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Syphilis: a Mysterious and Serious Ancient Disease

Posted 13 June 2017 | By Max Sherman 

Syphilis: a Mysterious and Serious Ancient Disease

This article alerts regulatory professionals to the continued presence of what may be a "forgotten" disease–syphilis. Although syphilis is unique and may be considered a "relic" of the past, it does not belong in the dust bin of history. To the contrary, regulatory professionals may wish to know more about its controversial medical history, epidemiology and clinical manifestations as syphilis remains a serious public health threat in many parts of the world. These issues in addition to the possible serious consequences of untreated syphilis provide a clear rationale for developing a vaccine.


Syphilis, an ancient and often "forgotten" disease, has recently re-emerged in an unlikely location—Oklahoma County, Oklahoma. Although responsive to penicillin, this unexpected outbreak of syphilis so close to home for many of us can serve as a reminder that the disease is still a serious public health threat.1

In North America and Western Europe, syphilis has increased dramatically in the past decade among gay men, particularly those with coexistent HIV infection.2 In low and middle income countries, syphilis is a relatively common problem and a source of substantial morbidities, including adverse pregnancy outcomes and acceleration of HIV transmission.3 While penicillin, an antibiotic available for more than 60 years, continues to be used the treatment of choice, many organisms have become or are becoming resistant to antibiotics.


How and why syphilis suddenly appeared in Europe at the end of the fifteenth century is one of the great mysteries in medical history. In the 1490s, it was a new disease that began in Europe, spread to India, China, Japan and, eventually, to the rest of the world. Interestingly, the disease became known by names varying according to the country of suspected origin. No country wished to assume ownership, however. In Russia, syphilis was known as the "Polish disease." In Portugal, it was called the "Castilian disease," while in Japan and India, one would refer to syphilis as the "Portuguese disease." In Italy, it was spoken of as the "French disease." The French, on the other hand, called it "the Spanish disease."

Some early medical historians believed it originated in the army of Charles VIII, the King of France, who, having launched an invasion on Italy in the autumn of 1494, attacked Naples in 1495. Others speculated that it started in that city and was transmitted to the French army and, as the remnants of Charles's army streamed home, his troops spread the disease to many parts of Europe.

The most credible theory of its origin stemmed from a report that the malady was "imported" from the West Indies by sailors on the 1492–1493 expedition led by Christopher Columbus, who traveled back from the West Indies with a crew of 44 men and 10 natives.4 While this hypothesis is certainly strong evidence for the onset of syphilis, it is not dispositive.

Another hypothesis (again unproven) maintains that syphilis originated in Africa and was introduced into Spain and Portugal through the importation of slaves. Adding to the feasibility of this suggestion, there is an African nonvenereal disease called "yaws," which is bacteriologically indistinguishable from syphilis. The causative organism for yaws, Treponema pallidum, is a spirochete,like that of syphilis. Yaws and syphilis are simply different manifestations of the same disease.5 Despite prevailing hypotheses, the origin of syphilis remains a controversial topic among anthropologists.


The secrets of its biology and the pathogenesis of syphilis remain to be discovered.6 Perhaps the greatest biological mystery of syphilis can be found in the manner in which T. pallidum causes the many clinical features of the disease as syphilis is a multi-stage disease with diverse and wide ranging manifestations. Worldwide, more than five million new cases of syphilis are diagnosed each year and congenital infections are not uncommon.7

Syphilis is a chronic disease. Its only known natural host is the human. It is usually acquired by direct sexual contact. Studies have shown that 16 to 30 percent of individuals who have had sexual contact with a syphilis-infected person in the preceding 30 days become infected. Compared to syphilis rates in developed countries, the worldwide burden of syphilis is formidable in lesser developed countries where the World Health Organization estimates that 12 million new cases occur each year. The vast majority of cases are seen in developing countries, but an increase in new cases also has been noted in Eastern Europe since the dissolution of the Soviet Union.8 Of particular importance to worldwide health is the recognition that syphilis infection greatly increases the transmission and acquisition of HIV.

