1. Chairman’s Rounds Steve Hart

2. Case Presentation History of present illness 18 y/o AAM presents to outpatient clinic with complaint of rash. Started on both forearms 3 weeks prior. Next spread to chest and back and later to lower extremities. No itching. No pus or drainage Afebrile, no N/V No URI symptoms No sores ever noted No discharge

3. Social Hx: Drinks up to ½ pint of rum daily Sexually active since the age of 15. 3-4 partners in last year heterosexual Family Hx: DM II in father, MGM Prostate CA – paternal uncle Seizures – father CVA – father (in late 50’s) Asthma - sister

4. Physical Exam Gen: well nourished HEENT: PERRLA, nl conj and sclera, sharp disk margin Neck: no mass, no LAD, nl thyroid Resp: nl effort, BCTA CV: RRR, nl S1 and S2, no murmur Abd: soft, NT/NT, nl bowel sound, no HSM Ext: +2 u/l ext pulses, no clubin, no cyanosis Skin: symmetric papular rash greatest on chest and back. Some involvement of abdomen, upper and lower extremities. No erythema, many lesions GU: tanner V male. No sores or ulcers. No discharge Lymph: two enlarged right femoral lymph nodes

6. Labs RPR: titer 0 Syphilis IgG: reactive Hep B suface Ag: negative Hep C antibody: negative Urine GC/CT: negative HIV: negative FTA: positive

7. Syphilis History Origin Naming of Treatments Diagnosis Modern Era Epidemiology Diagnosis Classification Treatment Follow up First medical illustration of syphilis, Vienna, 1498

8. Origin The Columbian (New World) Theory Outbreak in 1494 in Naples First well documented outbreak Link to Columbus’ crew in Naples Retrospective writings of early travelers to the New World describe similar symptoms in crew and Native Americans Skeletal remains – Hutchinson’s teeth “The first fruit the Spaniards brought from the New World was syphilis” - Voltaire Con: Many Native Americans died of syphilis in the 16 th century – after the arrival of Europeans

9. Origin Pre-Columbian Syphilis originated in the old world Unrecognized initially Confused with other diseases such as leprosy Urbanization, Increase promiscuity and social turmoil led to epidemic Hippocrates described symptoms Biblical references

10. Origin 3 rd theory – derived from Yaws Tropical infection caused by a spirochete Treponema pertenue Originated in the Old Evolved in the New World Brought back to the old Map of other treponemal diseases

11. 1494 – French army marches across Italy and takes Naples. Event marked by much rejoicing Crime rate soared Increase in sexual promiscuity Outbreak of mysterious disease in the French army led to the name morbus gallicus (the French Disease) 1495 – French army driven out of Naples and dispersed home all over Europe. Origin

12. Syphilis swept across Europe from Naples outbreak of 1494 Early form was much more virulent than today’s disease Shorter incubation More severe symptoms More frequently fatal By mid 1500’s disease evolved into present form Congenital syphilis quickly became a leading cause of infant morbidity and mortality.

13. Syphilis Named after the shepherd Syphilis Hero of poem, Syphilis sive morbus Gallicus (Syphilis or the French disease) Poem written by Girolamo Fracastro (1478- 53) Italian Renaissance physician published in 1530 Syphilis caught the disease for disrespecting the Gods

14. Syphilis - Also known as Spanish Disease La maladie anglaise (The English Disease) Polish Disease Disease of the Christians Neapolitan Disease Lues Miss Siff Great Pox evil pocks Bad blood Old Joe The great imitator

15. Girolamo Fracastro Described the disease in detail Syphilis was caused by ‘seeds’ or germs Observed that syphilis is transmitted through sexual intercourse Suspected milk or birthing caused congenital syphilis Argued the planets played a role in the outbreak of the disease. Believed that “late” syphilis, when the symptoms are at their worse, is when the disease is contagious.

