Chairman’s Rounds

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Chairmans Rounds

• Steve Hart

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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

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• 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 50s)
• Asthma - sister

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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

• Lymph two enlarged right femoral lymph nodes

• GU tanner V male. No sores or ulcers. No
  discharge

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(No Transcript)
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Labs

• RPR titer 0
• Syphilis IgG reactive
• Hep B suface Ag negative
• Hep C antibody negative
• Urine GC/CT negative
• HIV negative

• FTA positive

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Syphilis

• History
• Origin
• Naming of
• Treatments
• Diagnosis
• Modern Era
• Epidemiology
• Diagnosis
• Classification
• Treatment
• Follow up

First medical illustration of syphilis, Vienna,
1498
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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 Hutchinsons teeth
• The first fruit the Spaniards brought from the
  New World was syphilis - Voltaire
• Con Many Native Americans died of syphilis in
  the 16th century after the arrival of Europeans

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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

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Origin
Map of other treponemal diseases

• 3rd 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

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Origin

• 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.

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Origin

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

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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

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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

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• 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.

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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

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Diagnosis - Historical

• Wassermann Test (1906)
• First lab test
• Complement-fixation antibody test
• Low specificity
• Positive findings with
• TB
• Malaria
• Autoimmune diseases

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Diagnosis - Historical

• 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

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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

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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 1800s.
• Produced copious saliva

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Treatments -More on Mercury

• 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

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Treatments -More on Mercury

• 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.

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Treatments -More on Mercury

• 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

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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

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National Museum of Health and Medicine
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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
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An illustration from a 1685 book shows various
treatments for syphilis, including fumigation and
salivation. -Univ Kentucky
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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 1930s
• Given as IV or IM injections

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Treatments -Historical

• 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

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Depression-era U.S poster advocating early
syphilis treatment
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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

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U.S. Army poster 1940
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U.S. World War Two poster comparing Hitler,
Hirohito and VD, portrayed as the most serious
threat of all
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Etiology

• Treponema pallidum spirochaete bacterium
• Identified in 1905

• Spiral shaped
• Spin around their long axis in a corkscrew manner.

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Epidemiology -United States
Reported cases by stage of infection 1941-2004
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Cities with Highest Reported Rates of Primary and
Secondary Syphilis, 2004
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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

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Congenital syphilis - Rates for infants lt1 year
of age United States, 1981-2004

• 8.8 cases per 100,000 live births in 2004
• Decrease correlates well with decline in women

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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
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Epidemiology

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

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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.
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Transmission

• Sex vaginal, anal or oral through direct
  contact with syphilis chancre
• Person to person foreplay - rare
• Mother to fetus
• May only occur during early disease stages
• Primary and secondary
• 30 rate
• Requires exposure to open lesions with organisms
  present

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Stages

• Early
• Primary
• Secondary
• Early latent
• Late
• Latent
• Tertiary
• Neurosyphilis

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Primary

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

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Secondary

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

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Secondary

• Additional findings
• Condyloma lata
• Patchy Alopecia

Condyloma lata in the perineal region
Patchy alopecia. Note moth-eaten appearance.
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Early Latent

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

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Late Latent

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

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Tertiary

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

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Tertiary -Manifestations

• Gummas
• nodular lesions of skins and bones
• Tumor-like growths

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Tertiary -Manifestations

• Cardiovascular
• Aortitis, mostly
• Aortic aneurysm
• Aortic regurg

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Neurosyphilis

• General paresis of the insane
• Personality change
• Hyperactive reflexs
• Argyll-Robertson pupils
• Sensory deficits
• Tabes dorsalis -gt 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
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British Ministry of Health poster, circa 1950
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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

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Congenital Syphilis

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

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Congenital Syphilis
Bullae and vesicular rash
Osteochondritis of femur and tibia
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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
• Hutchinsons triad
• Abnormal teeth
• Interstitial keratitis (inflammation of corneal
  structure)
• Eighth nerve deafness
• Saddle Nose
• Perioral fissures

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Congenital Syphilis

• Manifestations
• Hutchinsons Teeth
• Smaller
• Widely spaced
• Central notches on biting surface
• Peg-shaped incisors

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Congenital Syphilis -Late Manifestations
Saber Shins
Saddle Nose
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American Journal of Syphilis advertisement by E.
R. Squibb and Sons, 1943. The Arms of the Octopus
(syphilis strikes everywhere)
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Diagnosis

• 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

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Diagnosis

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

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Diagnosis

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

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Diagnosis

• 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

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Diagnosis

• Nontrepomal test
• Tests for reactivity to cardiolipin-cholesterol-le
  cithin 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

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Diagnosis

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

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Diagnosis

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

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Diagnosis

• Prozone reaction
• Nontreponemal tests
• lt2 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.

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Diagnosis

• 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 gt 1 year or if duration
  unknown.

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Diagnosis

• Neurosyphilis
• CSF analysis
• Cell count (gt5 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

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Advertisement for penicillin from the late 1940s
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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!

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Treatment-Primary, secondary or early latent

• 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

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Treatment- Late Latent

• 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

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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

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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

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Treatment- Congenital

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

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Treatment- Congenital

• 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

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Treatment- Pregnancy

• Parental penicillin G
• Only therapy with documented efficacy during
  pregnancy
• Desensitize penicillin allergic patients

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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

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Treatment- other considerations

• Treating sex partners
• Patient in early stages
• Exposure within 90 day
• Treat partners presumptively
• Exposure gt90 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

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Treatment- other considerations

• All patients with syphilis should be tested for
  HIV
• Repeat HIV test in 3 months in areas with a high
  prevalence of HIV

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Follow Up- Early disease

• 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

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Follow Up- Latent disease

• Reassess response at 6, 12 and 24 months with
  titers
• 4 fold increase in titer indicative of failure or
  reinfection
• Study CSF
• If titer gt132, titer should decline x 4 within
  12-24 months. If not, retreat
• Retreat if signs or symptoms of syphilis

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Follow Up- Neurosyphilis

• Repeat CSF every 6 months until cell count normal
• Consider retreatment if not decreased after 6
  months or not normal at 2 years

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