Clinical Manifestations

The natural history of syphilis is one of a chronic infection capable of causing a series of highly variable clinical manifestations during the first two to three years of infection, followed by a typically latent stage that can evolve into clinically apparent tertiary infection stage years or even decades after an initial infection.9

Infection with T. pallidum begins with the growth of the organism at the site of infection followed by dissemination to various tissues, including the central nervous system. In primary syphilis, a chancre forms at the site of infection and regional lymphadenopathy (disease of the lymph nodes) occurs. Secondary syphilis is marked by a disseminated rash and generalized lymphadenopathy. Latent syphilis is divided into two stages based upon an approximation of the time of infection. For the first year after infection, patients are considered to have early latent syphilis; up to 25 percent may have recurrent secondary manifestations. Tertiary syphilis may not appear until 20 to 40 years after the onset of infection and can result in bone destruction, aortic insufficiency (cardiovascular syphilis) and late neurological complications, including personality changes, emotional instability, memory impairment and hallucinations. Loss of temperature, deep pain sensations and optic nerve damage also can occur.10


Penicillin, particularly long-acting benzathine benzylpenicillin, has been the treatment of choice for syphilis for many decades. Alternate therapy using multiple doses of procaine penicillin, doxycycline or ceftriaxone can be used when intravenous therapy might be difficult or, in the case of penicillin, when there is an allergy. Because dosage varies depending upon the stage of the disease, the US Centers for Disease Control has published dosage guidelines on its website.11 Why penicillin remains the drug of choice over decades is a mystery. The good news is that resistance to penicillin has not yet been found among clinical isolates, likely because T. pallidum is not capable of importing genes from other organisms. Most other bacteria, with the rare exception of T. pallidum, contain plasmids—tiny rings of DNA—that can help transfer antibiotic resistant genes from one organism to another. However, the bad news is that there is a potential for the acquisition for extrachromosomally mediated antibiotic resistance as at least one strain of T. pallidum has been shown to contain plasmid DNA.12

Final Thoughts

Syphilis remains a critical public health problem with both individual and public health impact as it can cause lifelong morbidity in children born to infected mothers. Without treatment, syphilis can progress over years through a series of clinical stages and eventually lead to irreversible neurological or cardiovascular complications. Research continues into both the biology of T. pallidum and the host response to infection as the disease biology and the host response must be considered to develop a badly needed vaccine. Unlike smallpox and polio, where much progress has been made to eradicate them, syphilis continues to plague our world.


  1. Editorial. The Lancet. 15 April 2017; Vol 389;1492.
  2. Hook, E.W. "Syphilis." The Lancet. 15 April 2017; Vol 389:10078;1550-1557
  3. Newman, et al. "Global Estimates of the Prevalence and Incidence of Four Curable Transmitted Infections in 2012 Based on Systematic Review and Global Reporting. PLOS One. 8 December 2015. Accessed 13 June 2017.
  4. Mroczkowski, T.F. "History, Sex and Syphilis." Bradenton, FL. 2015.
  5. Cartwright, F.F. and Biddiss, M.D. "Disease and History." Dorset Press, New York. 1972.
  6. LaFond, R.E. and Lukehart, S.A. "Biological Basis for Syphilis." Clin Microbiol Rev. 2006; Vol 19:1;29-49.
  7. World Health Organization (WHO) Report on Globally Transmitted Infection Surveillance 2015. August 2016. WHO website. Accessed 13 June 2017.
  8. Op cit 5.
  9. Op cit 2.
  10. Op cit 6.
  11. Centers for Disease Control and Prevention. Sexually Transmitted Diseases. Syphilis Treatment and Care. CDC website. Accessed 13 June 2017.
  12. Norgard, M.V. and Miller, J.N. "Plasmid DNA in T. pallidum (Nichols): Potential for Antibiotic Resistance by Syphilis Bacteria." Science. 31 July1981; Vol 213;553-555.

About the Author

Max Sherman is a retired regulatory professional. He has contributed to Regulatory Focus for more than a decade and is the author of the recently published book entitled "Eclectic Science and Regulatory Compliance: Stories for the Curious." The book contains 36 essays most of which appeared in Regulatory Focus. In 2012, RAPS published "From Alzheimer's to Zebrafish: Eclectic Science and Regulatory Stories." He is also the editor of "The Medical Device Validation Handbook" published in 2015. He can be contacted at

Cite as: Sherman, M. "Syphilis: a Mysterious and Serious Ancient Disease." Regulatory Focus. June 2017. Regulatory Affairs Professionals Society.


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