Syphilis

Syphilis
Electron micrograph of Treponema pallidum
Classification and external resources
Specialty	Infectious disease
ICD-10	A50-A53
ICD-9-CM	090-097
DiseasesDB	29054
MedlinePlus	000861
eMedicine	med/2224 emerg/563 derm/413
Patient UK	Syphilis
MeSH	D013587

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

Syphilis is most commonly spread through sexual activity.^[2] It may also be transmitted from mother to baby during pregnancy or at birth, resulting in congenital syphilis.^[2][4] Other human diseases caused by related Treponema pallidum include yaws (subspecies pertenue), pinta (subspecies carateum), and bejel (subspecies endemicum).^[3] Diagnosis is usually made by using blood tests; the bacteria can also be detected using dark field microscopy. The Center for Disease Control recommends all pregnant women be tested.^[2]

The risk of syphilis can be decreased by latex condom use or not having sex.^[2] Syphilis can be effectively treated with antibiotics. The preferred antibiotic for most cases is benzathine penicillin G injected into a muscle. In those who have a severe penicillin allergy, doxycycline or tetracycline may be used. In those with neurosyphilis intravenous penicillin G potassium or ceftriaxone is recommended. During treatment people may develop fever, headache, and muscle pains, a reaction known as Jarisch-Herxheimer.^[1]

In 2013 syphilis infected about 315,000 people.^[5] During 2010 it caused about 113,000 deaths down from 202,000 in 1990.^[6] After decreasing dramatically with the availability of penicillin in the 1940s, rates of infection have increased since the turn of the millennium in many countries, often in combination with human immunodeficiency virus (HIV).^[3][7] This is believed to be partly due to increased promiscuity, prostitution, decreasing use of condoms, and unsafe sexual practices among men who have sex with men.^[8][9][10] In 2015, Cuba became the first country in the world to eliminate mother-to-child transmission of syphilis.^[11]

Signs and symptoms

Syphilis can present in one of four different stages: primary, secondary, latent, and tertiary,^[3] and may also occur congenitally.^[12] It was referred to as "the great imitator" by Sir William Osler due to its varied presentations.^[3][13]

Primary

Primary chancre of syphilis at the site of infection on the penis

Primary syphilis is typically acquired by direct sexual contact with the infectious lesions of another person.^[14] Approximately 3 to 90 days after the initial exposure (average 21 days) a skin lesion, called a chancre, appears at the point of contact.^[3] This is classically (40% of the time) a single, firm, painless, non-itchy skin ulceration with a clean base and sharp borders between 0.3 and 3.0 cm in size.^[3] The lesion may take on almost any form.^[15] In the classic form, it evolves from a macule to a papule and finally to an erosion or ulcer.^[15] Occasionally, multiple lesions may be present (~40%),^[3] with multiple lesions more common when coinfected with HIV. Lesions may be painful or tender (30%), and they may occur outside of the genitals (2–7%). The most common location in women is the cervix (44%), the penis in heterosexual men (99%), and anally and rectally relatively commonly in men who have sex with men (34%).^[15] Lymph node enlargement frequently (80%) occurs around the area of infection,^[3] occurring seven to 10 days after chancre formation.^[15] The lesion may persist for three to six weeks without treatment.^[3]

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.^[3] While secondary disease is known for the many different ways it can manifest, symptoms most commonly involve the skin, mucous membranes, and lymph nodes.^[16] There may be a symmetrical, reddish-pink, non-itchy rash on the trunk and extremities, including the palms and soles.^[3][17] The rash may become maculopapular or pustular. It may form flat, broad, whitish, wart-like lesions known as condyloma latum on mucous membranes. All of these lesions harbor bacteria and are infectious. Other symptoms may include fever, sore throat, malaise, weight loss, hair loss, and headache.^[3] Rare manifestations include liver inflammation, kidney disease, joint inflammation, periostitis, inflammation of the optic nerve, uveitis, and interstitial keratitis.^[3][18] The acute symptoms usually resolve after three to six weeks;^[18] about 25% of people may present with a recurrence of secondary symptoms. Many people who present with secondary syphilis (40–85% of women, 20–65% of men) do not report previously having had the classic chancre of primary syphilis.^[16]

Latent

Latent syphilis is defined as having serologic proof of infection without symptoms of disease.^[14] It is further described as either early (less than 1 year after secondary syphilis) or late (more than 1 year after secondary syphilis) in the United States.^[18] The United Kingdom uses a cut-off of two years for early and late latent syphilis.^[15] Early latent syphilis may have a relapse of symptoms. Late latent syphilis is asymptomatic, and not as contagious as early latent syphilis.^[18]

Tertiary

Person with tertiary (gummatous) syphilis. Bust in Musée de l'Homme, Paris.

