In 1495, a mysterious and deadly plague struck the city of Naples. Over the next 500 years, the medical attempts to understand and treat this new disease -- syphilis -- would mold and shape medicine in surprising ways. In this episode, Tony Breu and I will perform an historical and physiological biography of syphilis, covering the development of germ theory, epic poetry, mercury saunas, intentionally infecting patients with malaria, magic bullets, and lots and lots of experiments on poor rabbits. This presentation was performed live at the American College of Physicians’ national meeting in Philadelphia on April 11, 2019.

Sources (WARNING -- LONG LIST):

Swain, K. ‘Extraordinarily arduous and fraught with danger’: syphilis, Salvarsan, and general paresis of the insane. Lancet Psychiatry 5, (2018).

Kępa, M. et al. Analysis of mercury levels in historical bone material from syphilitic subjects – pilot studies (short report). Kępa Małgorzata 69, 367-377(11) (2012).

Forrai, J. Syphilis - Recognition, Description and Diagnosis. (2011). doi:10.5772/24205

Parascandola, J. From mercury to miracle drugs: syphilis therapy over the centuries. Pharm Hist 51, 14–23 (2009).

Eisler, C. Who Is Dürer’s ‘Syphilitic Man’? Perspect Biol Med 52, 48–60 (2009).

Rothschild, B. M. History of Syphilis. Clin Infect Dis 40, 1454–1463 (2005).

Schwartz, R. S. Paul Ehrlich’s Magic Bullets. New Engl J Medicine 350, 1079–1080 (2004).

Fee, E. The wages of sin. Lancet 354, SIV61 (1999).

O’Shea, J. ‘Two Minutes with Venus, Two Years with Mercury’-Mercury as an Antisyphilitic Chemotherapeutic Agent. J Roy Soc Med 83, 392–395 (1989).

Mahoney, J., Arnold, R., Sterner, B. L., Harris, A. & Zwally, M. Penicillin Treatment of Early Syphilis: II. Jama 251, 2005–2010 (1984).

Waugh, M. Role played by Italy in the history of syphilis. Sex Transm Infect 58, 92–95 (1982).

Thorburn, A. Fritz Richard Schaudinn, 1871-1906: protozoologist of syphilis. Sex Transm Infect 47, 459–461 (1971).

CROSBY, A. W. The Early History of Syphilis: A Reappraisal. Am Anthropol 71, 218–227 (1969).

Clark, E. G. & Danbolt, N. The Oslo study of the natural history of untreated syphilis An epidemiologic investigation based on a restudy of the Boeck-Bruusgaard material a review and appraisal. J Chron Dis 2, 311–344 (1955).

MUNGER, R. S. Guaiacum, the Holy Wood from the New World. J Hist Med All Sci IV, 196–229 (1949).

Thomas, E. & r, W. Rapid Treatment of Early Syphilis with Multiple Injections of Mapharsen. J Nerv Ment Dis 99, 88 (1944).

WIEDER, L., FOERSTER, O. & FOERSTER, H. MAPHARSEN IN THE TREATMENT OF SYPHILIS: FURTHER EXPERIENCES. Arch Dermatol Syph 35, 402–413 (1937).

THON, L. SHOULD THE INTERNIST KNOW SYPHILIS? J Amer Med Assoc 97, 994–996 (1931).

Sarton, G. The Earliest Printed Literature on Syphilis, being Ten Tractates from the Years 1495-1498. Karl Sudhoff , Charles Singer , Henry E. Sigerist. Isis 8, 351–354 (1926).

COLE, H., GERICKE, A. & SOLLMANN, T. THE TREATMENT OF SYPHILIS BY MERCURY INHALATIONS: HISTORY, METHOD AND RESULTS. Arch Dermatol Syph 5, 18–33 (1922).

Mason, U. Observation: Use and Abuse of Salvarsan. J Natl Med Assoc 3, 340–3 (1911).

Fleming, A. & Colebrook, L. ON THE USE OF SALVARSAN IN THE TREATMENT OF SYPHILIS. Lancet 177, 1631–1634 (1911).

Evans, A. The Treatment of Syphilis by Salvarsan (Dioxy-diamido-arseno-benzol). Brit Med J 1, 617 (1911).

Boeck, W. History, Theory and Practice of Syphilisation. New Engl J Medicine 73, 20–25 (1865).

Veale, H. Remarks on Syphilis and Its Treatment. Edinb Medical J 10, 10–26 (1864).

LaFond RE and Lukehart SA, Biological Basis for Syphilis. Clinical Microbiology Reviews 2006.

Secher L et al, Treponema pallidum in peripheral nerve tissue of syphilitic chancres. Acta dermato-venereologica 1982.
Hollander DH, Turner TB, The role of temperature in experimental treponemal infection. American journal of syphilis, gonorrhea, and venereal diseases, 1954

Eagle H, et al. The effect of hyperpyrexia on the therapeutic efficacy of penicillin in experimental syphilis. American journal of syphilis, gonorrhea, and venereal diseases, 1947.

Kampmeier RH, Syphilis therapy: an historical perspective. Journal of the American Venereal Disease Association 1976.

