Syphilis

• 1. Introduction

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  Syphilis arrived in Naples in 1495, riding in with a French army, and within two years it had reached London. At St Bartholomew's Hospital, records noted it infecting 10 of just 20 patients. A disease that could devastate half a ward in a matter of weeks was something medieval Europe had never quite confronted before. It moved fast, it wore many disguises, and it killed in ways that took decades to become visible. The physician Sir William Osler called it "the great imitator" because its symptoms could look like almost anything else. How does a single bacterium manage to hide inside the body for years, then emerge as something unrecognizable? And how did a disease that once killed without mercy become, in our own century, both treatable and yet still rising in many parts of the world?

• 2. Four Faces of Infection

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  A single firm ulcer, roughly 0.3-3.0 centimetres across, is classically the first sign. It appears roughly 2-6 weeks after exposure, painless and clean-edged, most often on the genitals. About 80% of people develop swollen lymph nodes nearby, seven to ten days after the ulcer forms. Left alone, the sore heals within three to six weeks, and that apparent recovery is deceptive.

  Four to ten weeks after the initial infection, secondary syphilis arrives. A rash spreads across the trunk and extremities, including the palms and soles, a distribution unusual enough that it became one of the disease's signatures. Wart-like lesions called condyloma latum can appear on mucous membranes. Fever, hair loss, sore throat, and headache may all follow. Between 40% and 85% of women and 20% to 65% of men who reach this stage never even noticed the earlier chancre.

  The infection then retreats into what is called the latent phase, which can last many years with no symptoms at all. The World Health Organization defines early latent syphilis as the period within two years of infection; during this window, up to 25% of people can still develop a recurrent secondary episode in which bacteria actively replicate and spread.

  Without treatment, approximately 15-40% of people eventually reach tertiary syphilis, which can appear anywhere from 3 to 15 years after the original infection. Gummatous syphilis, which accounts for 15% of tertiary cases, produces soft, tumor-like growths that can appear in the skin, bone, or liver. Cardiovascular syphilis, seen in roughly 10% of tertiary cases and typically arising 10-30 years after infection, can produce an aortic aneurysm. Neurosyphilis, present in about 6.5% of tertiary cases, can manifest as dementia, personality changes, delusions, seizures, and psychosis, or as tabes dorsalis, a deterioration of the spinal cord that produces gait instability and sharp pains through the trunk and limbs.

• 3. The Bacterium Behind It

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  Treponema pallidum subspecies pallidum is a spiral-shaped, Gram-negative bacterium that cannot survive more than a few days outside a human host. Its genome is small, just 1.14 megabase pairs, and it lacks the genetic instructions to produce most of its own nutrients. It replicates slowly, with a doubling time of more than 30 hours. These are the traits of an organism that has become extraordinarily dependent on its host.

  Humans are its only known natural reservoir. Because it is so fragile outside the body, transmission through toilet seats, shared utensils, or clothing is essentially impossible. The bacterium passes through intact mucous membranes or broken skin, and roughly 30-60% of people exposed to an active primary or secondary infection will acquire the disease. Its infectivity in close contact is remarkable: a person inoculated with as few as 57 organisms faces a 50% chance of becoming infected.

  The bacterium's strength lies in its ability to evade the immune system and spread through tissue. Most new cases in the United States, some 60%, occur in men who have sex with men, and in that population, oral sex alone accounts for 20% of transmissions. Blood transfusion can theoretically transmit syphilis, but screening programs in many countries have made that route rare. Sharing needles appears to carry limited risk by comparison.

• 4. Diagnosing the Imitator

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  Blood testing is the standard approach to diagnosis, and it proceeds in two stages. Nontreponemal tests, including the venereal disease research laboratory test and the rapid plasma reagin test, provide an initial screen. These can produce false positives in the presence of chickenpox, measles, lymphoma, tuberculosis, malaria, or even pregnancy. Because of this, a positive result requires confirmation through a treponemal test such as the Treponema pallidum particle agglutination assay or the fluorescent treponemal antibody absorption test. Treponemal antibodies typically become detectable two to five weeks after infection and remain positive for many years.

  For patients where immediate bedside diagnosis is needed, dark field microscopy of fluid from a chancre can identify the bacterium directly, but the sample must be examined within ten minutes. Direct fluorescent antibody testing and polymerase chain reaction testing are less time-sensitive alternatives, since they do not require living bacteria. Neurosyphilis is confirmed by finding elevated white blood cell counts, predominantly lymphocytes, together with high protein levels in cerebrospinal fluid.

  The Centers for Disease Control and Prevention recommends that all pregnant women be tested for syphilis. The United States Preventive Services Task Force extends this to universal screening of all pregnant women, while the World Health Organization recommends testing at the first antenatal visit and again in the third trimester. Syphilis is a notifiable disease in Canada, the European Union, and the United States, obligating clinicians to report cases to public health authorities so that partners can be traced.

• 5. Mercury, Arsphenamine, Penicillin

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  Elemental mercury was already being used to treat skin diseases in Europe as early as 1363. As syphilis spread after 1495, mercury preparations became the first systematic weapon against it. Applied to ulcers or inhaled, mercury was sometimes found sufficient to halt early disease. By the 16th century, mercury salts were a standard prescription; mercury (II) chloride was still in prominent medical use as late as 1916.

  The problem was dose. Once the infection was well established, the quantities of mercury required to suppress it exceeded what the human body could tolerate. Medically directed mercury poisoning became widespread across Europe, North America, and India through the 17th, 18th, and 19th centuries. Treatment could be worse than the disease itself.