Tertiary syphilis may occur approximately 3 to 15 years after the initial infection, and may be divided into three different forms: gummatous syphilis (15%), late neurosyphilis (6.5%), and cardiovascular syphilis (10%).^[3][18] Without treatment, a third of infected people develop tertiary disease.^[18] People with tertiary syphilis are not infectious.^[3]

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

Neurosyphilis refers to an infection involving the central nervous system. It may occur early, being either asymptomatic or in the form of syphilitic meningitis, or late as meningovascular syphilis, general paresis, or tabes dorsalis, which is associated with poor balance and lightning pains in the lower extremities. Late neurosyphilis typically occurs 4 to 25 years after the initial infection. Meningovascular syphilis typically presents with apathy and seizure, and general paresis with dementia and tabes dorsalis.^[3] Also, there may be Argyll Robertson pupils, which are bilateral small pupils that constrict when the person focuses on near objects, but do not constrict when exposed to bright light.

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

Congenital

Congenital syphilis is that which is transmitted during pregnancy or during birth. Two-thirds of syphilitic infants are born without symptoms. 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%). If untreated, late congenital syphilis may occur in 40%, including saddle nose deformation, Higoumenakis sign, saber shin, or Clutton's joints among others.^[4]

Cause

Bacteriology

Histopathology of Treponema pallidum spirochetes using a modified Steiner silver stain

Treponema pallidum subspecies pallidum is a spiral-shaped, Gram-negative, highly mobile bacterium.^[7][15] Three other human diseases are caused by related Treponema pallidum, including yaws (subspecies pertenue), pinta (subspecies carateum) and bejel (subspecies endemicum).^[3] Unlike subtype pallidum, they do not cause neurological disease.^[4] Humans are the only known natural reservoir for subspecies pallidum.^[12] It is unable to survive without a host for more than a few days. This is due to its small genome (1.14 MDa) failing to encode the metabolic pathways necessary to make most of its macronutrients. It has a slow doubling time of greater than 30 hours.^[15]

Transmission

Syphilis is transmitted primarily by sexual contact or during pregnancy from a mother to her fetus; the spirochaete is able to pass through intact mucous membranes or compromised skin.^[3][12] It is thus transmissible by kissing near a lesion, as well as oral, vaginal, and anal sex.^[3] Approximately 30 to 60% of those exposed to primary or secondary syphilis will get the disease.^[18] Its infectivity is exemplified by the fact that an individual inoculated with only 57 organisms has a 50% chance of being infected.^[15] Most (60%) of new cases in the United States occur in men who have sex with men. It can be transmitted via blood products. It is tested for in many countries and thus the risk is low. The risk of transmission from sharing needles appears limited.^[3]

It is not generally possible to contract syphilis through toilet seats, daily activities, hot tubs, or sharing eating utensils or clothing.^[19] This is mainly because the bacteria die very quickly outside of the body, making transmission via objects extremely difficult.^[20]

Diagnosis

This poster acknowledges the social stigma of syphilis, while urging those who possibly have the disease to be tested (circa 1936).

