathine penicillin for three weeks 2 Treatment at this stage solely limits further progression of the disease and has a limited effect on damage which has already occurred 2 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 19 Jarisch Herxheimer reaction Jarisch Herxheimer reaction in a person with syphilis and human immunodeficiency virus 64 One of the potential side effects of treatment is the Jarisch Herxheimer reaction 2 It frequently starts within one hour and lasts for 24 hours with symptoms of fever muscle pains headache and a fast heart rate 2 It is caused by cytokines released by the immune system in response to lipoproteins released from rupturing syphilis bacteria 65 Pregnancy Penicillin is an effective treatment for syphilis in pregnancy 66 but there is no agreement on which dose or route of delivery is most effective 67 EpidemiologyMain 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 Age standardized disability adjusted life years from syphilis per 100 000 inhabitants in 2004 68 no data lt 35 35 70 70 105 105 140 140 175 175 210 210 245 245 280 280 315 315 350 350 500 gt 500 In 2012 about 0 5 of adults were infected with syphilis with 6 million new cases 8 In 1999 it is believed to have infected 12 million additional people with greater than 90 of cases in the developing world 14 It affects between 700 000 and 1 6 million pregnancies a year resulting in spontaneous abortions stillbirths and congenital syphilis 6 During 2015 it caused about 107 000 deaths down from 202 000 in 1990 5 9 In sub Saharan Africa syphilis contributes to approximately 20 of perinatal deaths 6 Rates are proportionally higher among intravenous drug users those who are infected with HIV and men who have sex with men 11 12 13 In the United States about 55 400 people are newly infected each year 69 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 19 African Americans accounted for almost half of all cases in 2010 70 As of 2014 syphilis infections continue to increase in the United States 71 72 Syphilis was very common in Europe during the 18th and 19th centuries 10 Flaubert found it universal among nineteenth century Egyptian prostitutes 73 In the developed world during the early 20th century infections declined rapidly with the widespread use of antibiotics until the 1980s and 1990s 10 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 14 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 74 Increased rates among heterosexuals have occurred in China and Russia since the 1990s 14 This has been attributed to unsafe sexual practices such as sexual promiscuity prostitution and decreasing use of barrier protection 14 74 75 Left untreated it has a mortality rate of 8 to 58 with a greater death rate among males 2 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 21 With early treatment few complications result 20 Syphilis increases the risk of HIV transmission by two to five times and coinfection is common 30 60 in some urban centers 2 14 In 2015 Cuba became the first country to eliminate mother to child transmission of syphilis 76 HistoryMain article History of syphilis Portrait of Gerard de Lairesse by 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 77 Paleopatholgists have known for decades that syphilis was present in the Americas before European contact 78 The situation in Europe and Afro Eurasia has been murkier and caused considerable debate 79 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 sixteenth century physicians wrote extensively about the new disease inflicted on them by the returning explorers 80 Most historians and paleopathologists initially accepted the Columbian theory but over several decades beginning in the 1960s examples of probable treponematosis the parent disease of syphilis bejel and yaws in skeletal remains have shifted opinion 81 As a result the pre Columbian hypothesis is now more widely accepted 82 It argues that treponemal disease in the form of bejel and yaws was a common childhood ailment in Europe and Afro Eurasia beginning in ancient times Largely benign if still unpleasant infections occurred among the young transmitted via shared drinking vessels or bedding with only a small bacterial load In adulthood people infected as children had a certain degree of immunity that prevented serious symptoms