16. Historical Highlights 1530 – Gonorrhea thought to be an early stage of syphilis 1767 – gonorrhea and syphilis the same disease 1793 – Benjamin Bell experimented on himself and medical students to demonstrate that syphilis and GC were distinct 1905 – German researches discovered the bacteria that causes syphilis

17. Diagnosis - Historical Wassermann Test (1906) First lab test Complement-fixation antibody test Low specificity Positive findings with: TB Malaria Autoimmune diseases

18. Hinton test (1930s) Developed by William Augustus Hinton First African American to become a professor at Harvard Medical School Had fewer false positive results Davies-Hinton Test Further refined test to be more specific Diagnosis - Historical

19. Treatments -Prior to 1900 Guaiacum wood Hardwood of the Americas Popularized by Ulrich von Hatten 1519 Hung in churches and homes to ward of disease Probably ineffective Guaiacum prescription : -Grind the wood -Boil in water -Drink while hot -Lock yourself in heated, sealed or chamber and sweat out the ill-humours

20. Treatments -Prior to 1900 Mercury “A night in the arms of Venus leads to a lifetime on Mercury” The only ‘effective’ treatment used for 400 years. 1495 to 1800’s. Produced copious saliva

21. Oral Absorbed internally Caused gastric distress Sometimes give PR Topical Rubbed several times a day to different parts of the body Salves the metal was kept in continuous close contact with the skin Treatments -More on Mercury

22. Fumigation – least effective Patient placed in closed compartment with only the head sticking out Fire set underneath the compartment Mercury in the compartment would vaporize Grueling process for patient Provided means for punishment for acquiring disease. Treatments -More on Mercury

23. Goal of Therapy – make saliva! Saliva carried away the venereal poison Three pints of saliva a day was considered a good prognosis. More mercury was used for ‘treatment failures’ Up to 16 lbs of mercury was given in a single course of treatment Treatments -More on Mercury

24. Vaugirard Hospital Leaders recognized importance of healthy children for future Opened in 1780 Dedicated to therapy of congenital syphilis with state of the art therapy Mother treated with mercury Infants received milk of mothers First attempt by a government to deal with syphilis as a demographic and medical problem rather than moral or religious Closed in 1790 due high cost and lack of effectiveness

25. National Museum of Health and Medicine

26. An engraving from about 1660. A syphilis sufferer gets fumigated in a special oven. The caption on the oven translates as "For one pleasure a thousand pains." -pbs

27. An illustration from a 1685 book shows various treatments for syphilis, including fumigation and salivation. - Univ Kentucky

28. Treatments -Historical Arsphenamine (Salvarsan) An aresenic-containing drug discovered in 1908 in Germany Use after 1910 First specific chemotherapeutic agent for a bacterial disease Phased out in 1930’s Given as IV or IM injections

29. Neosalvarsan Arsenic containing replacement for Salvarsan. Not as effective as Salvarsan but easier to handle and produce with less side effects Predominant treatment until 1940s Treatments -Historical

30. Depression-era U.S poster advocating early syphilis treatment

31. Treatments -Historical Malaria Therapy – 1917 Julius Von Wagner-Jauregg febrile illness could cure syphilis Induces high fevers and could be cured by quinine Used mostly in tertiary syphilis due to difficulty treating with (neo)Salvarsan Neosalvarsan given after the fever resolution as adjunctive therapy. Reported 20-30% remission therapy Won Nobel prize in 1917

32. U.S. Army poster 1940

33. U.S. World War Two poster comparing Hitler, Hirohito and VD, portrayed as the most serious threat of all

34. Etiology Treponema pallidum – spirochaete bacterium Identified in 1905 Spiral shaped Spin around their long axis in a corkscrew manner.

35. Epidemiology -United States Reported cases by stage of infection 1941-2004

36. Cities with Highest Reported Rates of Primary and Secondary Syphilis, 2004

37. Epidemiology -interesting facts Male to female ratio is trending up 1996 – 1.2 2004 – 5.9 Due to increased rates among MSM Overall rate has increased since 2000. Up to 2.7 cases per 100,000 in US Rates among women had trended down until 2004 Rate in African Americans 6x higher than Causations

38. Congenital syphilis - Rates for infants <1 year of age: United States, 1981-2004 - 8.8 cases per 100,000 live births in 2004 -Decrease correlates well with decline in women

39. Local Facts Ohio 237 cases in 2004 2.1 cases per 100,000 Ranked #17 by state 3 cases of congenital Cincinnati 18 cases reported in 2004 2.2 per 100,000 Ranked #48 in United States 2003 by county

40. Epidemiology Risk factors Illicit drug use Exchanging sex for money or drugs Unprotected sexual intercourse Multiple sex partners

41. American Journal of Syphilis advertisement by E. R. Squibb and Sons, 1943, "More insidious than a snake, the Treponema pallidum gives no sting of pain, yet it saps the strength of man, leaving crippled bodies and shattered minds.”