Syphilis is difficult to diagnose clinically early in its presentation.^[15] Confirmation is either via blood tests or direct visual inspection using microscopy. Blood tests are more commonly used, as they are easier to perform.^[3] Diagnostic tests are unable to distinguish between the stages of the disease.^[21]

Blood tests

Blood tests are divided into nontreponemal and treponemal tests.^[15] Nontreponemal tests are used initially, and include venereal disease research laboratory (VDRL) and rapid plasma reagin tests. As these tests are occasionally false positives, confirmation is required with a treponemal test, such as treponemal pallidum particle agglutination (TPHA) or fluorescent treponemal antibody absorption test (FTA-Abs).^[3] False positives on the nontreponemal tests can occur with some viral infections such as varicella and measles, as well as with lymphoma, tuberculosis, malaria, endocarditis, connective tissue disease, and pregnancy.^[14] Treponemal antibody tests usually become positive two to five weeks after the initial infection.^[15] 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.^[3][14]

Direct testing

Dark ground microscopy of serous fluid from a chancre may be used to make an immediate diagnosis. Hospitals do not always have equipment or experienced staff members, whereas testing must be done within 10 minutes of acquiring the sample. Sensitivity has been reported to be nearly 80%, thus can only be used to confirm a diagnosis but not rule one out. Two other tests can be carried out on a sample from the chancre: direct fluorescent antibody testing and nucleic acid amplification tests. Direct fluorescent testing uses antibodies tagged with fluorescein, which attach to specific syphilis proteins, while nucleic acid amplification uses techniques, such as the polymerase chain reaction, to detect the presence of specific syphilis genes. These tests are not as time-sensitive, as they do not require living bacteria to make the diagnosis.^[15]

Prevention

As of 2010, there is no vaccine effective for prevention.^[12] Several vaccines based on treponemal proteins reduce lesion development in an animal model, and research is ongoing.^[22] Abstinence from intimate physical contact with an infected person is effective at reducing the transmission of syphilis, as is the proper use of a latex condom. Condom use does not completely eliminate the risk.^[23][24] Thus, the Centers for Disease Control and Prevention recommends a long-term, mutually monogamous relationship with an uninfected partner and the avoidance of substances such as alcohol and other drugs that increase risky sexual behavior.^[23]

Congenital syphilis in the newborn can be prevented by screening mothers during early pregnancy and treating those who are infected.^[25] The United States Preventive Services Task Force (USPSTF) strongly recommends universal screening of all pregnant women,^[26] while the World Health Organization recommends all women be tested at their first antenatal visit and again in the third trimester.^[27] If they are positive, they recommend their partners also be treated.^[27] 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,^[25] and it still occasionally occurs in the developed world, as those most likely to acquire syphilis (through drug use, etc.) are least likely to receive care during pregnancy.^[25] Several measures to increase access to testing appear effective at reducing rates of congenital syphilis in low- to middle-income countries.^[27] Point-of-care testing to detect syphilis appeared to be good although more research is needed to assess its effectiveness and into improving outcomes in mothers and babies.^[28]

Syphilis is a notifiable disease in many countries, including Canada^[29] the European Union,^[30] and the United States.^[31] This means health care providers are required to notify public health authorities, which will then ideally provide partner notification to the person's partners.^[32] Physicians may also encourage patients to send their partners to seek care.^[33] The CDC recommends that sexually active men who have sex with men be tested at least yearly.^[34]

Several strategies have been found to improve follow-up for STI testing including email and text messaging as reminders of appointments.^[35]

Treatment

Early infections

The first-choice treatment for uncomplicated syphilis remains a single dose of intramuscular benzathine penicillin G.^[36] 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.^[36] Resistance to macrolides, rifampin, and clindamycin is often present.^[12] Ceftriaxone, a third-generation cephalosporin antibiotic, may be as effective as penicillin-based treatment.^[3] It is recommended that a treated person avoid sex until the sores are healed.^[19]

Late infections

For neurosyphilis, due to the poor penetration of penicillin G into the central nervous system, those affected are recommended to be given large doses of intravenous penicillin for a minimum of 10 days.^[3][12] If a person is allergic, ceftriaxone may be used or penicillin desensitization attempted. Other late presentations may be treated with once-weekly intramuscular penicillin G for three weeks. If allergic, as in the case of early disease, doxycycline or tetracycline may be used, albeit for a longer duration. Treatment at this stage limits further progression, but has only slight effect on damage which has already occurred.^[3]

Jarisch-Herxheimer reaction

One of the potential side effects of treatment is the Jarisch-Herxheimer reaction. It frequently starts within one hour and lasts for 24 hours, with symptoms of fever, muscles pains, headache, and a fast heart rate.^[3] It is caused by cytokines released by the immune system in response to lipoproteins released from rupturing syphilis bacteria.^[37]