Pachner AR, Spirochetal Diseases of the CNS. Neurologic clinics, 1986.

Sell S et al, Experimental syphilitic orchitis in rabbits: ultrastructural appearance of Treponema pallidum during phagocytosis and dissolution by macrophages in vivo. Laboratory investigation; a journal of technical methods and pathology, 1982.

Taylor SH, Diuretics in cardiovascular therapy. Perusing the past, practising in the present, preparing for the future. Zeitschrift für Kardiologie, 1985.

Ovchinnikov NM, [Treponema pallidum in peripheral nerves of rabbit syphiloma]. Vestnik dermatologii i venerologii, 1975.

Cheek DB, Wu F, The Effect of Calomel on Plasma Epinephrine in the Rat and the Relationship to Mechanisms in Pink Disease, Archives of Disease in Childhood, 1959

Vogl A, The discovery of the organic mercurial diuretics, American Heart Journal, 1950

Schwemlein GX et al, Penicillin and fever therapy in early syphilis, Journal of the American Medical Association, 1948.

Stringham JS, On the Diuretic Effects of Mercury in a Case of Syphilis. The Medical and physical journal, 1807

Evanson RL et al, Effect of mercurial diuretics on tubular sodium and potassium transport in the dog. The American journal of physiology, 1972

Sell S and Salman J, Demonstration of Treponema pallidum in Axons of Cutaneous Nerves in Experimental Chancres of Rabbits, Sexually Transmitted Diseases, 1992

Penn CW, Avoidance of Host Defences by Treponema pallidum in Situ and on Extraction from Infected Rabbit Testes, Microbiology 1981.

Beutler B and Munford RS, Tumor Necrosis Factor and the Jarisch–Herxheimer Reaction, The New England Journal of Medicine 1996.

Radolf JD et al, Treponema pallidum: doing a remarkable job with what it's got. Trends in Microbiology, 1999

Tight RR, Perkins RL, Treponema pallidum infection in subcutaneous polyethylene chambers in rabbits. Infection and immunity, 1976

Salazar JC et al, Treponema pallidum Elicits Innate and Adaptive Cellular Immune Responses in Skin and Blood during Secondary Syphilis: A Flow-Cytometric Analysis. The Journal of Infectious Diseases, 2007

Azevedo BF et al, Toxic Effects of Mercury on the Cardiovascular and Central Nervous Systems. Journal of Biomedicine and Biotechnology 2012,

Clarkson TW and Magos L, The Toxicology of Mercury and Its Chemical Compounds, Critical Reviews in Toxicology 2008.

Fitzgerald TJ, The Th1/Th2-like switch in syphilitic infection: is it detrimental? Infection and immunity, 1992

Batterman RC et al, THE SUBCUTANEOUS ADMINISTRATION OF MERCAPTOMERIN (THIOMERIN®): Effective Mercurial Diuretic for the Treatment of Congestive Heart Failure. Journal of the American Medical Association, 1949

Batterman RC, The status of mercurial diuretics for the treatment of congestive heart failure. American Heart Journal, 1951

Bleich HL et al, The Role of Regional Body Temperature in the Pathogenesis of Disease, The New England Journal of Medicine, 1981

Vander Veer JB et al, The Prolonged Use of an Oral Mercurial Diuretic in Ambulatory Patients with Congestive Heart Failure. Circulation 1950

Cox DL et al, The outer membrane, not a coat of host proteins, limits antigenicity of virulent Treponema pallidum. Infection and immunity, 1992.

Fildes P, The Mechanism of the Anti-bacterial Action of Mercury. Br J Exp Pathol, 1940

Clarkson TW, THE MECHANISM OF ACTION OF MERCURIAL DIURETICS IN RATS; THE METABOLISM OF 203Hg‐LABELLED CHLORMERODRIN. British Journal of Pharmacology and Chemotherapy, 1965

Engelkens HJ et al, The localisation of treponemes and characterisation of the inflammatory infiltrate in skin biopsies from patients with primary or secondary syphilis, or early infectious yaws. Genitourinary Medicine, 1993

Belum GR et al, The Jarisch–Herxheimer reaction: Revisited. Travel Medicine and Infectious Disease, 2013

Arando M et al, The Jarisch–Herxheimer reaction in syphilis: could molecular typing help to understand it better? Journal of the European Academy of Dermatology and Venereology, 2018.

Butler T, The Jarisch–Herxheimer Reaction After Antibiotic Treatment of Spirochetal Infections: A Review of Recent Cases and Our Understanding of Pathogenesis. The American Journal of Tropical Medicine and Hygiene, 2016

Carlson JA et al, The Immunopathobiology of Syphilis: The Manifestations and Course of Syphilis Are Determined by the Level of Delayed-Type Hypersensitivity. The American Journal of Dermatopathology 2011.