  The causative organism was not identified until 1905, when Fritz Schaudinn and Erich Hoffmann named Treponema pallidum. Four years later, Sahachiro Hata discovered arsphenamine during a survey of hundreds of newly synthesized organic arsenical compounds led by Paul Ehrlich. Marketed from 1910 under the trade name Salvarsan by Hoechst AG, it was the first modern chemotherapeutic agent. Penicillin was discovered in 1928, and its effectiveness against syphilis was confirmed in trials in 1943. A treated individual is typically rendered non-infective within about 24 hours. A single dose of intramuscular benzathine benzylpenicillin remains the first-line treatment for uncomplicated syphilis to this day.

  For neurosyphilis, which benzathine penicillin penetrates poorly, large doses of intravenous penicillin G given for a minimum of 10 days are required. Treatment at the late stage limits further damage but cannot reverse what has already occurred.

• 6. Tuskegee and Guatemala

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  Between 1932 and 1972, the U.S. Public Health Service, in collaboration with Tuskegee University in Alabama, enrolled 600 poor African American sharecroppers from Macon County in what was called the "Tuskegee Study of Untreated Syphilis in the Negro Male". Of those men, 399 had already contracted syphilis before the study began, and 201 did not have the disease. Participants were told the study would last six months. It ran for 40 years.

  The men were told they were receiving treatment for "bad blood", a term used locally to describe conditions including fatigue, anemia, and syphilis. In reality, they received no treatment for syphilis. When penicillin was confirmed as effective in 1943, none of the infected men in the study were offered it. When participation flagged, the Macon County Health Department wrote to subjects offering a "last chance" at a special "treatment" that turned out to be a spinal tap conducted purely for diagnostic data.

  A whistleblower named Peter Buxtun revealed the details of the study in 1972. The exposure triggered sweeping changes in U.S. law and regulation covering participant protection in clinical research, including requirements for informed consent and accurate communication of test results.

  A parallel set of experiments ran in Guatemala from 1946 to 1948, during the administrations of U.S. President Harry S. Truman and Guatemalan President Juan Jose Arevalo. Physician John Charles Cutler, who also participated in the later stages of Tuskegee, led the Guatemalan work. Doctors deliberately infected soldiers, prisoners, prostitutes, and psychiatric patients with syphilis and other sexually transmitted infections without consent. Most subjects were subsequently treated with antibiotics, but the experiments resulted in at least 83 deaths. In October 2010, Secretary of State Hillary Clinton and Health and Human Services Secretary Kathleen Sebelius issued a formal U.S. apology to Guatemala.

• 7. Origins and Naming

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  Where syphilis came from remains one of medicine's more fiercely debated historical questions. The Columbian theory holds that it was brought to Spain by the men who sailed with Christopher Columbus in 1492 and then spread, with a serious epidemic recorded in Naples as early as 1495. 16th-century physicians wrote at length about this new disease, and contemporaries widely associated it with the returning explorers.

  Beginning in the 1960s, evidence from skeletal remains suggested a possible pre-Columbian presence of treponemal disease in Afro-Eurasia. In 2020, a group of leading paleopathologists concluded that enough bone and tooth evidence had accumulated to show that treponemal disease, almost certainly including syphilis, had existed in Europe before Columbus sailed. A 2024 study published in Nature supported syphilis having first emerged in the Americas in the mid-Holocene. The underlying complication is that syphilis, bejel, and yaws produce overlapping damage to bone, and distinguishing among them from skeletal evidence alone remains difficult. Ancient DNA analysis offers the only definitive method of telling the three diseases apart, but the bacterium is rare and fragile in archaeological remains, making recovery slow.

  Researcher Marylynn Salmon has found depictions of saddle nose deformity, a collapsed nasal bridge characteristic of advanced syphilis, in medieval illuminated manuscripts, particularly in scenes of the crucifixion. Historian Jon Arrizabalaga, working on records from Castile, found evidence that some medieval writers deliberately avoided describing the disease because it disproportionately affected elites and carried politically sensitive implications.

  The name syphilis itself dates to 1530, when the Italian physician and poet Girolamo Fracastoro published a Latin poem in dactylic hexameter titled Syphilis sive morbus gallicus, or Syphilis or The French Disease. The poem's protagonist was a shepherd named Syphilis. Before that, the disease had been called the "great pox" or "the French disease" in England, Germany, and Italy, while the French called it the "Neapolitan disease", the Dutch called it the "Spanish disease", and the Turks called it the "Christian disease".

• 8. A Disease Still Rising

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  In 1990, syphilis caused approximately 202,000 deaths worldwide. By 2015, that figure had fallen to about 107,000, a real improvement, and one largely attributable to penicillin's reach. Yet rates of new infection have been climbing since roughly the year 2000 in the United States, Canada, the United Kingdom, Australia, and Europe, primarily among men who have sex with men. In the United States by 2020, the rate of syphilis infections had increased more than threefold compared to earlier years.

  Congenital syphilis, which is preventable through routine prenatal screening, remains common in the developing world, where antenatal care is inconsistent. In sub-Saharan Africa, syphilis accounts for roughly 20% of perinatal deaths. The infection affects between 700,000 and 1.6 million pregnancies each year worldwide, with consequences including miscarriage, stillbirth, and congenital disease in the newborn. In 2021, preliminary CDC data recorded 2,677 cases of congenital syphilis in the United States alone, a country of 332 million people.

  Syphilis also multiplies the risk of HIV transmission by two to five times, and co-infection is common, reaching 30-60% in some urban centers. In 2015, Cuba became the first country to eliminate mother-to-child transmission of syphilis, a milestone that demonstrated elimination is achievable with sustained screening and treatment programs. No vaccine effective for prevention yet exists, though several vaccine candidates based on treponemal proteins have reduced lesion development in animal models.