Pregnancy

Penicillin is an effective treatment for syphilis in pregnancy^[38] but there is no agreement on which dose or way of giving it is most effective.^[39] More research is needed into how much antibiotic to give and when to give it.^[39]

Epidemiology

Age-standardized death from syphilis per 100,000 inhabitants in 2004^[40]

no data   <35   35-70   70-105   105-140   140-175   175-210

210-245   245-280   280-315   315-350   350-500   >500

In 2013 syphilis infected about 315,000 people.^[5] Syphilis is believed to have infected 12 million additional people in 1999, with greater than 90% of cases in the developing world.^[12] It affects between 700,000 and 1.6 million pregnancies a year, resulting in spontaneous abortions, stillbirths, and congenital syphilis.^[4] During 2010 it caused about 113,000 deaths down from 202,000 in 1990.^[6] In sub-Saharan Africa, syphilis contributes to approximately 20% of perinatal deaths.^[4] Rates are proportionally higher among intravenous drug users, those who are infected with HIV, and men who have sex with men.^[8][9][10] In the United States, rates of syphilis as of 2007 were six times greater in men than women; they were nearly equal in 1997.^[41] African Americans accounted for almost half of all cases in 2010.^[42] As of 2014, syphilis infections continue to increase in the United States.^[43]

Syphilis was very common in Europe during the 18th and 19th centuries.^[7] Flaubert found it universal among nineteenth-century Egyptian prostitutes.^[44] In the developed world during the early 20th century, infections declined rapidly with the widespread use of antibiotics, until the 1980s and 1990s.^[7] Since 2000, rates of syphilis have been increasing in the USA, Canada, the UK, Australia and Europe, primarily among men who have sex with men.^[12] Rates of syphilis among American women have remained stable during this time, and rates among UK women have increased, but at a rate less than that of men.^[45] Increased rates among heterosexuals have occurred in China and Russia since the 1990s.^[12] This has been attributed to unsafe sexual practices, such as sexual promiscuity, prostitution, and decreasing use of barrier protection.^[12][45][46]

Untreated, it has a mortality of 8% to 58%, with a greater death rate in males.^[3] The symptoms of syphilis have become less severe over the 19th and 20th centuries, in part due to widespread availability of effective treatment and partly due to decreasing virulence of the spirochaete.^[16] With early treatment, few complications result.^[15] Syphilis increases the risk of HIV transmission by two to five times, and coinfection is common (30–60% in some urban centers).^[3][12] In 2015 Cuba became the first country in the world to eradicate mother to child transmission of syphilis.^[11]

History

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.^[47]

The exact origin of syphilis is disputed.^[3] Syphilis was indisputably present in the Americas before European contact. The dispute is over whether or not syphilis was also present elsewhere in the world at that time. One of the two primary hypotheses proposes that syphilis was carried from the Americas to Europe by the returning crewmen from Christopher Columbus's voyage to the Americas. The other hypothesis says that syphilis existed in Europe previously, but went unrecognized until shortly after Columbus' return. These are referred to as the Columbian and pre-Columbian hypotheses, respectively.^[21] The Columbian hypothesis is best supported by the available evidence.^[48][49] The first written records of an outbreak of syphilis in Europe occurred in 1494 or 1495 in Naples, Italy, during a French invasion (Italian War of 1494–98).^[7][21] As it was claimed to have been spread by French troops, it was initially known as the "French disease" by the people of Naples.^[50] 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 describing the ravages of the disease in Italy.^[51][52] It was also known historically as the "Great Pox".^[53][54]

The causative organism, Treponema pallidum, was first identified by Fritz Schaudinn and Erich Hoffmann in 1905.^[7] The first effective treatment (Salvarsan) was developed in 1910 by Paul Ehrlich, which was followed by trials of penicillin and confirmation of its effectiveness in 1943.^[7][53] Before the discovery and use of antibiotics in the mid-twentieth century, mercury and isolation were commonly used, with treatments often worse than the disease.^[53]

Many famous historical figures, including Franz Schubert, Arthur Schopenhauer, and Édouard Manet, are believed to have had the disease.^[7] Friedrich Nietzsche was long believed to have gone mad as a result of tertiary syphilis, but that diagnosis has recently come into question.^[55]