upon reinfection Once living conditions began to change with urbanization however and certain more elite social groups separated themselves from their inferiors and regularly practiced better hygiene 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 83 The importance of bacterial load was first noted by the physician Ernest Grin in 1952 in his study of syphilis in Bosnia 84 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 they keep turning up most recently in 2015 85 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 86 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 87 A healthy man and a diseased man torture Christ before his crucifixion Books of Hours c 1375 1435 detail France Getty Museum Open Content Program A man with a diseased penis torments Christ Diptych with the Passion of Christ c 1400 detail Austria Styria Cleveland Museum of Art Open Access Program 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 disgust 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 88 Progress on uncovering the historical extent of syndromes through aDNA remains slow however because the spirochete responsible for treponematosis is rare in skeletal remains and fragile making it notoriously difficult to recover and analyze 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 89 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 90 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 men perceived to be so evil they would kill the son of God indicates the artists were thinking of syphilis which is typically transmitted through sexual intercourse with promiscuous partners a mortal sin in medieval times One illuminator goes so far as to show a flagellant with an exposed penis red at the tip as though infected with a syphilitic sore Others show the deformed teeth associated with congenital syphilis Hutchinson s incisors or the eye deformity ptosis that often appears in victims of the disease It remains mysterious why the authors of medieval medical treatises so uniformly refrained from describing syphilis or commenting on its existence in the population Probably many 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 appears 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 twentieth 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 91 The first written records of an outbreak of syphilis in Europe occurred in 1495 in Naples Italy during a French invasion Italian War of 1494 98 10 37 Since it was claimed to have been spread by French troops it was initially called the French disease by the people of Naples 92 The disease reached London in 1497 and was recorded at St Batholomew s Hospital as infected 10 out of the 20 patients 93 In 1530 the pastoral name syphilis the name of a character was first used by the Italian physician and poet Girolamo Fracastoro as the title of his Latin poem in dactylic hexameter Syphilis sive morbus gallicus Syphilis or The French Disease describing the ravages of the disease in Italy 94 95 In Great Britain it was also called the Great Pox 96 97 In the 16th through 19th centuries syphilis was one of the largest public health burdens in prevalence symptoms and disability 98 208 209 99 although records of its true prevalence were generally not kept because of the fearsome and sordid status of sexually transmitted infections in those centuries 98 208 209 According to a 2020 study more than 20 of individuals in the age range 15 34 years in late 18th century London were treated for syphilis 100 At the time the causative agent was unknown but it was well known that it was spread sexually and also often from mother to child Its association with sex especially 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 96 The causative organism Treponema pallidum was first identified by Fritz Schaudinn and Erich Hoffmann in 1905 101 The first effective treatment for syphilis was arsphenamine discovered by Sahachiro Hata in 1909 during a survey of hundreds of newly synthesized organic arsenical compounds led by Paul Ehrlich It was manufactured and marketed from 1910 under the trade name Salvarsan by Hoechst AG 102 This organoarsenic compound was the first modern chemotherapeutic agent During the 20th century as both microbiology and pharmacology advanced greatly syphilis like many other infectious diseases