Aronson IK and Soltani K, The enigma of the pathogenesis of the Jarisch-Herxheimer reaction. The British Journal of Venereal Diseases, 1976

Sellato TJ et al, The Cutaneous Response in Humans to Treponema pallidum Lipoprotein Analogues Involves Cellular Elements of Both Innate and Adaptive Immunity, The Journal of Immunology 2001

Spiller HA, Rethinking mercury: the role of selenium in the pathophysiology of mercury toxicity. Clinical Toxicology 2017

Sell S et al, Reinfection of chancre-immune rabbits with Treponema pallidum. I. Light and immunofluorescence studies. The American journal of pathology 1985.

Grant SS and Hung DT, Persistent bacterial infections, antibiotic tolerance, and the oxidative stress response, Virulence 2013

Lant AF, Modern diuretics and the kidney. Journal of Clinical Pathology, 1981

Kamath SU et al, Mercury-based traditional herbo-metallic preparations: a toxicological perspective, Archives of Toxicology 2012.

Yeter et al, Mercury Promotes Catecholamines Which Potentiate Mercurial Autoimmunity and Vasodilation: Implications for Inositol 1,4,5-Triphosphate 3-Kinase C Susceptibility in Kawasaki Syndrome. Korean Circulation Journal 2013

Wöβmann W et al, Mercury intoxication presenting with hypertension and tachycardia. Archives of Disease in Childhood, 1999

Giacani L et al, Identification of the Treponema pallidum subsp. pallidum TP0092 (RpoE) Regulon and Its Implications for Pathogen Persistence in the Host and Syphilis Pathogenesis. Journal of Bacteriology 2013.

Edwards AM, From tooth to hoof: treponemes in tissue‐destructive diseases. Journal of Applied Microbiology, 2003

Wolgemuth CW, Flagellar motility of the pathogenic spirochetes. Seminars in Cell & Developmental Biology 2015.

Solomon HC and Kopp I, Fever Therapy. The New England Journal of Medicine 1937.

Rice KM et al, Environmental Mercury and Its Toxic Effects. Journal of Preventive Medicine and Public Health 2014.

Drusin LM, Electron microscopy of Treponema pallidum occurring in a human primary lesion. Journal of bacteriology 1969.

McNeely MC et al, Cutaneous secondary syphilis: Preliminary immunohistopathologic support for a role for immune complexes in lesion pathogenesis. Journal of the American Academy of Dermatology 1986.

Borenstein LA et al, Contribution of rabbit leukocyte defensins to the host response in experimental syphilis. Infection and immunity 1991.

Cabot RC et al, Case 51-1976 — Bicentennial CPC — Syphilis, Diarrhea and Death in the 1820's. The New England Journal of Medicine 1976.

Hobman JL and Crossman LC, Bacterial antimicrobial metal ion resistance. Journal of Medical Microbiology 2015

Gelpi A and Tucker JD, After Venus, mercury: syphilis treatment in the UK before Salvarsan. Sexually Transmitted Infections 2015.

MacHaffie et al, A study of the effectiveness of mercurial diuretics in treatment of cardiac decompensation. The American Journal of Cardiology 1958

Aberer W et al, Ammoniated mercury ointment: outdated but still in use. Contact Dermatitis 1990

Farhi D, Dupin N, Origins of syphilis and management in the

immunocompetent patient: Facts and controversies. Clinics in Dermatology (2010) 28, 533–538

Frith J, “Syphilis – Its early history and Treatment until Penicillin and the Debate on its Origins,” Journal of Military and Veterans’ Health, 20(4), retrieved online at: http://jmvh.org/article/syphilis-its-early-history-and-treatment-until-penicillin-and-the-debate-on-its-origins/

Howes OD et al, “Julius Wagner-Jauregg, 1857-1940,” American Journal of Psychiatry, April 2009 Volume 166 Number 4, Volume 166, Issue 4, April, 2009, pp. 409-409.

Karamanou M et al, “Julius Wagner-Jauregg (1857-1940): Introducing fever therapy in the treatment of neurosyphilis.” Psychiatriki. 2013 Jul-Sep;24(3):208-12.

Simpson WM, “Artificial fever therapy of syphilis,” JAMA. 1935;105(26):2132-2140.

Tsay CJ, “Julius Wagner-Jauregg and the Legacy of Malarial Therapy for the Treatment of General Paresis of the Insane,” Yale J Biol Med. 2013;86(2): 245–254

Wagner-Jauregg J, “The history of malaria treatment of general paralysis.” Am J Psychiatry. 1946;02: 577-582

Shafer JK et al, Untreated syphilis in the male Negro: A prospective study of the effect on life expectancy. Public Health Rep. 1954 Jul; 69(7): 684–690.

Abara WE et al, Syphilis Trends among Men Who Have Sex with Men in the United States and Western Europe: A Systematic Review of Trend Studies Published between 2004 and 2015. PLoS One. 2016; 11(7): e0159309.

Nutton V, The Reception of Fracastoro's Theory of Contagion: The Seed That Fell among Thorns? Osiris, Vol. 6, Renaissance Medical Learning: Evolution of a Tradition (1990)

Tsaraklis A, Preventing syphilis in the 16th century: the distinguished Italian anatomist Gabriele Falloppio (1523-1562) and the invention of the condom. Le Infezioni in Medicina, n. 4, 395-398, 2017.

O.C.

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