Arts and literature

The earliest known medical illustration of people with syphilis, Vienna, 1498

The earliest known depiction of an individual with syphilis is Albrecht Dürer's Syphilitic Man, a woodcut believed to represent a Landsknecht, a Northern European mercenary.^[56] 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.^[57][58]

The artist Jan van der Straet painted a scene of a wealthy man receiving treatment for syphilis with the tropical wood guaiacum sometime around 1580.^[59] The title of the work is "Preparation and Use of Guayaco for Treating Syphilis". That the artist chose to include this image in a series of works celebrating the New World indicates how important a treatment, however ineffective, for syphilis was to the European elite at that time. The richly colored and detailed work depicts four servants preparing the concoction while a physician looks on, hiding something behind his back while the hapless patient drinks.^[60]

Tuskegee and Guatemala studies

A Work Projects Administration poster about syphilis circa 1940.

One of the most infamous United States cases of questionable medical ethics in the 20th century was the Tuskegee syphilis study.^[61] The study took place in Tuskegee, Alabama, and was supported by the U.S. Public Health Service (PHS) in partnership with the Tuskegee Institute.^[62] The study began in 1932, when syphilis was a widespread problem and there was no safe and effective treatment.^[13] The study was designed to measure the progression of untreated syphilis. By 1947, penicillin had been shown to be an effective cure for early syphilis and was becoming widely used to treat the disease.^[62] Its use in later syphilis was still unclear.^[13] Study directors continued the study and did not offer the participants treatment with penicillin.^[62] This is debated, and some have found that penicillin was given to many of the subjects.^[13]

In the 1960s, Peter Buxtun sent a letter to the CDC, who controlled the study, expressing concern about the ethics of letting hundreds of black men die of a disease that could be cured. The CDC asserted that it needed to continue the study until all of the men had died. In 1972, Buxton went to the mainstream press, causing a public outcry. As a result, the program was terminated, a lawsuit brought those affected nine million dollars, and Congress created a commission empowered to write regulations to deter such abuses from occurring in the future.^[62]

On 16 May 1997, thanks to the efforts of the Tuskegee Syphilis Study Legacy Committee formed in 1994, survivors of the study were invited to the White House to be present when President Bill Clinton apologized on behalf of the United States government for the study.^[63]

Syphilis experiments were also carried out in Guatemala from 1946 to 1948. They were United States-sponsored human experiments, conducted during the government of Juan José Arévalo with the cooperation of some Guatemalan health ministries and officials. Doctors infected soldiers, prisoners, and mental patients with syphilis and other sexually transmitted diseases, without the informed consent of the subjects, and then treated them with antibiotics. In October 2010, the U.S. formally apologized to Guatemala for conducting these experiments.^[64]