became more of a manageable burden than a scary and disfiguring mystery at least in 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 96 at which time it became the main treatment 103 Many famous historical figures including Franz Schubert Arthur Schopenhauer Edouard Manet 10 Charles Baudelaire 104 and Guy de Maupassant are believed to have had the disease 105 Friedrich Nietzsche was long believed to have gone mad as a result of tertiary syphilis but that diagnosis has recently come into question 106 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 Albrecht Durer s Syphilitic Man 1496 a woodcut believed to represent a Landsknecht a Northern European mercenary 107 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 108 109 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 110 Tuskegee and Guatemala studies See also Tuskegee syphilis experiment and Guatemala syphilis experiment A Work Projects Administration poster about syphilis c 1940 The Tuskegee Study of Untreated Syphilis in the Negro Male was an infamous unethical and racist clinical study conducted between 1932 and 1972 by the U S Public Health Service 111 112 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 113 The Public Health Service started working on this study in 1932 in collaboration with Tuskegee University a historically black college in Alabama Researchers enrolled 600 poor African American sharecroppers from Macon County Alabama in the study Of these men 399 had contracted syphilis before the study began and 201 did not have the disease 112 Medical care hot meals and free burial insurance were given to those who participated The men were told that the study would last six months but in the end it continued for 40 years 112 After funding for treatment was lost the study was continued without informing the men that they were only being studied and would not be treated Facing insufficient participation the Macon County Health Department nevertheless wrote to subjects to offer them a last chance to get a special treatment which was not a treatment at all but a spinal tap administered exclusively for diagnostic purposes 111 None of the men infected were ever told that they had the disease and none were treated with penicillin even after the antibiotic had been proven to successfully treat syphilis According to the 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 112 The 40 year study became a textbook example of poor medical ethics because researchers had knowingly withheld treatment with penicillin and because the subjects had been misled concerning the purposes of the study The revelation in 1972 of these study failures by a 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 114 communication of diagnosis and accurate reporting of test results 115 Preparation and Use of Guayaco for Treating Syphilis after Stradanus 1590 Similar experiments were carried out in Guatemala from 1946 to 1948 It was done during the administration of American President Harry S Truman and Guatemalan President Juan Jose Arevalo with the cooperation of some Guatemalan health ministries and officials 116 Doctors infected soldiers prostitutes prisoners and 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 117 118 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 119 The experiments were led by physician John Charles Cutler who also participated in the late stages of the Tuskegee syphilis experiment 120 Names It 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 121 122 Since it was a disgraceful disease the disease was known in several countries by the name of their neighbouring country 103 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 103 To the Turks it was known as the Christian disease whilst in India the Hindus and Muslims named the disease after each other 103 References a b c d e f g h i j k l m n o p 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931 983 1932 Dutour O et al Eds 1994 L origine de la syphilis in Europe avant ou apres 1493 Paris France Editions Errance Baker B J et al 2020 Advancing the Understanding of Treponemal Disease in the Past and Present Yearbook of Physical Anthropology 171 5 41 doi 10 1002 ajpa 23988 Harper K N Zuckerman M K Harper M L Kingston J D Armelagos G J 2011 The origin and antiquity of syphilis revisited An