42. Transmission 1. Sex – vaginal, anal or oral through direct contact with syphilis chancre 2. Person to person foreplay - rare 3. Mother to fetus oMay only occur during early disease stages oPrimary and secondary o30% rate oRequires exposure to open lesions with organisms present

43. Stages Early Primary Secondary Early latent Late Latent Tertiary Neurosyphilis

44. Primary Chancre at site of inoculation Usually painless Heal spontaneously Syphilis quickly becomes systemic Spread to local lymph nodes Dividing time of 30 hours

45. Secondary Weeks to months after initial infection 25% with untreated initial infection Symptoms vary Rash (most common) Fever HA Malaise Anorexia Diffuse LAD

46. Additional findings: Condyloma lata Patchy Alopecia Secondary Condyloma lata in the perineal region Patchy alopecia. Note moth-eaten appearance.

47. Early Latent Infection demonstrable by serologic testing with T. pallidum No signs/symptoms Duration of 1 year or less Potentially infectious

48. Late Latent Asymptomatic infection beyond one year Slower metabolism and prolonged dividing time Requires longer treatment duration Thought to not be infectious

49. From 1 to 30 years after initial exposure May never have clinically apparent primary or secondary lesions Untreated, 25-40% develop tertiary Tertiary

50. Gummas nodular lesions of skins and bones Tumor-like growths Tertiary -Manifestations

51. Cardiovascular Aortitis, mostly Aortic aneurysm Aortic regurg

52. Neurosyphilis General paresis of the insane Personality change Hyperactive reflexs Argyll-Robertson pupils Sensory deficits Tabes dorsalis -> suffling gait Opthalmic involvement Uveitis Neuroretinitis Optic neuritis Auditory symptoms Cranial nerve palsies Meningitis symptoms Cerebral atrophy, most prominent in frontal lobes seen in general paresis

53. British Ministry of Health poster, circa 1950

54. Congenital Syphilis Transmission to fetus at any stage of disease in mother Most likely primary or secondary 40% result in stillborn 40-70% of survivors infected at birth 12% of infected die of complications

55. Manifestations, early 2/3’s asymptomatic at birth Hydrops fetalis Cutaneous lesions Palms and soles most common Highly contagious if ulcerative Hepatoslenomegaly Jaundice Anemia Snuffles Metaphyseal dystrophy, Periostitis, Rickets Congenital Syphilis

56. Osteochondritis of femur and tibia Bullae and vesicular rash

57. Congenital Syphilis -Late Manifestations Caused by scarring from early infection Prevented by treating before 3 months Variable findings: Frontal Bossing Short maxilla High palatal arch Hutchinson’s triad Abnormal teeth Interstitial keratitis (inflammation of corneal structure) Eighth nerve deafness Saddle Nose Perioral fissures

58. Manifestations Hutchinson’s Teeth Smaller Widely spaced Central notches on biting surface Peg-shaped incisors Congenital Syphilis

59. Congenital Syphilis -Late Manifestations Saber Shins Saddle Nose

60. American Journal of Syphilis advertisement by E. R. Squibb and Sons, 1943. The Arms of the Octopus (syphilis strikes everywhere)

61. Darkfield microscopy Quickest and most direct method Primary and secondary syphilis Direct visualization of spirochete from moist lesions Requires experienced lab tech and proper equipment be readily available Negative results do not exclude disease. Rarely used in practice Diagnosis

62. Fluorescent antibody testing Permits organism visualization when smears cannot be examined immediately More specific as antigens specific for T. pallidum Not widely available

63. PCR High sensitivity and specificity Rarely used in practice thus far Multiplex PCR T. palldium Hemophilus ducreyi (chancroid) Herpes simplex Diagnosis

64. Cultures – not currently possible Serologic tests Nontrepomal test VDRL - Venereal Disease Research Lab RPR - Rapid Plasma Reagin Treponemal test FTA-ABS - fluorescent treponemal antibody absorption MHA-TP - microhemaglutination test for antibiody to T. pallidum TPPA - T. pallidum particle agglutination assay Diagnosis

65. Nontrepomal test Tests for reactivity to cardiolipin-cholesterol- lecithin antigen Used as screening tests Cheap Sensitive Reported as titers -useful to assess success of treatment or reinfection False positives to autoimmune diseases, viral infections Diagnosis