References

1. "Syphilis". CDC. June 4, 2015. Retrieved 3 February 2016.
2. "Syphilis - CDC Fact Sheet (Detailed)". CDC. November 2, 2015. Retrieved 3 February 2016.
3. Kent ME, Romanelli F (February 2008). "Reexamining syphilis: an update on epidemiology, clinical manifestations, and management". Annals of Pharmacotherapy 42 (2): 226–36. doi:10.1345/aph.1K086. PMID 18212261.
4. Woods CR (June 2009). "Congenital syphilis-persisting pestilence". Pediatr. Infect. Dis. J. 28 (6): 536–7. doi:10.1097/INF.0b013e3181ac8a69. PMID 19483520.
5. Global Burden of Disease Study 2013, Collaborators (22 August 2015). "Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.". Lancet (London, England) 386 (9995): 743–800. doi:10.1016/s0140-6736(15)60692-4. PMID 26063472.
6. Lozano, R (15 December 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.". Lancet 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
7. Franzen, C (December 2008). "Syphilis in composers and musicians--Mozart, Beethoven, Paganini, Schubert, Schumann, Smetana". European Journal of Clinical Microbiology & Infectious Diseases 27 (12): 1151–7. doi:10.1007/s10096-008-0571-x. PMID 18592279.
8. Coffin, L. S.; Newberry, A.; Hagan, H.; Cleland, C. M.; Des Jarlais, D. C.; Perlman, D. C. (January 2010). "Syphilis in Drug Users in Low and Middle Income Countries". The International journal on drug policy 21 (1): 20–7. doi:10.1016/j.drugpo.2009.02.008. PMC 2790553. PMID 19361976.
9. Gao, L; Zhang, L; Jin, Q (September 2009). "Meta-analysis: prevalence of HIV infection and syphilis among MSM in China". Sexually transmitted infections 85 (5): 354–8. doi:10.1136/sti.2008.034702. PMID 19351623.
10. Karp, G; Schlaeffer, F; Jotkowitz, A; Riesenberg, K (January 2009). "Syphilis and HIV co-infection". European journal of internal medicine 20 (1): 9–13. doi:10.1016/j.ejim.2008.04.002. PMID 19237085.
11. "WHO validates elimination of mother-to-child transmission of HIV and syphilis in Cuba". WHO. 30 June 2015. Retrieved 30 August 2015.
12. Stamm, LV (February 2010). "Global challenge of antibiotic-resistant Treponema pallidum.". Antimicrobial Agents and Chemotherapy 54 (2): 583–9. doi:10.1128/aac.01095-09. PMC 2812177. PMID 19805553.
13. White, RM (13 March 2000). "Unraveling the Tuskegee Study of Untreated Syphilis". Archives of Internal Medicine 160 (5): 585–98. doi:10.1001/archinte.160.5.585. PMID 10724044.
14. Committee on Infectious Diseases (2006). Larry K. Pickering, ed. Red book 2006 Report of the Committee on Infectious Diseases (27th ed.). Elk Grove Village, IL: American Academy of Pediatrics. pp. 631–44. ISBN 978-1-58110-207-9.
15. Eccleston, K; Collins, L; Higgins, SP (March 2008). "Primary syphilis". International journal of STD & AIDS 19 (3): 145–51. doi:10.1258/ijsa.2007.007258. PMID 18397550.
16. Mullooly, C; Higgins, SP (August 2010). "Secondary syphilis: the classical triad of skin rash, mucosal ulceration and lymphadenopathy". International journal of STD & AIDS 21 (8): 537–45. doi:10.1258/ijsa.2010.010243. PMID 20975084.
17. Dylewski J, Duong M (2 January 2007). "The rash of secondary syphilis". Canadian Medical Association Journal 176 (1): 33–5. doi:10.1503/cmaj.060665. PMC 1764588. PMID 17200385.
18. Bhatti MT (2007). "Optic neuropathy from viruses and spirochetes". Int Ophthalmol Clin 47 (4): 37–66, ix. doi:10.1097/IIO.0b013e318157202d. PMID 18049280.
19. "Syphilis & MSM (Men Who Have Sex With Men) - CDC Fact Sheet". Centers for Disease Control and Prevention (CDC). 16 September 2010. Retrieved 18 October 2014.
20. G. W. Csonka (1990). Sexually transmitted diseases: a textbook of genitourinary medicine. Baillière Tindall. p. 232. ISBN 978-0-7020-1258-7.
21. Farhi, D; Dupin, N (September–October 2010). "Origins of syphilis and management in the immunocompetent patient: facts and controversies". Clinics in Dermatology 28 (5): 533–8. doi:10.1016/j.clindermatol.2010.03.011. PMID 20797514.