appraisal of Old World Pre Columbian evidence of treponemal infections Yearbook of Physical Anthropology 54 99 133 https doi org 10 1002 ajpa 21613 For an introduction to this literature see Quetel C 1990 History of syphilis Baltimore MD The Johns Hopkins University Press Early work includes Henneberg M amp Henneberg R J 1994 Treponematosis in an ancient Greek colony of Metaponto southern Italy 580 250 BCE and Roberts C A 1994 Treponematosis in Gloucester England A theoretical and practical approach to the Pre Columbian theory Both in O Dutour et al Eds L origine de la syphilis in Europe avant ou apres 1493 pp 92 98 101 108 Paris France Editions Errance 1 Baker B J Crane Kramer G Dee M W Gregoricka L A Henneberg M Lee C Lukehart S A Mabey D C Roberts C A Stoddard A L W Stone A C Winingear S 2020 Advancing the Understanding of Treponemal Disease in the Past and Present Yearbook of Physical Anthropology 171 5 41 doi 10 1002 ajpa 23988 Salmon M 2022 https theconversation com manuscripts and art support archaeological evidence that syphilis was in europe long before explorers could have brought it home from the americas 182114 Hudson E H 1946 A unitarian view of treponematosis American Journal of Tropical Medicine and Hygiene 26 1946 135 139 https doi org 10 4269 ajtmh 1946 s1 26 135 The treponematoses or treponematosis The British Journal of Venereal Diseases 34 1958 22 23 Historical approach to the terminology of syphilis Archives of Dermatology 84 1961 545 562 Treponematosis and man s social evolution American Anthropologist 67 4 885 901 doi 10 1001 archderm 1961 01580160009002 On status see also Marylynn Salmon Medieval Syphilis and Treponemal Disease Leeds Arc Humanities Press 8 30 33 Grin E I 1952 Endemic Treponematosis in Bosnia Clinical and epidemiological observations on a successful mass treatment campaign Bulletin of the World Health Organization 7 11 25 Walker D Powers N Connell B amp Redfern R 2015 Evidence of skeletal treponematosis from the Medieval burial ground of St Mary Spital London and implications for the origins of the disease in Europe American Journal of Physical Anthropology 156 90 101 https doi org 10 1002 ajpa 22630 and Gaul J S Grossschmidt K Budenbauer C amp Kanz Fabian 2015 A probable case of congenital syphilis from pre Columbian Austria Anthropologischer Anzeiger 72 451 472 DOI 10 1127 anthranz 2015 0504 Baker B J et al 2020 Advancing the Understanding of Treponemal Disease in the Past and Present Yearbook of Physical Anthropology 171 5 41 doi 10 1002 ajpa 23988 They include Henneberg M amp Henneberg R J 1994 Treponematosis in an ancient Greek colony of Metaponto southern Italy 580 250 BCE In O Dutour et al Eds L origine de la syphilis in Europe Avant ou apres 1493 pp 92 98 Paris France Editions Errance Stirland Ann Evidence for Pre Columbian Treponematosis in Europe In Dutour O Palfi G Berato J amp Brun J P Eds 1994 L origine de la syphilis in Europe avant ou apres 1493 Paris France Editions Errance and Criminals and Paupers The Graveyard of St Margaret Fyebriggate in combusto Norwich With Contributions from Brian Ayers and Jayne Brown East Anglian Archaeology 129 Dereham Historic Environment Norfolk Museums and Archaeology Service 2009 Erdal Y S 2006 A pre Columbian case of congenital syphilis from Anatolia Nicaea 13th century AD International Journal of Osteoarchaeology 16 16 33 https doi org 10 1002 oa 802 Cole G and T Waldron Apple Down 152 a putative case of syphilis from sixth century AD Anglo Saxon England American Journal of Physical Anthropology 2011 Jan 144 1 72 9 doi 10 1002 ajpa 21371 Epub 2010 Aug 18 PMID 20721939 Roberts C A 1994 Treponematosis in Gloucester England A theoretical and practical approach to the Pre Columbian theory In O Dutour et al Eds L origine de la syphilis in Europe avant ou apres 1493 pp 101 108 Paris France Editions Errance Fraser C M Norris S J Weinstock G M White O Sutton G G Dodson R Venter J C 1998 Complete genome sequence of Treponema pallidum the syphilis spirochete Science 281 5375 375 388 https doi org 10 1371 journal pntd 0001832 Cejkova D Zobanikova M Chen L Pospisilova P Strouhal M Qin X Smajs D 2012 Whole genome sequences of three Treponema pallidum ssp pertenue strains yaws and syphilis treponemes differ in less than 0 2 of the genome sequence PLoS Neglected Tropical