66. Treponemal test Used as confirmatory tests Detect antibodies directed against treponemal cellular components Qualitative – reactive or nonreactive False positive to other Treponemal bacteria Diagnosis

67. False negatives Testing prior to development of antibodies Most common cause Usually due to testing with presentation of chancre Diagnosis

68. Prozone reaction Nontreponemal tests <2% of samples Usually in secondary syphilis when antibodies are at their highest Mismatch between antigen and antibody nonreactive test exhibits a rough or granular appearance When diluted, test becomes positive At Lab One, a screening antibody test is done prior to doing the actual test to avoid false negatives At CCHMC this is not done routinely. Diagnosis

69. Neurosyphilis Assess positive patients for signs symptoms LP with CSF studies needed if any evidence of neuro involvement Indications Opthalmic signs or symptoms Evidence of tertiary syphilis Any treatment failures HIV with syphilis > 1 year or if duration unknown. Diagnosis

70. Neurosyphilis CSF analysis Cell count (>5 WBC) Protein concentration - elevated VDRL (specific, not sensitive) Diagnositic in absence of blood contamination Treponemal tests not routinely recommended FTA highly sensitive Many false positives

71. Advertisement for penicillin from the late 1940 s

72. Treatment -approach T. pallidum reproduces slowly Sustained spirocheticidal levels are required Thus, prolonged serum concentrations of antimicrobial is essential Sensitive to beta-lactum antibiotics among others!

73. First line Penicillin G benzathine 2.4 million units IM once 50,000 units/kg IM for children Alternatives Doxycycline 100mg PO BID x 14 days Investigational Azithromycin 2gm PO daily Treatment -Primary, secondary or early latent

74. First line Penicillin G benzathine 2.4 million units IM weekly x 3 weeks – in adults 50,000 units/kg per week x 3 doses in children Alternative Doxycycline 100mg PO BID x 4 weeks Treatment - Late Latent

75. Treatment - tertiary syphilis (not neuro) Penicillin G benzathine 2.4 million units IM weekly x 3 weeks – in adults 50,000 units/kg per week x 3 doses in children Check CSF to rule out neurosyphilis prior to treatment No alternative therapy

76. Treatment -Neurosyphilis First line Penicillin G 3-4 million units IV Q4hour (or) 24 million units continuous IV infusion Qday Over 10 to 14 days Alternatives Pen G 2.4 mil IM daily plus Probenecid 500mg QID orally for 10-14 days Ceftriaxone 2g IV daily for 10-14 days

77. Treatment - Congenital Newborn Aqueous Penicillin G 50,000 U/kg IV Q12 during first seven days of life Q8 after 7 th DOL Total 10 days Restart course if a single day is missed

78. Older Infants and Children Possible neurological involvement Aqueous Pen G 200-300,000 U/kg per day Q 6 hours 10 days +/- addition 50,000 U/kg IM injections weekly for 3 weeks Unlikely neuro involement with minimal disease Three weekly injections Treatment - Congenital

79. Treatment - Pregnancy Parental penicillin G Only therapy with documented efficacy during pregnancy Desensitize penicillin allergic patients

80. Treatment - other considerations Jarisch-Herxheimer reaction Occurs within 24 hours of treatment in early syphilis Fever, HA, myalgia Anti-pyretics may be useful? Can cause early labor in pregnant women or fetal distress Should not delay or prevent treatment

81. Treating sex partners Patient in early stages Exposure within 90 day Treat partners presumptively Exposure >90 days Treat presumptively if no test available or f/u not likely Otherwise, okay to treat by evaluation Late stages – evaluate partner clinically Unknown stage – approach as early Treatment - other considerations

82. All patients with syphilis should be tested for HIV Repeat HIV test in 3 months in areas with a high prevalence of HIV Treatment - other considerations

83. Reassess response at 6 months and 12 months with titers 4 fold increase in titer indicative of failure or reinfection CSF should be performed. 15% of patients with early will not have improvement in titers Follow Up - Early disease

84. Reassess response at 6, 12 and 24 months with titers 4 fold increase in titer indicative of failure or reinfection Study CSF If titer >1:32, titer should decline x 4 within 12- 24 months. If not, retreat Retreat if signs or symptoms of syphilis Follow Up - Latent disease

85. Repeat CSF every 6 months until cell count normal Consider retreatment if not decreased after 6 months or not normal at 2 years Follow Up - Neurosyphilis

86. The End - Any Questions??? Public Health Service Poster, c. 1945