22. Cameron, CE; Lukehart, SA (20 March 2014). "Current status of syphilis vaccine development: need, challenges, prospects.". Vaccine 32 (14): 1602–9. doi:10.1016/j.vaccine.2013.09.053. PMID 24135571.
23. "Syphilis - CDC Fact Sheet". Centers for Disease Control and Prevention (CDC). 16 September 2010. Retrieved 30 May 2007.
24. Koss CA, Dunne EF, Warner L (July 2009). "A systematic review of epidemiologic studies assessing condom use and risk of syphilis". Sex Transm Dis 36 (7): 401–5. doi:10.1097/OLQ.0b013e3181a396eb. PMID 19455075.
25. Schmid, G (June 2004). "Economic and programmatic aspects of congenital syphilis prevention". Bulletin of the World Health Organization 82 (6): 402–9. PMC 2622861. PMID 15356931.
26. U.S. Preventive Services Task, Force (19 May 2009). "Screening for syphilis infection in pregnancy: U.S. Preventive Services Task Force reaffirmation recommendation statement". Annals of Internal Medicine 150 (10): 705–9. doi:10.7326/0003-4819-150-10-200905190-00008. PMID 19451577.
27. Hawkes, S; Matin, N; Broutet, N; Low, N (15 June 2011). "Effectiveness of interventions to improve screening for syphilis in pregnancy: a systematic review and meta-analysis". The Lancet infectious diseases 11 (9): 684–91. doi:10.1016/S1473-3099(11)70104-9. PMID 21683653.
28. Shahrook, S; Mori, R; Ochirbat, T; Gomi, H (29 October 2014). "Strategies of testing for syphilis during pregnancy.". The Cochrane database of systematic reviews 10: CD010385. doi:10.1002/14651858.CD010385.pub2. PMID 25352226.
29. "National Notifiable Diseases". Public Health Agency of Canada. 5 April 2005. Retrieved 2 August 2011.
30. Viñals-Iglesias, H; Chimenos-Küstner, E (1 September 2009). "The reappearance of a forgotten disease in the oral cavity: syphilis". Medicina oral, patologia oral y cirugia bucal 14 (9): e416–20. PMID 19415060.
31. "Table 6.5. Infectious Diseases Designated as Notifiable at the National Level-United States, 2009 [a]". Red Book. Retrieved 2 August 2011.
32. Brunner & Suddarth's textbook of medical-surgical nursing. (12th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 2010. p. 2144. ISBN 978-0-7817-8589-1.
33. Hogben, M (1 April 2007). "Partner notification for sexually transmitted diseases". Clinical Infectious Diseases. 44 Suppl 3: S160–74. doi:10.1086/511429. PMID 17342669.
34. "Trends in Sexually Transmitted Diseases in the United States: 2009 National Data for Gonorrhea, Chlamydia and Syphilis". Centers for Disease Control and Prevention. 22 November 2010. Retrieved 3 August 2011.
35. Desai, Monica; Woodhall, Sarah C; Nardone, Anthony; Burns, Fiona; Mercey, Danielle; Gilson, Richard (2015). "Active recall to increase HIV and STI testing: a systematic review". Sexually Transmitted Infections: sextrans–2014–051930. doi:10.1136/sextrans-2014-051930. ISSN 1368-4973.
36. Center for Disease Control and Prevention (CDC). "Syphilis-CDC fact sheet". CDC. Retrieved 1 March 2015.
37. Radolf, JD; Lukehart SA (editors) (2006). Pathogenic Treponema: Molecular and Cellular Biology. Caister Academic Press. ISBN 1-904455-10-7.
38. Alexander, JM; Sheffield, JS; Sanchez, PJ; Mayfield, J; Wendel GD, Jr (January 1999). "Efficacy of treatment for syphilis in pregnancy.". Obstetrics and gynecology 93 (1): 5–8. doi:10.1016/s0029-7844(98)00338-x. PMID 9916946.
39. Walker, GJ (2001). "Antibiotics for syphilis diagnosed during pregnancy.". The Cochrane database of systematic reviews (3): CD001143. doi:10.1002/14651858.CD001143. PMID 11686978.
40. "Disease and injury country estimates". World Health Organization (WHO). 2004. Retrieved 11 November 2009.
41. "Trends in Reportable Sexually Transmitted Diseases in the United States, 2007". Centers for Disease Control and Prevention (CDC). 13 January 2009. Retrieved 2 August 2011.
42. "STD Trends in the United States: 2010 National Data for Gonorrhea, Chlamydia, and Syphilis". Centers for Disease Control and Prevention (CDC). 22 November 2010. Retrieved 20 November 2011.