Diseases 6 1 e1471 doi 10 1371 journal pone 0015713 Mikalova L Strouhal M Cejkova D Zobanikova M Pospisilova P Norris S J Smajs D 2010 Genome analysis of Treponema pallidum subsp pallidum and subsp pertenue strains Most of the genetic differences are localized in six regions PLoS ONE 5 e15713 doi org 10 1371 journal pone 0015713 Staudova B Strouhal M Zobanikova M Cejkova D Fulton L L Chen L Smajs D 2014 Whole genome sequence of the Treponema pallidum subsp endemicum strain Bosnia A The genome is related to yaws treponemes but contains few loci similar to syphilis treponemes PLoS Neglected Tropical Diseases 8 11 e3261 https doi org 10 1371 journal pntd 0003261 Majander K Pfrengle S Kocher A Kuhnert J K Schuenemann V J 2020 Ancient Bacterial Genomes Reveal a High Diversity of Treponema pallidum Strains in Early Modern Europe Current Biology 30 3788 3803 Elsevier Inc doi org 10 1016 j cub 2020 07 058 See her Medieval Syphilis and Treponemal Disease Leeds Arc Humanities Press 2022 61 79 Arrizabalaga Jon The Changing Identity of the French Pox in Early Renaissance Castile In Between Text and Patient The Medical Enterprise in Medieval and Early Modern Europe edited by Florence Eliza Glaze and Brian K Nance 397 417 Florence SISMEL 2011 Winters Adam 2006 Syphilis New York Rosen Pub Group p 17 ISBN 9781404209060 Archived from the original on 18 August 2020 Retrieved 15 September 2017 Hidden Killers of the Tudor Home The Horrors of Tudor Dentistry etc Dormandy Thomas 2006 The worst of evils man s fight against pain a history Uncorrected page proof ed New Haven Yale University Press p 99 ISBN 978 0300113228 Anthony Grafton March 1995 Drugs and Diseases New World Biology and Old World Learning New Worlds Ancient Texts The Power of Tradition and the Shock of Discovery Harvard University Press pp 159 194 ISBN 9780674618763 a b c Dayan L Ooi C October 2005 Syphilis treatment old and new Expert Opinion on Pharmacotherapy 6 13 2271 80 doi 10 1517 14656566 6 13 2271 PMID 16218887 S2CID 6868863 Knell RJ 7 May 2004 Syphilis in renaissance Europe rapid evolution of an introduced sexually transmitted disease Proceedings Biological Sciences 271 Suppl 4 Suppl 4 S174 6 doi 10 1098 rsbl 2003 0131 PMC 1810019 PMID 15252975 a b de Kruif Paul 1932 Ch 7 Schaudinn The Pale Horror Men Against Death New York Harcourt Brace OCLC 11210642 Archived from the original on 28 August 2021 Retrieved 30 September 2020 Rayment Michael Sullivan Ann K et al 2011 He who knows syphilis knows medicine the return of an old friend British Journal of Cardiology 18 56 58 archived from the original on 7 August 2020 retrieved 7 April 2018 He who knows syphilis knows medicine said Father of Modern Medicine Sir William Osler at the turn of the 20th Century So common was syphilis in days gone by all physicians were attuned to its myriad clinical presentations Indeed the 19th century saw the development of an entire medical subspecialty syphilology devoted to the study of the great imitator Treponema pallidum Szreter Simon Siena Kevin 2020 The pox in Boswell s London an estimate of the extent of syphilis infection in the metropolis in the 1770s The Economic History Review 74 2 372 399 doi 10 1111 ehr 13000 ISSN 1468 0289 Schaudinn Fritz Richard Hoffmann Erich 1905 Vorlaufiger Bericht uber das Vorkommen von Spirochaeten in syphilitischen Krankheitsprodukten und bei Papillomen Preliminary report on the occurrence of Spirochaetes in syphilitic chancres and papillomas Arbeiten aus dem Kaiserlichen Gesundheitsamte 22 527 534 Salvarsan Chemical amp Engineering News Archived from the original on 10 October 2018 Retrieved 1 February 2010 a b c d Tampa M Sarbu I Matei C Benea V Georgescu SR 15 March 2014 Brief History of Syphilis Journal of Medicine and Life 7 1 4 10 PMC 3956094 PMID 24653750 Hayden Deborah 2008 Pox Genius Madness and the Mysteries of Syphilis Basic Books p 113 ISBN 978 0786724130 Archived from the original on 19 August 2020 Retrieved 15 September 2017 Halioua Bruno 30 June 2003 Comment la syphilis emporta Maupassant La Revue du Praticien www larevuedupraticien fr Archived from the original on 2 June 2016 Retrieved 29 November 2016 Bernd Magnus Nietzsche Friedrich Encyclopaedia Britannica Archived from the original on 23 July 2012 Retrieved 19 May 2012 Eisler CT Winter 2009 Who is Durer s