43. Clement, Meredith E.; Okeke, N. Lance; Hicks, Charles B. (2014). "Treatment of Syphilis". JAMA 312 (18): 1905. doi:10.1001/jama.2014.13259. ISSN 0098-7484.
44. Francis Steegmuller (1979). Flaubert in Egypt, A Sensibility on Tour. ISBN 9780897330183.
45. Kent, ME; Romanelli, F (February 2008). "Reexamining syphilis: an update on epidemiology, clinical manifestations, and management". Annals of Pharmacotherapy 42 (2): 226–36. doi:10.1345/aph.1K086. PMID 18212261.
46. Ficarra, G; Carlos, R (September 2009). "Syphilis: The Renaissance of an Old Disease with Oral Implications". Head and neck pathology 3 (3): 195–206. doi:10.1007/s12105-009-0127-0. PMC 2811633. PMID 20596972.
47. The Metropolitan Museum of Art Bulletin, Summer 2007, pp. 55–56.
48. Rothschild, BM (15 May 2005). "History of syphilis". Clinical Infectious Diseases 40 (10): 1454–63. doi:10.1086/429626. PMID 15844068.
49. Harper, KN; Zuckerman, MK; Harper, ML; Kingston, JD; Armelagos, GJ (2011). "The origin and antiquity of syphilis revisited: an appraisal of Old World pre-Columbian evidence for treponemal infection". American Journal of Physical Anthropology. 146 Suppl 53: 99–133. doi:10.1002/ajpa.21613. PMID 22101689.
50. Winters, Adam (2006). Syphilis. New York: Rosen Pub. Group. p. 17. ISBN 9781404209060.
51. 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.
52. 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.
53. 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.
54. Knell, RJ (7 May 2004). "Syphilis in renaissance Europe: rapid evolution of an introduced sexually transmitted disease?" (PDF). Proceedings. Biological sciences / the Royal Society. 271 Suppl 4 (Suppl 4): S174–6. doi:10.1098/rsbl.2003.0131. PMC 1810019. PMID 15252975.
55. Bernd, Magnus. "Nietzsche, Friedrich". Encyclopædia Britannica. Retrieved May 19, 2012.
56. Eisler, CT (Winter 2009). "Who is Dürer's "Syphilitic Man"?". Perspectives in biology and medicine 52 (1): 48–60. doi:10.1353/pbm.0.0065. PMID 19168944.
57. 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.
58. Wilson, [ed]: Joanne Entwistle, Elizabeth (2005). Body dressing ([Online-Ausg.] ed.). Oxford: Berg Publishers. p. 205. ISBN 978-1-85973-444-5.
59. 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.
60. "Preparation and Use of Guayaco for Treating Syphilis". Jan van der Straet. Retrieved 6 August 2007.
61. Katz RV, Kegeles SS, Kressin NR, et al. (November 2006). "The Tuskegee Legacy Project: Willingness of Minorities to Participate in Biomedical Research". J Health Care Poor Underserved 17 (4): 698–715. doi:10.1353/hpu.2006.0126. PMC 1780164. PMID 17242525.
62. "U.S. Public Health Service Syphilis Study at Tuskegee". Centers for Disease Control and Prevention. 15 June 2011. Retrieved 7 July 2010.
63. "Bad Blood: The Tuskegee Syphilis Study: President Bill Clinton's Apology". University of Virginia Health Sciences Library. Retrieved 2 December 2014.
64. "U.S. apologizes for newly revealed syphilis experiments done in Guatemala". The Washington Post. 1 October 2010. Retrieved 1 October 2010. The United States revealed on Friday that the government conducted medical experiments in the 1940s in which doctors infected soldiers, prisoners and mental patients in Guatemala with syphilis and other sexually transmitted diseases.

Further reading

• Bliss, Katherine Elaine. "The Science of Redemption: Syphilis, Sexual Promiscuity, and Reformism in Revolutionary Mexico City" Hispanic American Historical Review 79:1 1999, pp. 1–40.
• Parascandola, John. Sex, Sin, and Science: A History of Syphilis in America (Praeger, 2008) 195 pp. ISBN 978-0-275-99430-3 excerpt and text search
• Shmaefsky, Brian, Hilary Babcock and David L. Heymann. Syphilis (Deadly Diseases & Epidemics) (2009)
• Stein, Claudia. Negotiating the French Pox in Early Modern Germany (2009)

External links

• "Syphilis - CDC Fact Sheet" Centers for Disease Control and Prevention (CDC)
• UCSF HIV InSite Knowledge Base Chapter: Syphilis and HIV