Syphilitic Man Perspectives in Biology and Medicine 52 1 48 60 doi 10 1353 pbm 0 0065 PMID 19168944 S2CID 207268142 Hughes Robert 2007 Things I didn t know a memoir 1st Vintage Book ed New York Vintage p 346 ISBN 978 0 307 38598 7 Wilson Elizabeth 2005 Entwistle Joanne ed Body dressing Online Ausg ed Oxford Berg Publishers p 205 ISBN 978 1 85973 444 5 Reid Basil A 2009 Myths and realities of Caribbean history Online Ausg ed Tuscaloosa University of Alabama Press p 113 ISBN 978 0 8173 5534 0 Archived from the original on 2 February 2016 a b Brandt Allan M December 1978 Racism and Research The Case of the Tuskegee Syphilis Study The Hastings Center Report 8 6 21 29 doi 10 2307 3561468 JSTOR 3561468 PMID 721302 Archived from the original on 18 January 2021 Retrieved 9 December 2020 a b c d Tuskegee Study Timeline NCHHSTP CDC 25 June 2008 Archived from the original on 3 September 2011 Retrieved 4 December 2008 Reverby Susan M 2009 Examining Tuskegee the infamous syphilis study and its legacy Chapel Hill University of North Carolina Press ISBN 9780807833100 OCLC 496114416 Code of Federal Regulations Title 45 Part 46 Protections of Human Subjects 46 1 1 i PDF U S Department of Health and Humand Services 15 January 2009 Archived PDF from the original on 28 March 2016 Retrieved 22 February 2010 Final Report of the Tuskegee Syphilis Study Legacy Committee May 1996 University of Virginia Archived from the original on 5 July 2017 Retrieved 5 August 2019 Fact Sheet on the 1946 1948 U S Public Health Service Sexually Transmitted Diseases STD Inoculation Study United States Department of Health and Human Services nd Archived from the original on 25 April 2013 Retrieved 15 April 2013 Guatemalans died in 1940s US syphilis study BBC News 29 August 2011 Archived from the original on 1 December 2019 Retrieved 29 August 2011 Reverby Susan M 3 June 2012 Ethical Failures and History Lessons The U S Public Health Service Research Studies in Tuskegee and Guatemala Public Health Reviews 34 1 doi 10 1007 BF03391665 Hensley Scott 1 October 2010 U S Apologizes For Syphilis Experiments in Guatemala National Public Radio Archived from the original on 10 November 2014 Retrieved 1 October 2010 Chris McGreal 1 October 2010 US says sorry for outrageous and abhorrent Guatemalan syphilis tests The Guardian Archived from the original on 14 May 2019 Retrieved 2 October 2010 Conducted between 1946 and 1948 the experiments were led by John Cutler a US health service physician who would later be part of the notorious Tuskegee syphilis study in Alabama in the 1960s Grauer Anne L 2011 A Companion to Paleopathology John Wiley amp Sons ISBN 9781444345926 Archived from the original on 11 January 2022 Retrieved 23 August 2020 Tagarelli A Lagonia P Tagarelli G Quattrone A Piro A April 2011 The relation between the names and designations of syphilis in the 16th century and its clinical gravity Sexually Transmitted Infections 87 3 247 doi 10 1136 sti 2010 048405 PMID 21325442 S2CID 19185641 Further readingGhanem KG Ram S Rice PA February 2020 The Modern Epidemic of Syphilis N Engl J Med 382 9 845 54 doi 10 1056 NEJMra1901593 PMID 32101666 S2CID 211537893 Ropper AH October 2019 Neurosyphilis N Engl J Med 381 14 1358 63 doi 10 1056 NEJMra1906228 PMID 31577877 S2CID 242487360 External linksPortal medicine Wikipedia s health care articles can be viewed offline with the Medical Wikipedia app Syphilis at Wikipedia s sister projects Definitions from Wiktionary Media from Commons News from Wikinews Quotations from Wikiquote Texts from Wikisource Textbooks from Wikibooks Resources from Wikiversity Syphilis CDC Fact Sheet Centers for Disease Control and Prevention CDC UCSF HIV InSite Knowledge Base Chapter Syphilis and HIV Archived 20 January 2013 at the Wayback Machine Recommendations for Public Health Surveillance of Syphilis in the United States Pastuszczak M Wojas Pelc A 2013 Current standards for diagnosis and treatment of syphilis Selection of some practical issues based on the European IUSTI and U S CDC guidelines Advances in Dermatology and Allergology 30 4 203 210 doi 10 5114 pdia 2013 37029 PMC 3834708 PMID 24278076 Retrieved from https en wikipedia org w index php title Syphilis amp oldid 1141812625, wikipedia, wiki, book, books, library,

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